22.2 Biosynthesis of Amino Acids in Chapter 22 Biosynthesis of Amino Acids, Nucleotides, and Related Molecules

22.2 Biosynthesis of Amino Acids

All amino acids are derived from intermediates in glycolysis, the citric acid cycle, or the pentose phosphate pathway (Fig. 22-11). Nitrogen enters these biosynthetic pathways by way of glutamate and glutamine. Some pathways are simple, others are not. Ten of the amino acids are just one or several steps removed from the common metabolite from which they are derived. The biosynthetic pathways for others, such as the aromatic amino acids, are more complex.

A figure shows an overview of amino acid biosynthesis highlighting three sources of carbon skeleton precursors: glycolysis, the citric acid cycle, and the pentose phosphate pathway. — FIGURE 22-11 Overview of amino acid biosynthesis. The carbon skeleton precursors derive from three sources: glycolysis (light red), the citric acid cycle (blue), and the pentose phosphate pathway (purple).

An arrow points down from glucose to glucose 6-phosphate. Two arrows point away from glucose 6-phosphate. An arrow labeled 4 steps points right from glucose 6-phosphate to a dark blue box labeled ribose 5-phosphate, from which an arrow points down to a box labeled histidine. A second arrow labeled 4 steps points down from glucose 6-phopshate to a light red box labeled 3 phosphoglycerate. An arrow points right from 3-phosphoglycerate to a box labeled serine, from which an arrow points down to a box labeled glycine, cysteine. Right- and left-pointing arrows extend from 3-phosphoglycerate to a dark blue box labeled erythrose 4-phosphate on the left, from which an arrow points down to a box labeled tryptophan, phenylalanine, tyrosine. A series of two arrows points down from 3-phosphoglycerate to a light red box labeled phosphoenolpyruvate, from which one arrow points to the box to the lower left labeled tryptophan, phenylalanine, tyrosine and the second arrow points down to a light red box labeled pyruvate. An arrow points right from pyruvate to a box labeled alanine, valine, leucine, isoleucine. An arrow points down from pyruvate to citrate at the type of a reaction cycle. A series of two arrows points from citrate at the twelve o’clock position to a light blue box at the three o’clock position labeled alpha-ketoglutarate. An arrow points down from alpha-ketoglutarate to a box labeled glutamate, from which an arrow points down to a box labeled glutamine, proline, arginine. A series of four clockwise arrows representing the reaction cycle point from alpha-ketoglutarate to a light blue box at the nine o’clock position labeled oxaloacetate, from which an arrow curves up to citrate at the twelve o’clock position to complete the cycle and a second arrow points down to a box labeled aspartate, from which an arrow points down to a box labeled asparagine, isoleucine, methionine, threonine, lysine.

Organisms Vary Greatly in Their Ability to Synthesize the 20 Common Amino Acids

Whereas most bacteria and plants can synthesize all 20 amino acids, mammals can synthesize only about half of them — generally those with simple pathways. These are often called nonessential amino acids (see Table 18-1). The label is somewhat misleading, however, because innate biosynthetic pathways often do not provide enough of these amino acids to support optimal growth and health. The remaining amino acids, the essential amino acids, cannot be synthesized by most mammals and must be obtained from food. A few amino acids are conditionally essential in mammals, required at particular stages of development. Unless otherwise indicated, the pathways for the 20 common amino acids presented below are those operative in bacteria.

A useful way to organize these biosynthetic pathways is to group them into six families corresponding to their metabolic precursors (Table 22-1), and we use this approach to structure the detailed descriptions that follow. In addition to these six precursors, there is a notable intermediate in several pathways of amino acid and nucleotide synthesis: 5-phosphoribosyl-1-pyrophosphate (PRPP):

TABLE 22-1 Amino Acid Biosynthetic Families, Grouped by Metabolic Precursor
α-Ketoglutarate Glutamate Glutamine Proline Arginine		Pyruvate Alanine Valine^a Leucine^a Isoleucine^a
3-Phosphoglycerate Serine Glycine Cysteine		Phosphoenolpyruvate and erythrose 4-phosphate Tryptophan^a Phenylalanine^a Tyrosine^b
Oxaloacetate Aspartate Asparagine Isoleucine Methionine^a Threonine^a Lysine^a		Ribose 5-phosphate Histidine^a
^aEssential amino acids in mammals. ^bDerived from phenylalanine in mammals.

A five-membered ring has O at its top vertex; C 1 bonded to H above and O below bonded to a series of two phosphate; C 2 and C 3 each bonded to H above and O H below; and C 4 bonded to H below and C 5 above bonded to 2 H and to O to the left further bonded to P double bonded to O above and bonded to O minus to the lower left and below. The phosphates bonded to C 1 are shown as O bonded to C 1 above and bonded to P to the right double bonded to O above, bonded to O minus below, and bonded to O to the right further bonded to P double bonded to O above and bonded to O minus to the right and below.

PRPP is synthesized from ribose 5-phosphate derived from the pentose phosphate pathway (see Fig. 14-31), in a reaction catalyzed by ribose phosphate pyrophosphokinase:

Ribose 5 -phosphate + ATP \to 5-phosphoribosyl-1-pyrophosphate + AMP

$Ribose 5 hyphen phosphate plus ATP right-arrow 5 hyphen phosphoribosyl hyphen 1 hyphen pyrophosphate plus AMP$

This enzyme is allosterically regulated by many of the biomolecules for which PRPP is a precursor.

α-Ketoglutarate Gives Rise to Glutamate, Glutamine, Proline, and Arginine

A blue box labeled alpha-ketoglutarate has an arrow pointing down to glutamate, from which arrows point down to glutamine at the lower left, proline below, and arginine at the lower right.

We have already described the biosynthesis of glutamate and glutamine. Proline is a cyclized derivative of glutamate (Fig. 22-12). In the first step of proline synthesis, ATP reacts with the γ-carboxyl group of glutamate to form an acyl phosphate, which is reduced by NADPH or NADH to glutamate γ-semialdehyde. This intermediate undergoes rapid spontaneous cyclization and is then reduced further to yield proline.

A figure shows how bacteria synthesize proline and arginine from glutamate. — FIGURE 22-12 Biosynthesis of proline and arginine from glutamate in bacteria. All five carbon atoms of proline arise from glutamate. In many organisms, glutamate dehydrogenase is unusual in that it uses *either* NADH or NADPH as a cofactor. The same may be true of other enzymes in these pathways. The γ-semialdehyde in the proline pathway undergoes a rapid, reversible cyclization to $Δ^{1}$ $upper Delta Superscript 1$ -pyrroline-5-carboxylate (P5C), with the equilibrium favoring P5C formation. Cyclization is averted in the ornithine/arginine pathway by acetylation of the α-amino group of glutamate in the first step and removal of the acetyl group after the transamination. This acetyl group is highlighted in yellow. Although some bacteria lack arginase and thus the complete urea cycle, they can synthesize arginine from ornithine in steps that parallel the mammalian urea cycle, with citrulline and argininosuccinate as intermediates (see Fig. 18-10).

Here, and in subsequent figures in this chapter, the reaction arrows indicate the linear path to the final products, without considering the reversibility of individual steps. For example, the step of the pathway leading to arginine that is catalyzed by N-acetylglutamate dehydrogenase is chemically similar to the glyceraldehyde 3-phosphate dehydrogenase reaction in glycolysis (see Fig. 14-7) and is readily reversible.

FIGURE 22-12 Biosynthesis of proline and arginine from glutamate in bacteria. All five carbon atoms of proline arise from glutamate. In many organisms, glutamate dehydrogenase is unusual in that it uses *either* NADH or NADPH as a cofactor. The same may be true of other enzymes in these pathways. The γ-semialdehyde in the proline pathway undergoes a rapid, reversible cyclization to $Δ^{1}$ $upper Delta Superscript 1$ -pyrroline-5-carboxylate (P5C), with the equilibrium favoring P5C formation. Cyclization is averted in the ornithine/arginine pathway by acetylation of the α-amino group of glutamate in the first step and removal of the acetyl group after the transamination. This acetyl group is highlighted in yellow. Although some bacteria lack arginase and thus the complete urea cycle, they can synthesize arginine from ornithine in steps that parallel the mammalian urea cycle, with citrulline and argininosuccinate as intermediates (see Fig. 18-10).

Here, and in subsequent figures in this chapter, the reaction arrows indicate the linear path to the final products, without considering the reversibility of individual steps. For example, the step of the pathway leading to arginine that is catalyzed by N-acetylglutamate dehydrogenase is chemically similar to the glyceraldehyde 3-phosphate dehydrogenase reaction in glycolysis (see Fig. 14-7) and is readily reversible.

Glutamate at the upper left is shown as a five-carbon chain with C 1 double bonded to O to the upper left, bonded to O minus to the lower left, and bonded to C H 2 to the right bonded to C H 2 bonded to C H bonded to N H 3 above with a positive charge on N and bonded to C O O minus to the right. Arrows point to the right and down. An arrow labeled acetylglutamate synthase points right from glutamate to italicized N-acetylglutamate and is accompanied by a curved arrow showing the addition of a molecule with a yellow box containing C H 3 bonded to C double bonded to O above and bonded to S outside of the yellow box further bonded to Co A and the loss of Co A-S H. This yields N-acetylglutamate, which is similar to glutamate except that N H 3 with a positive charge on N is now N H bonded to C in a yellow box further double bonded to O above and bonded to C H 3 to the right within the same yellow box. An arrow labeled italicized N end italics-acetylglutamate kinase points down to italicized N end italics-acetyl-italicized gamma-end italics-glutamyl phosphate and is accompanied by a curved arrow showing the addition of an orange oval labeled A T P and loss of A D P. N end italics-acetyl-italicized gamma-end italics-glutamyl phosphate is similar to the reactant except that C 1 is double bonded to O to the upper left and bonded to O to the lower left further bonded to a circle labeled P. An arrow labeled italicized N end italics-acetylglutamate dehydrogenase points down from N end italics-acetyl-italicized gamma-end italics-glutamyl phosphate to italicized N end italics-acetylglutamate-gamma-semialdehyde and is accompanied by a curved arrow showing the addition of an orange oval labeled N A D (P) H plus H plus and loss of N A D (P) plus and by a branched arrow below showing the loss of P subscript i end subscript. Italicized N end italics-acetylglutamate-gamma-semialdehyde resembles the reactant except that C 1 is double bonded to O to the upper left and bonded to H to the lower left. An arrow labeled aminotransferase points down from italicized N end italics-acetylglutamate-gamma-semialdehyde to italicized N end italics-acetylornithine and is accompanied by a curved arrow showing the addition of a green box labeled glutamate and loss of alpha-ketoglutarate. Italicized N end italics-acetylornithine is similar to the reactant except that the former C 1 has been replaced by a green box labeled N H 3 with a positive charge on N. An arrow labeled italicized N end italics-acetylornithinase points down to ornithine in a gray box labeled urea cycle and is accompanied by a curved arrow showing the addition of H 2 O and loss of a yellow box containing C H 3 C O O minus. Ornithine is H 3 N plus in a green box bonded to C H 2 bonded to C H 2 bonded to C H 2 bonded to C H bonded to N H 3 above with a positive charge on N and to C O O minus to the right. An arrow labeled ornithine carbamoyltransferase points down from ornithine to L-citrulline accompanied by a curved arrow showing the addition of carbamoyl phosphate and loss of P subscript i end subscript. An arrow labeled argininosuccinate synthetase points down from L-citrulline to argininosuccinate accompanied by a curved arrow showing the addition of an orange oval labeled A T P plus aspartate and loss of A M P plus P P subscript i end subscript. An arrow points down from argininosuccinate to arginine accompanied by a curved line showing the loss of fumarate. Arginine is shown as C bonded to N H 2 to the upper left, double bonded to N H 2 with a positive charge on N to the lower left, and bonded to N H in a green box to the right bonded to C H 2 outside of the box bonded to C H 2 bonded to C H 2 bonded to C H bonded to N H 3 above with a positive charge on N and to C O O minus to the right. A second series of reactions from glutamate is also shown. An arrow labeled glutamate kinase points down from glutamate to gamma-glutamyl phosphate and is accompanied by an arrow showing the addition of an orange oval labeled A T P and loss of A D P. Gamma-glutamyl phosphate has a similar structure to glutamate except that C 1 is double bonded to O to the upper left and bonded to O to the lower left further bonded to a circle labeled P. An arrow labeled gamma-glutamyl phosphate reductase points down from gamma-glutamyl phosphate to glutamate gamma-semialdehyde accompanied by a curved arrow showing the addition of an orange oval labeled N A D (P) H plus H plus and loss of N A D (P) plus and by a branched arrow below showing the loss of P subscript i end subscript. Glutamate gamma-semialdehyde resembles gamma-glutamyl phosphate except that C 1 is double bonded to O to the upper left and bonded to H to the lower left. An arrow labeled nonenzymatic points down to delta superscript 1 end superscript-pyrroline-5-carboxylate (P 5 C), which is a five-membered ring with N plus substituted for C at the bottom vertex and bonded to H, a double bond at the left side vertex, the lower left vertex bonded to H, the upper left vertex bonded to 2 H, the upper right vertex bonded to 2 H, and the lower right vertex bonded o H and to C O O minus. An arrow labeled pyrroline carboxylate reductase points down from delta superscript 1 end superscript-pyrroline-5-carboxylate to proline and is accompanied by a curved arrow showing the addition of an orange oval labeled N A D (P) H plus H plus and loss of N A D (P) plus. This yields proline, which is similar to the reactant except that N plus substituted for C at the bottom vertex is bonded to 2 H, there is no double bond at the lower left side, and the lower left vertex is bonded to 2 H.

Arginine is synthesized from glutamate via ornithine and the urea cycle in animals (Chapter 18). In principle, ornithine could also be synthesized from glutamate γ-semialdehyde by transamination, but the spontaneous cyclization of the semialdehyde in the proline pathway precludes a sufficient supply of this intermediate for ornithine synthesis. Bacteria have a de novo biosynthetic pathway for ornithine (and thus arginine) that parallels some steps of the proline pathway but includes two additional steps that avoid the problem of the spontaneous cyclization of glutamate γ-semialdehyde (Fig. 22-12). In the first step, the α-amino group of glutamate is blocked by an acetylation requiring acetyl-CoA; then, after the transamination step, the acetyl group is removed to yield ornithine.

The pathways to proline and arginine are somewhat different in mammals. Proline can be synthesized by the pathway shown in Figure 22-12, but it is also formed from arginine obtained from dietary or tissue protein. Arginase, a urea cycle enzyme, converts arginine to ornithine and urea (see Figs. 18-10, 18-26). The ornithine is converted to glutamate γ-semialdehyde by the enzyme ornithine γ-aminotransferase (Fig. 22-13). The semialdehyde cyclizes to $Δ^{1}$ $upper Delta Superscript 1$ -pyrroline-5-carboxylate, which is then converted to proline (Fig. 22-12). The pathway for arginine synthesis shown in Figure 22-12 is absent in mammals. When arginine from dietary intake or protein turnover is insufficient for protein synthesis, the ornithine δ-aminotransferase reaction operates in the direction of ornithine formation. Ornithine is then converted to citrulline and arginine in the urea cycle.

A figure shows the ornithine delta-aminotransferase reaction, which is a step in the mammalian pathway that synthesizes proline. — FIGURE 22-13 Ornithine δ-aminotransferase reaction: a step in the mammalian pathway to proline. This enzyme is found in the mitochondrial matrix of most tissues. Although the equilibrium favors P5C formation, the reverse reaction is the only mammalian pathway for synthesis of ornithine (and thus arginine) when arginine levels are insufficient for protein synthesis.

Ornithine is a vertical five-carbon chain with C 1 forming C O O minus; C 2 bonded to H and to N H 3 with a positive charge on N; C 3 and C 4 bonded to 2 H; and C 5 bonded to N H 3 with a positive charge on N. Right- and left-pointing arrows labeled ornithine delta-aminotransferase indicate a reversible reaction. The right-pointing arrow is accompanied by a curved arrow showing the addition of alpha-ketoglutarate and loss of glutamate. This yields two molecules shown in brackets. The left-hand molecule is glutamate gamma-semialdehyde, which is similar to ornithine except that C 5 is bonded to H to the lower left and double bonded to O to the lower right. Right- and left-pointing arrows indicate a reversible reaction and both include a branched arrow showing the loss of H 2 O. This yields delta superscript 1 end superscript-pyrroline-5-carboxylate (P 5 C), which is a five-membered ring with N plus substituted for C at the bottom vertex and bonded to H, a double bond at the lower left side, a lower left vertex bonded to H, an upper left vertex bonded to 2 H, an upper right vertex bonded 2 H, and a lower right vertex bonded to H and to C O O minus.

Serine, Glycine, and Cysteine Are Derived from 3-Phosphoglycerate

A light red box labeled 3-phosphoglycerate has an arrow pointing down to serine, from which arrows point down to glycine at the lower left and cysteine at the lower right.

The major pathway for the formation of serine is the same in all organisms (Fig. 22-14). In the first step, the hydroxyl group of 3-phosphoglycerate is oxidized by a dehydrogenase (using ${NAD}^{+}$ $NAD Superscript plus$ ) to yield 3-phosphohydroxypyruvate. Transamination from glutamate yields 3-phosphoserine, which is hydrolyzed to free serine by phosphoserine phosphatase.

A series of reactions shows how all organisms convert 3-phosphoglycerate to serine and then glycine. — FIGURE 22-14 Biosynthesis of serine from 3-phosphoglycerate and of glycine from serine in all organisms. As indicated in the text, this is only one of multiple pathways to synthesize glycine.

3-phosphoglycerate is a vertical three-carbon chain with C 1 forming C O O minus, C 2 bonded to H on the left and O H on the right, and C 3 bonded to H on the left and below and to O on the right further bonded to a circle labeled P. An arrow labeled phosphoglycerate dehydrogenase points down from 3-phosphoglycerate to 3-phosphohydroxypyruvate accompanied by a curved arrow showing the addition of N A D plus and loss of N A D H plus H plus. 3-phosphohydroxypyruvate is a vertical three-carbon chain with C 1 forming C O O minus, C 2 double bonded to O, and C 3 bonded to 2 H and to O on the right further bonded to a circle labeled P. An arrow labeled phosphoserine aminotransferase points down from 3-phosphohydroxypyruvate to 3-phosphoserine accompanied by a curved arrow showing the addition of a green box labeled glutamate and the loss of alpha-ketoglutarate. This yields 3-phosphoserine, which is similar to the reactant except that C 2 is bonded to N H 3 with a positive charge on N and enclosed on a green box on the left and to H on the right. An arrow labeled phosphoserine phosphatase points down from 3-phosphoserine to serine accompanied by a curved arrow showing the addition of H 2 O and loss of P subscript i end subscript. This yields serine, which is similar to the reactant except that C 3 is bonded to 2 H and to O H. An arrow labeled serine hydroxymethyltransferase points down from serine to glycine accompanied by a curved arrow showing the addition of H subscript 4 end subscript folate and loss of italicized N end italics superscript 5, italicized N end italics superscript 10 end superscript-methylene H subscript 4 end subscript folate. The inflection point of the arrow is labeled P L P. An additional arrow branches off to show the loss of H 2 O. This yields glycine, which is a green box labeled H 3 N plus bonded to C outside of the box bonded to C O O minus above and H to the right and below.

Serine (three carbons) is the precursor of glycine (two carbons) through removal of a carbon atom by serine hydroxymethyltransferase (Fig. 22-14). Tetrahydrofolate accepts the β carbon (C-3) of serine, which forms a methylene bridge between N-5 and N-10 to yield $N^{5}, N^{10}$ $upper N Superscript 5 Baseline comma upper N Superscript 10$ -methylenetetrahydrofolate (see Fig. 18-17). The overall reaction, which is reversible, also requires pyridoxal phosphate. In the liver of vertebrates, glycine can be made by another route: the reverse of the reaction shown in Figure 18-20c, catalyzed by glycine synthase (also called glycine cleavage enzyme):

\begin{matrix} {CO}_{2} + {NH}_{4}^{+} + N^{5}, ​ N^{10} -methylenetetrahydrofolate + \\ NADH + H^{+} \to glycine + tetrahydrofolate + {NAD}^{+} \end{matrix}

$StartLayout 1st Row CO Subscript 2 Baseline plus NH Subscript 4 Superscript plus Baseline plus upper N Superscript 5 Baseline comma zero width space upper N Superscript 10 Baseline hyphen methylenetetrahydrofolate plus 2nd Row NADH plus upper H Superscript plus Baseline right-arrow glycine plus tetrahydrofolate plus NAD Superscript plus EndLayout$

Plants and bacteria produce the reduced sulfur required for the synthesis of cysteine (and methionine, described later) from environmental sulfates; the pathway is shown on the right side of Figure 22-15. Sulfate is activated in two steps to produce $3^{'}$ $3 prime$ -phosphoadenosine $5^{'}$ $5 prime$ -phosphosulfate (PAPS), which undergoes an eight-electron reduction to sulfide. The sulfide is then used in the formation of cysteine from serine in a two-step pathway. Mammals synthesize cysteine from two amino acids: methionine furnishes the sulfur atom, and serine furnishes the carbon skeleton. Methionine is first converted to S-adenosylmethionine (see Fig. 18-18), which can lose its methyl group to any of a number of acceptors to form S-adenosylhomocysteine (adoHcy). This demethylated product is hydrolyzed to free homocysteine, which undergoes a reaction with serine, catalyzed by cystathionine β-synthase, to yield cystathionine (Fig. 22-16). Finally, cystathionine δ-lyase, a PLP-requiring enzyme, catalyzes removal of ammonia and cleavage of cystathionine to yield free cysteine.

A figure shows the biosynthesis of cysteine from serine and how the reduced sulfur used in the process is generated. — FIGURE 22-15 Biosynthesis of cysteine from serine in bacteria and plants. The origin of reduced sulfur is shown in the pathway on the right.

Serine is a vertical three-carbon chain with C 1 at the top forming C O O minus, C 2 bonded to N H 3 to the left with a positive charge on N and to H on the right, and C 3 bonded to 2 H and to O H below. An arrow labeled serine acetyltransferase points down to italicized O end italics-acetylserine accompanied by a curved arrow showing the addition of C bonded to C H 3 to the left, double bonded to O to the upper right, and bonded to S to the lower right further bonded to Co A and loss of Co A bonded to S H. Italicized O end italics-acetylserine is similar to serine except that C 3 is bonded to 2 H and to O below further bonded to C double bonded to O to the right and bonded to C H 3 below. An arrow labeled italicized O end italics-acetylserine (thiol) lyase points down to cysteine and is accompanied by a curved arrow showing the addition of S superscript 2 minus end superscript in a yellow box plus H plus and the loss of C H 3 C O O minus. This yields cysteine, shown as a similar molecule in which C 3 is bonded to 2 H and to S H below in a yellow box. A vertical series of reactions on the right shows how S superscript 2 minus end superscript in a yellow box is produced to participate in the conversion of italicized O end italics-acetylserine to cysteine. An orange oval labeled A T P is added to a yellow square labeled S O subscript 4 end subscript superscript 2 minus end superscript. An arrow labeled A T P sulfurylase points down accompanied by a curved arrow showing the addition of H plus and loss of P P subscript i end subscript. This yields adenosine 5 prime-phosphosulfate (A P S), which is a five-membered ring with O at the top vertex with C 1 prime bonded to a box labeled adenine above and H below; C 2 and C 3 bonded to H above and O H below; C 4 bonded to H below and C 5 above; and C 5 bonded to 2 H and to O on the left further bonded to P double bonded to O above, bonded to O minus below, and bonded to O to the left further bonded to S in a yellow box double bonded to O above and bonded to O minus to the left and below within the same yellow box. An arrow labeled A P S kinase points down to 3 prime-phosphoadenosine 5 prime-phosphosulfate (P A P S) and is accompanied by a curved arrow showing the addition of an orange oval labeled A T P and loss of A D P. 3 prime-phosphoadenosine 5 prime-phosphosulfate (P A P S) is similar to the reactant except that C 3 prime at the lower left vertex of the ring is bonded to H above and to O below further bonded to P double bonded to O to the right and bonded to O minus below and to the left. An arrow labeled P A P S reductase points down to sulfite accompanied by a curved arrow showing the addition of an orange oval labeled N A D P H and low of N A D P plus and a branched arrow below showing the loss of 3 prime-phosphoadenosine 5 prime-phosphate (P A P). This yields sulfite, shown as a yellow box containing S O subscript 3 end subscript superscript 2 minus end superscript. An arrow labeled sulfide reductase points down to sulfide and is accompanied by a curved arrow showing the addition of an orange oval labeled 3 N A D P H and the loss of 3 N A D P plus. This yields sulfide, shown as S 2 minus in a yellow box. An arrow points from S 2 minus in a yellow box at the bottom of this series of reactions to S 2 minus that is added to H plus above the curved arrow that yields C H 3 C O O minus after meeting the downward-pointing arrow labeled italicized O-acetylserine (thiol) lyase that converts italicized O-acetylserine to cysteine.

A figure shows how homocysteine and serine can be added to undergo a series of reactions to yield cysteine in mammals. — FIGURE 22-16 Biosynthesis of cysteine from homocysteine and serine in mammals. The homocysteine is formed from methionine.

Homocysteine is a four-carbon chain with C 1 on the left forming C O O minus, C 2 bonded to H and to N H 3 in a green box below with a positive charge on N, C 3 bonded to 2 H, and C 4 bonded to 2 H and to S H in a yellow box. Serine has a central C bonded to H, to N H 3 above with a positive charge on H, to C O O minus on the right, and to C H 2 O H on the left. An arrow labeled cystathionine beta-synthase points down to cystathionine. P L P is shown at the top right of the vertical arrow and a curved arrow below P L P shows that H 2 O is lost. Cystathionine has a four-carbon chain on the left with C bonded to C O O minus to the left, bonded to H, bonded to N H 3 in a green box below with a positive charge on N, and to C H 2 on the right further bonded to C H 2 bonded to S in a yellow box to the right that is further bonded to C H 2 bonded to C H bonded to N H 3 above with a positive charge on N and to C O O minus. An arrow labeled cystathionine gamma-lyase points down to yield alpha-ketobutyrate and a box labeled cysteine. This arrow is accompanied by a curved arrow showing the addition of H 2 O and loss of a green box labeled N H 4 plus with P L P shown at the inflection point. Alpha-ketobutyrate is C bonded to C O O minus to the left, double bonded to O below, and bonded to C H 2 to the right further bonded to C H 3. Cysteine is C H 2 bonded to S H in a yellow box to the left and to C H on the right bonded to N H 3 with a positive charge on N above and to C O O minus to the right.

Three Nonessential and Six Essential Amino Acids Are Synthesized from Oxaloacetate and Pyruvate

A figure shows how oxaloacetate and pyruvate are used to synthesize three nonessential and six essential amino acids.

Alanine and aspartate are synthesized from pyruvate and oxaloacetate, respectively, by transamination from glutamate. Asparagine is synthesized by amidation of aspartate, catalyzed by the enzyme asparagine synthetase. The ${NH}_{4}^{+}$ $NH Subscript 4 Superscript plus$ is donated by glutamine. These are nonessential amino acids, and their simple biosynthetic pathways occur in all organisms.

The malignant lymphocytes present in childhood acute lymphoblastic leukemia (ALL) produce little or no asparagine synthetase, and they are thus sensitive to asparagine depletion. The chemotherapy for ALL is administered together with an l-asparaginase derived from bacteria, with the enzyme functioning to reduce serum asparagine. The combined treatment results in a greater than 95% remission rate in cases of childhood ALL (l-asparaginase treatment alone produces remission in 40% to 60% of cases). However, the asparaginase treatment has some deleterious side effects, and about 10% of patients who achieve remission eventually suffer relapse, with tumors resistant to drug therapy. Researchers are now developing inhibitors of human asparagine synthetase to augment these therapies for childhood ALL.

Methionine, threonine, lysine, isoleucine, valine, and leucine are essential amino acids; humans cannot synthesize them. Their biosynthetic pathways in bacteria are complex and interconnected (Fig. 22-17). In some cases, the pathways in bacteria, fungi, and plants differ significantly.

A figure shows the steps by which six essential amino acids are synthesized from oxaloacetate and pyruvate in bacteria. The pathways shown yield methionine, threonine, lysine, isoleucine, valine, and leucine. — FIGURE 22-17 Biosynthesis of six essential amino acids from oxaloacetate and pyruvate in bacteria: methionine, threonine, lysine, isoleucine, valine, and leucine. Some of the most complex pathways for amino acid biosynthesis are found here. Pathways are abbreviated to emphasize precursors and pathway products.

Oxaloacetate is a three-carbon zigzag chain with C 1 on the left bonded to O H to the lower left and double bonded to O above, C 2 double bonded to O below, and C 3 double bonded to O below and bonded to O H to the upper right. A vertical arrow points down from oxaloacetate to a box labeled aspartate below and this arrow is intercepted by a horizontal arrow from glutamate in a green box on the left to alpha-ketoglutarate on the right. Aspartate is C double bonded to O to the upper left, bonded to O minus to the lower left, and bonded to C H 2 to the right further bonded to C H bonded to N H 3 above with a positive charge on N and to C O O minus on the right. An arrow labeled two steps points down from aspartate to aspartate beta-semialdehyde. This arrow is crossed by an arrow from A T P in an orange oval on the left to A D P on the right above an arrow from an orange oval from N A D P H plus H plus on the left to N A D P plus on the right. Beneath these two arrows, a short arrow branches to show the loss of P subscript i end subscript. Aspartate beta-semialdehyde is similar to aspartate except that the left-hand C atom is double bonded to O to the upper left and bonded to H to the lower left. Arrows point down and right from aspartate beta-semialdehyde. The vertical downward arrow points from aspartate beta-semialdehyde to a box labeled lysine. The top of the arrow is labeled 8 steps. From top to bottom, molecules are added and lost. A short curved line indicates the addition of a light red box labeled pyruvate. Below, a curved arrow shows the loss of H 2 O. Below, an orange oval labeled N A D P H plus H plus has an arrow pointing across the vertical arrow to an orange oval labeled N A D P plus on the right. Below, an arrow points from a yellow box labeled succinyl bonded to Co A outside of the box plus H 2 O on the left to Co A on the right. Below, an arrow points from a green box labeled glutamate on the left to alpha-ketoglutarate on the right. Below, an arrow points from H 2 O on the left to a yellow box labeled succinate on the right. Below, an arrow points from H plus on the left to C O 2 on the right. Lysine below is C H bonded to C O O minus on the left, bonded to N H 3 above with a positive charge on N, and bonded to (C H 2) 3 on the right further bonded to C H 2 bonded to N H 3 with a positive charge on N. The second arrow from aspartate beta-semialdehyde points right to homoserine and is accompanied by a curved arrow showing the addition of an orange oval labeled N A D P H plus H plus and the loss of an orange oval labeled N A D P plus. Homoserine is C H 2 bonded to O H below and bonded to C H 2 to the right bonded to C H bonded to N H 3 above with a positive charge on N and to C O O minus to the right. Arrows point up and down from homoserine. A vertical arrow points down from homoserine to a box labeled methionine. The top of the arrow is labeled 4 steps. From top to bottom, molecules are added and lost. A yellow box labeled succinyl bonded to Co A outside of the box on the left of the vertical arrow has an arrow pointing across the vertical arrow to Co A on the right. Below, an arrow points from a blue box labeled cysteine on the left to a yellow box labeled succinate on the right. Below, a curved arrow show the loss of a blue box labeled pyruvate plus N H 3. Below, an arrow points from italicized N end italics superscript 5 end superscript-blue box labeled methyl H subscript 4 end subscript folate on the left to a H subscript 4 end subscript folate on the right. Methionine below has C H 3 in a blue box bonded to S outside of the box further bonded to C H 2 bonded to C H 2 bonded to C H bonded to N H 3 above with a positive charge and to C O O minus on the right. The second arrow from homocysteine points up to a box labeled threonine. The bottom of the arrow is labeled 2 steps. From top to bottom, molecules are added and lost. A D P on the left has an arrow pointing across the vertical arrow to an orange oval labeled A T P on the right. Above, an arrow points from H 2 O on the left to P subscript i end subscript on the right side of the arrow. Threonine is C H 3 bonded to C H bonded to O H below and to C H to the right bonded to N H 3 above with a positive charge on H and to C O O minus on the right. A dashed arrow points right to another box labeled threonine from which an arrow points down to alpha-ketobutyrate. Just beneath P L P at the top of the arrow, an arrow branches off to show the loss of N H 4 with a positive charge on N plus H 2 O. Alpha-ketobutyrate is C H 3 bonded to C H bonded to H above and below and to C on the right double bonded to O below and bonded to C O O minus to the right. A vertical arrow points down from alpha-ketobutyrate to a box labeled isoleucine and is joined by a line from a reaction above that begins with pyruvate. Pyruvate is shown as a light red box containing H 3 C bonded to C double bonded to O below and bonded to C O O minus to the right outside of the box. An arrow points down to a molecule in brackets. Just below T P P at the top of the arrow, an arrow branches off to show the loss of C O 2. This yields a molecule with a light red box containing H 3 C bonded to C minus bonded to O below that is further bonded to H outside of the box and bonded to T P P to the right that is outside of the box. Two arrows curve down from this structure, one to the left to the vertical downward arrow from alpha-ketobutyrate to a box labeled isoleucine and one to the right to a vertical arrow between pyruvate and valine. The top of the arrow pointing down from alpha-ketobutyrate is labeled 4 steps and the line from the molecule above that was produced from pyruvate joins here. From top to bottom, molecules are added and lost. An orange oval labeled N A D (P) H plus H plus has an arrow pointing across the vertical arrow to a N A D (P) plus on the right. Below, an arrow branches off to show the loss of H 2 O. Below, an arrow points from a green box labeled glutamate on the left to alpha-ketoglutarate on the right. This yields isoleucine, shown as a light red box containing H 3 C bonded to C bonded to H below and bonded to C H 2 above outside of the box further bonded to C H 3 and bonded to C to the right outside of the box further bonded to H below, C O O minus to the right, and N H 3 in a green box above with a positive charge on N. To the right, a vertical downward arrow extends from pyruvate to alpha-ketoisovalerate, from which an arrow points to a box labeled valine. The arrow from the molecule that was produced by pyruvate joins near the top. Just below this, the arrow is labeled 3 steps. From top to bottom, molecules are added and lost. An orange oval labeled N A D (P) H plus H plus has an arrow pointing across the vertical arrow to N A D (P) plus on the right. Below, an arrow branches off to show the loss of H 2 O. This yields alpha-ketoisovalerate and a dashed arrow points from here to the top of a reaction to the right that converts alpha-ketoisovalerate to a box labeled leucine. A vertical arrow points down from alpha-ketoisovalerate to a box labeled valine and is crossed by an arrow from a green box labeled glutamate on the left to alpha-ketoglutarate on the right. This yields valine, shown as a light red box containing H 3 C bonded to C bonded to H below, bonded to C H 3 above outside of the box, and bonded to C to the right outside of the box further bonded to H below, to C O O minus to the right, and to N H 3 above in a green box with a positive charge on N. To the right, a vertical downward arrow points from alpha-ketoisovalerate produced from pyruvate to a box labeled leucine. The top of the arrow pointing down from alpha-ketoisovalerate is labeled 4 steps. From top to bottom, molecules are added and lost. A blue box labeled acetyl bonded to Co A outside of the box on the left has an arrow pointing across the vertical arrow to Co A on the right. Below, N A D plus on the left has an arrow pointing across the vertical arrow to an orange oval labeled N A D H plus H plus on the right. Below, an arrow branches off to show the loss of C O 2. Below, an arrow points from a green box labeled glutamate on the left to alpha-ketoglutarate on the right. This yields a box labeled leucine. Leucine is shown as a light red box containing H 3 C bonded to C bonded to H below, bonded to C H 3 above outside of the box, and bonded to C to the right outside of the box further bonded to H above and below and to C on the right in a blue box that is bonded to H below and to C O O minus within the same box and to N H 3 above in a green box with a positive charge on N.

Aspartate gives rise to methionine, threonine, and lysine. Branch points occur at aspartate β-semialdehyde, an intermediate in all three pathways, and at homoserine, a precursor of threonine and methionine. Threonine, in turn, is one of the precursors of isoleucine. The valine and isoleucine pathways share four enzymes (Fig. 22-17). Pyruvate gives rise to valine and isoleucine in pathways that begin with condensation of two carbons of pyruvate (in the form of hydroxyethyl thiamine pyrophosphate; see Fig. 14-13b) with another molecule of pyruvate (the valine path) or with α-ketobutyrate (the isoleucine path). The α-ketobutyrate is derived from threonine in a reaction that requires pyridoxal phosphate. An intermediate in the valine pathway, α-ketoisovalerate, is the starting point for a four-step branch pathway leading to leucine.

Chorismate Is a Key Intermediate in the Synthesis of Tryptophan, Phenylalanine, and Tyrosine

A light red box labeled phosphoenolpyruvate plus a blue box labeled erythrose 4-phosphate have three arrows pointing down: an arrow to phenylalanine at the lower left from which an arrow points down to tyrosine; an arrow to tyrosine in the center; and an arrow to tryptophan at the lower right.

The three amino acid side chains that contain aromatic rings, tryptophan, phenylalanine, and tyrosine, present a special chemical problem for biosynthesis. Aromatic rings are not readily available in the environment, even though the benzene ring is very stable. The branched pathway to tryptophan, phenylalanine, and tyrosine, occurring in bacteria, fungi, and plants, is the main biological route of aromatic ring formation. It proceeds through ring closure of an aliphatic precursor followed by stepwise addition of double bonds. The first four steps produce shikimate, a seven-carbon molecule derived from erythrose 4-phosphate and phosphoenolpyruvate (Fig. 22-18). Shikimate is converted to chorismate in three steps that include the addition of three more carbons from another molecule of phosphoenolpyruvate. Chorismate is the first branch point of the pathway, with one branch leading to tryptophan, the other to phenylalanine and tyrosine.

A figure shows how chorismate is synthesized with carbons highlighted to indicate whether they originate from erythrose 4-phosphate or phosphoenolpyruvate. — FIGURE 22-18 Biosynthesis of chorismate, an intermediate in the synthesis of aromatic amino acids in bacteria and plants. All carbons are derived from either erythrose 4-phosphate (light purple) or phosphoenolpyruvate (light red). Note that the ${NAD}^{+}$ $NAD Superscript plus$ required as a cofactor in step is released unchanged; it may be transiently reduced to NADH during the reaction, with formation of an oxidized reaction intermediate. Step is competitively inhibited by glyphosate $(^{-} COO — {CH}_{2} — NH — {CH}_{2} — {PO}_{3}^{2 -}),$ $left-parenthesis Superscript en-dash Baseline COO em-dash CH Subscript 2 Baseline em-dash NH em-dash CH Subscript 2 Baseline em-dash PO Subscript 3 Superscript 2 minus Baseline right-parenthesis comma$ the active ingredient in the widely used herbicide Roundup. The herbicide is relatively nontoxic to mammals, which lack this biosynthetic pathway. The intermediates quinate and shikimate are named after the plants in which they have been found to accumulate.

FIGURE 22-18 Biosynthesis of chorismate, an intermediate in the synthesis of aromatic amino acids in bacteria and plants. All carbons are derived from either erythrose 4-phosphate (light purple) or phosphoenolpyruvate (light red). Note that the ${NAD}^{+}$ $NAD Superscript plus$ required as a cofactor in step is released unchanged; it may be transiently reduced to NADH during the reaction, with formation of an oxidized reaction intermediate. Step is competitively inhibited by glyphosate $(^{-} COO — {CH}_{2} — NH — {CH}_{2} — {PO}_{3}^{2 -}),$ $left-parenthesis Superscript en-dash Baseline COO em-dash CH Subscript 2 Baseline em-dash NH em-dash CH Subscript 2 Baseline em-dash PO Subscript 3 Superscript 2 minus Baseline right-parenthesis comma$ the active ingredient in the widely used herbicide Roundup. The herbicide is relatively nontoxic to mammals, which lack this biosynthetic pathway. The intermediates quinate and shikimate are named after the plants in which they have been found to accumulate.

The legend is as follows: 1 equals 2-keto-3-deoxy-D-arabinoheptulosonate 7-phosphate synthase; 2 equals dehydroquinate synthase; 3 equals 3-dehydroquinate dehydratase; 4 equals shikimate dehydrogenase; 5 equals shikimate kinase; 6 equals 5-enolpyruvylshikimate 3-phosphate synthase; and 7 equals chorismate synthase. The reaction begins with the addition of phosphoenolpyruvate (P E P) and erythrose 4-phosphate. Phosphoenolpyruvate has a central C that is bonded to O to the upper left and further bonded to a circle labeled P, double bonded to C H 2 below, and bonded to C O O minus to the upper right. The carbon chain is highlighted in light red. Erythrose 4-phosphate is a vertical four-carbon chain with C 1 double bonded to O to the upper left and bonded to H to the upper right, C 2 bonded to H on the left and O H on the right, C 3 bonded to H on the left and O H on the right, and C 4 bonded to 2 H and to O further bonded to a circle labeled P. The carbon chain is highlighted in blue. Arrow 1 points downward accompanied by a curved arrow showing the addition of H 2 O and loss of P subscript 1 end subscript. This yields 2-keto-3-deoxy-D-arabinoheptulosonate 7-phospahte, shown as a seven-carbon chain with C 2 double bonded to O to the upper left and bonded to C O O minus to the upper right, C 3 bonded to 2 H, C 4 bonded to O H on the left and H on the right, C 5 bonded to H on the left and O H on the right, C 6 bonded to H on the left and O H on the right, and C 7 bonded to 2 H and to O further bonded to a circle labeled P. C 1 through C 3 at the top are highlighted in red and C 4 through C 7 at the bottom are highlighted in blue. An arrow labeled 2 points down with N A D plus to the upper right and an arrow branching off below showing the loss of P subscript i end subscript. This yields 3-dehydroquinate, which is a six-membered ring. The top vertex contains C hashed wedge bonded to O H to the upper left and bonded to C O O minus to the upper right. The lower right vertex is solid wedge bonded to O H and hashed wedge bonded to H, the bottom vertex is hashed wedge bonded to O H and solid wedge bonded to H, and the lower left vertex is double bonded to O. The carbon chain clockwise from the upper left vertex to the lower right vertex is highlighted in blue and the carbons at the upper right vertex and top vertex and bonded to the top vertex are highlighted in red. An arrow labeled 3 points down accompanied by an arrow branching off to show the loss of H 2 O. This yields 3-dehydroshikimate. It is similar to 3-dehydroquinate except that the top vertex is bonded to C O O mins and there is a double bond at the upper left side. The blue and red highlighting of the carbon chains is unchanged. Arrow 4 points down from 3-dehydroshikimate at the upper right and is accompanied by a curved arrow showing the addition of an orange oval labeled N A D P H plus H plus and the loss of N A D plus. This yields shikimate, which is similar to 3-dehydroshikimate except that the lower left vertex is hashed wedge bonded to O H and solid wedge bonded to H. The blue and red highlighting of the carbon chains is unchanged. Arrow 5 points down from shikimate and is accompanied by a curved arrow showing the addition of an orange oval labeled A T P and the loss of A D P. This yields shikimate 3-phosphate, which is similar to shikimate except that the lower left vertex is solid wedge bonded to H and hashed wedge bonded to O further bonded to a circle labeled P. The blue and red highlighting of the carbon chains is unchanged. Arrow 6 points down from shikimate 3-phosphate and is accompanied by a curved arrow showing the addition of a light red box labeled P E P and loss of P subscript i end subscript. This yields 5-enolpyruvylshikimate 3-phosphate, which has a similar structure to shikimate 3-phosphate except that the lower right vertex has a hashed wedge bond to H and a solid wedge bond to O further bonded to C in a light red box that is double bonded to C H 2 above and bonded to C O O minus to the right, all within the light red box. Arrow 7 points down from 5-enolpyruvylshikimate 3-phosphate and is accompanied by a curved arrow showing the loss of P subscript i end subscript. This yields chorismate, which has a similar structure except that the lower left vertex is no longer bonded to O bonded to a circle labeled P. From the upper left vertex, the carbon chain is highlighted in blue until the lower right vertex. The upper right vertex, top vertex, and carbon bonded to the top vertex are highlighted in light red. Additionally, O that is hashed wedge bonded to the lower right vertex is further bonded to C in a red highlighted box that is further double bonded to C H 2 above and bonded to C O O minus to the right, all of which are within the box.

In the tryptophan branch (Fig. 22-19), chorismate is converted to anthranilate in a reaction in which glutamine donates the nitrogen that will become part of the indole ring. Anthranilate then condenses with PRPP. The indole ring of tryptophan is derived from the ring carbons and amino group of anthranilate plus two carbons derived from PRPP. The final reaction in the sequence is catalyzed by tryptophan synthase. This enzyme has an $α_{2} β_{2}$ $alpha 2 beta 2$ subunit structure and can be dissociated into two α subunits and a $β_{2}$ $beta 2$ unit that catalyze different parts of the overall reaction:

\begin{array}{l} Indole- 3 -glycerol phosphate \underset{α subunit}{\to} indole + glyceraldehyde 3 -phosphate \\ Indole + serine \underset{β_{2} subunit}{\to} tryptophan + H_{2} O \end{array}

$StartLayout 1st Row Indole hyphen 3 hyphen glycerol phosphate right-arrow Underscript alpha subunit Endscripts indole plus glyceraldehyde 3 hyphen phosphate 2nd Row Indole plus serine right-arrow Underscript beta 2 subunit Endscripts tryptophan plus upper H Subscript 2 Baseline upper O EndLayout$

A figure the steps involved in the synthesis of tryptophan from chorismate in bacteria and plants. — FIGURE 22-19 Biosynthesis of tryptophan from chorismate in bacteria and plants. In *E. coli,* enzymes catalyzing steps and are subunits of a single complex.

FIGURE 22-19 Biosynthesis of tryptophan from chorismate in bacteria and plants. In *E. coli,* enzymes catalyzing steps and are subunits of a single complex.

A box at the lower right contains the following list from top to bottom: anthranilate synthase, anthranilate phosphoribosyltransferase, italicized N end italics-(5 prime-phosphoribosyl)-anthranilate isomerase, indole-3-glycerol phosphate synthase, and tryptophan synthase. Chorismate at the top is a six-membered ring with double bonds at the left side and upper right side. It has a top vertex bonded to C O O minus, a lower right vertex hashed wedge bonded to H and solid wedge bonded to O bonded to C double bonded to C H 2 above and bonded to C O O minus to the right, and a bottom vertex hashed wedge bonded to O H and solid wedge bonded to H. An arrow points down from chorismate to anthranilate accompanied by a curved arrow showing the addition of a green box labeled glutamine and loss of glutamate and by an arrow that branches off to show the loss of pyruvate. This yields anthranilate, shown as a benzene ring with the top vertex bonded to C O O minus and the upper right vertex bonded to N H 2 in a green box. An arrow points down from anthranilate to italicized N end italics-(5 prime-phosphoribosyl)-anthranilate accompanied by a curve showing the addition of a red box labeled P R P P and loss of P P subscript i end subscript. This yields italicized N end italics-(5 prime-phosphoribosyl)-anthranilate, shown as a benzene ring with its bottom vertex bonded to C O O minus and its lower left vertex bonded to N in a green box bonded to H in the same box and further bonded to the right side vertex of a five-membered ring below that is entirely enclosed in a light red box. O is substituted for C at the top vertex of the ring. In addition to being bonded to N in the green box above, the right side vertex is also bonded to H below. The lower right vertex is bonded to H above and O H below, the lower left vertex is bonded to H above and O H below, and the left side vertex is bonded to H below and to C H 2 above further bonded to O bonded to a circle labeled P. An arrow points down from N end italics-(5 prime-phosphoribosyl)-anthranilate to enol-1-italicized o end italics-carboxyphenylamino-1-deoxyribulose phosphate, which is a benzene ring with its upper right vertex bonded to C O O minus and its lower right vertex bonded to N in a green box bonded to H below in the same box and bonded to C to the upper right in a light red box that is bonded to H and double bonded to C above that is bonded to O H to the left and bonded to C to the right bonded to O H above, H below, and C to the right bonded to O H above, H below, and C H 2 to the right bonded to O bonded to a circle labeled P, all in the same light red box. An arrow points down from enol-1-italicized o end italics-carboxyphenylamino-1-deoxyribulose phosphate to indole-3-glycerol phosphate and is accompanied by an arrow that branches off to show the loss of H 2 O and C O 2. Indole-3-glycerol phosphate is a benzene ring that shares its right side with a five-membered ring that has N substituted for C at its lower right vertex that is in a green box and bonded to H below in the same green box and that has a light red highlighted double bond at its upper right side from the right side vertex to the top vertex. The top vertex is bonded to a chain above that is entirely highlighted in light red beginning with C H bonded to O H above and bonded to C H to the right that is bonded to O H above and to C H 2 to the right further bonded to O bonded to a circle labeled P. An arrow points down from indole-3-glyerol phosphate to a box labeled tryptophan and is accompanied by a branched arrow showing the loss of a red box labeled glyceraldehyde 3-phosphate and a curved arrow showing the addition of a blue box labeled serine and loss of H 2 O with P L P in the inflection point of the curved arrow. This yields tryptophan, which is similar to indole-3-glycerol phosphate except that the top vertex of the five-membered ring is bonded to C H 2 in a blue box that is bonded to C H to the right bonded to N H 3 above with a positive charge on N further bonded to C O O minus, all in the same blue box.

The second part of the reaction requires pyridoxal phosphate (Fig. 22-20). Indole formed in the first part is not released by the enzyme, but instead moves through a channel from the α-subunit active site to one of the β-subunit active sites, where it condenses with a Schiff base intermediate derived from serine and PLP. Intermediate channeling of this type may be a feature of the entire pathway from chorismate to tryptophan. Enzyme active sites catalyzing different steps (sometimes not sequential steps) of the pathway to tryptophan are found on single polypeptides in some species of fungi and bacteria, but they are separate proteins in other species. In addition, the activity of some of these enzymes requires a noncovalent association with other enzymes of the pathway. These observations suggest that all the pathway enzymes are components of a large, multienzyme complex, a metabolon, in both bacteria and eukaryotes. Such complexes are generally not preserved intact when the enzymes are isolated using traditional biochemical methods (see Section 16.4).

A two-part figure shows the steps of the tryptophan synthase reaction in part a and the positioning and movement of indole within the enzyme in part b. — MECHANISM FIGURE 22-20 Tryptophan synthase reaction. (a) This enzyme catalyzes a multistep reaction with several types of chemical rearrangements. The PLP-facilitated transformations occur at the β carbon (C-3) of the amino acid, as opposed to the α-carbon reactions described in Figure 18-6. The β carbon of serine is attached to the indole ring system. (b) Indole generated on the α subunit (white) moves through a tunnel to the β subunit (blue), where it condenses with the serine moiety. [(b) Data from PDB ID 1KFJ, V. Kulik et al., *J. Mol. Biol.* 324:677, 2002.]

Part a begins with indole-3-glycerol phosphate at the top, which is a benzene ring that shares its right side with a five-membered ring that has N substituted for C at its lower right vertex that is in a green box and bonded to H below in the same green box and that has a light red highlighted double bond at its upper right side from the right side vertex to the top vertex. The top vertex is bonded to a chain above that is entirely highlighted in light red beginning with C H bonded to O H above and bonded to C H to the right that is bonded to O H above and to C H 2 to the right further bonded to O bonded to a circle labeled P. Arrow 1, labeled tryptophan synthase alpha subunits, points down from indole-3-glycerol phosphate to indole and is accompanied by a curved arrow showing the loss of glyceraldehyde 3-phosphate. Glyceraldehyde 3-phosphate is shown highlighted in light red as C double bonded to O to the upper left, bonded to H to the lower left, and bonded to C H to the right bonded to O H above and to C H 2 to the right further bonded to O bonded to a circle labeled P. Accompanying text reads, An aldol cleavage produces indole and glyceraldehyde 3-phosphate; P L P is not required. This yields indole, which is shown in a vertical channel between two blue sides. Indole is a benzene ring that shares its eight side with the left side of a five-membered ring with N substituted for C at its lower right vertex in a green box and bonded to H in the same green box and with a red highlighted double bond at its upper right side. The right side and top vertices on either side of the double bond are highlighted. Accompanying text reads, Indole traverse tunnel between alpha and beta subunits. Arrow 2, labeled tryptophan synthase beta subunits, points down from indole to show an interaction between indole and other molecules within an opening between two beta subunits of the enzyme. A curved arrow accompanying arrow 2 shows the addition of serine and loss of H 2 O with P L P at the inflection point of the arrow. Serine is highlighted in blue and is C H 2 with a beta on C bonded to O H below and to C H to the right bonded to N H 3 above with a positive charge on N and to C O O Minus to the right. Accompanying text reads, dehydration of serine forms a P L P-aminoacrylate intermediate. The figure below the arrow shows an irregular opening that is roughly round but with wavy sides, a wide opening at the top, and a narrow opening at the lower left. The blue sides around this opening are each labeled beta. Text below reads, P L P-aminoacrylate adduct. Indole is shown at the upper left with its benzene ring projecting into an invagination in the left side wall. The top vertex is shown bonded to H and a red pair of electrons is shown on N. At the upper right, the blue boundary of the enzyme has a bond to B to the left in the opening. B has a red pair of electrons. Serine is highlighted in blue and oriented with a central C double bonded to C H 2 at the upper left with the C labeled as beta, to C O O minus to the upper right, and to N H below with a positive charge on N, which is double bonded to C H outside of the blue highlighting that is bonded to the top vertex of a six-membered ring with double bonds at its upper left, right, and lower left sides and with its upper right vertex bonded to O H, its lower right vertex bonded to C H 3, N plus substituted for C at its bottom vertex and bonded to H, and its upper left vertex bonded to C H 2 bonded to O bonded to a circle labeled P. Red arrows point from the red electrons on N in indole to the lower right side of its five-membered ring, from the red highlighted double bond at the upper right side of the five-membered ring of indole to the C labeled beta and highlighted in blue, from the double bond between the double bond between C labeled beta and the central C to its lower right and the bond between the same central C and N plus below, from the double bond between N H with a positive charge on N and the bond between C H bonded to the top vertex of the ring and the top vertex of the ring, between the double bond at the upper left side of the ring and the left side of the ring, and between the double bond at the lower left side of the ring and N H plus at the bottom vertex of the ring. Arrow 3 points down to show further interactions in the opening with text below reading, quinonoid intermediate. Accompanying text reads, Indole condenses with the aminoacrylate intermediate (2 steps). The blue region of enzyme at the upper left is gone and the right side is still labeled beta. B with a red pair of electrons is still bonded to the boundary of the enzyme at the upper right. The six-membered ring joined with a five-membered ring is angled downward with the benzene ring to the upper left and the five-membered ring lower down. The five-membered ring has a double bond at its bottom right side; an upper right vertex, upper right side bond, and lower right vertex highlighted in red; N plus at the bottom vertex and bonded to H within a green box; and an upper right vertex bonded to H above and to C H 2 in a blue box to the right further bonded to C bonded to C O O minus to the right and double bonded to N H to the lower right with a positive charge on N and a bond to C H to the lower left that is double bonded to the six-membered ring below that has double bonds at its left and right sides, an upper right vertex bonded to O H, a lower right vertex bonded to C H 3, N substituted for C at its bottom vertex with a red pair of electrons and bonded to H, and an upper left vertex bonded to C H 2 bonded to O further bonded to a circle labeled P. Red arrows point from the red pair of electrons on B at the upper right to H bonded to the upper right vertex of the five-membered ring, from the bond between the same H and the upper right vertex of the ring to the upper right side of the same ring, from the double bond at the lower right side of the same ring to N plus at the bottom vertex of the same ring, from the pair of electrons on N H at the bottom of the six-membered ring to the lower left side of the same ring, from the double bond at the left side of the six-membered ring to the upper left side of the same ring, from the double bond from the top vertex of the six-membered ring to C H above to the bond between the same C H and N H with a positive charge on N above, and from the double bond between N H with a positive charge on N and the central C above to an individual H plus above. Arrow 4 points right to another illustration with text below reading, aldimine with tryptophan. The upper right boundary of the enzyme is bonded to B H within the opening. The five-membered ring joined with a six-membered ring has N at its bottom vertex bonded to H, both within the same green box, has a double bond at its right side, has a red highlighted chain from the lower right vertex to the upper right vertex, and has an upper right vertex bonded to C H 2 in a blue box further bonded to C H bonded to C O O minus to the right and bonded to N H to the lower right with a positive charge on N, all within the blue box, that is double bonded to C H outside of the blue box bonded to the top vertex of a six-membered ring with double bonds at its upper left, right, and lower left sides, with an upper right vertex bonded to O H, with a lower right vertex bonded to C H 3, with N plus substituted for C at the bottom vertex and bonded to H, and with an upper left vertex bonded to C H 2 bonded to O further bonded to a circle labeled P. Arrow 5 points right accompanied by a curved arrow showing the addition of H 2 O and loss of a blue oval labeled enzyme bonded to P L P. Text below reads, Imine linkage joining tryptophan to P L P is hydrolyzed. This yields a six-membered ring with its lower right side shared with the upper left side of a five-membered ring with N substituted for C at its bottom vertex within a green box and bonded to H within the same box, with a double bond at its upper right side, with a red highlighted chain from the lower right to upper right vertex, and with an upper right vertex bonded to C H 2 in a blue box further bonded to C H bonded to N H 3 above with a positive charge on N and to C O O minus. Text below reads, tryptophan. Part b shows a blue half-oval cut off across the bottom and with irregular sizes beneath a white region that extends up almost vertically above it for a short distance. The blue region is labeled beta and the white region is labeled alpha. A rounded opening in the middle of the blue region contains a quinoid, shown as a wireframe ring with a blue vertex at the bottom, bonds from the upper and lower right vertex, a chain bonded to its upper left vertex, and a long chain extending from its top vertex labeled, from serine. A six-membered ring joined with a five-membered ring that has a blue vertex is labeled indole. The opening narrows and a thin region from this opening to a widening at the start of the blue region is labeled, tunnel. A slightly wider vertical region in the white part contains another indole molecule and then bends right slightly, where a wireframe model of glyceraldehyde 3-phosphate is visible as a vertical chain that branches at its right end.

In plants and bacteria, phenylalanine and tyrosine are synthesized from chorismate in pathways much less complex than the tryptophan pathway. The common intermediate is prephenate (Fig. 22-21). The final step in both cases is transamination with glutamate.

A figure shows how phenylalanine and tyrosine are synthesized from chorismate in bacteria and plants. — FIGURE 22-21 Biosynthesis of phenylalanine and tyrosine from chorismate in bacteria and plants. Conversion of chorismate to prephenate is a rare biological example of a Claisen rearrangement.

A legend at the bottom shows that 1 equals prephenate dehydrogenase and 2 equals prephenate dehydratase. Chorismate is shown at the top as a six-membered ring with double bonds at the left and upper right sides, with a top vertex bonded to C O O minus, with a lower right vertex hashed wedge bonded to H and solid wedge bonded to O bonded to C double bonded to C H 2 above and bonded to C O O minus to the right, and with a bottom vertex hashed wedge bonded to O H and solid wedge bonded to H. An arrow labeled chorismate mutase points down to prephenate, which is a six-membered ring with double bonds on the left and right sides, a top vertex hashed wedge bonded to C O O minus and solid wedge bonded to C H 2 bonded to C double bonded to O below and bonded to C O O minus to the right, and with a bottom vertex hashed wedge bonded to O H and solid wedge bonded to H. From prephenate, arrow 1 points down to the lower left and arrow 2 points down to the lower right. Arrow 1 points down to 4-hydroxyphenylpyruvate and is accompanied by a curved arrow showing the addition of N A D plus and loss of N A D H plus H plus and by a branched arrow showing the loss of C O 2. This yields 4-hydroxyphenylpyruvate, which is a benzene ring with a top vertex bonded to C H 2 bonded to C double bonded to O above and bonded to C O O minus to the right and a bottom vertex bonded to O H. An arrow labeled aminotransferase points down to a box labeled tyrosine and is accompanied by a curved arrow showing the addition of a green box labeled glutamate and the loss of alpha-ketoglutarate. This yields tyrosine, which is a benzene ring with its top vertex bonded to C H 2 bonded to C H bonded to N H 3 above in a green box with a positive charge on N and to C O O minus to the right and with its bottom vertex bonded to O H. Arrow 2 points down to a box labeled phenylpyruvate and is accompanied by an arrow that branches off to show the loss of C O 2 plus O H minus. This yields phenylpyruvate, which is a benzene ring with its top vertex bonded to C H 2 bonded to C double bonded to O above and bonded to C O O minus to the right. An arrow labeled aminotransferase points down and accompanied by a curved arrow showing the addition of a green box labeled glutamate and the loss of alpha-ketoglutarate. This yields phenylalanine, which is a benzene ring with its top vertex bonded to C H 2 bonded to C H bonded to N H 3 above in a green box with a positive charge on N and bonded to C O O minus to the right.

Animals can produce tyrosine directly from phenylalanine through hydroxylation at C-4 of the phenyl group by phenylalanine hydroxylase; this enzyme also participates in the degradation of phenylalanine (see Figs. 18-23, 18-24). Tyrosine is considered a conditionally essential amino acid, or as nonessential insofar as it can be synthesized from the essential amino acid phenylalanine.

Histidine Biosynthesis Uses Precursors of Purine Biosynthesis

A blue box labeled ribose 5-phosphate has an arrow pointing down to a box labeled histidine.

The pathway to histidine in all plants and bacteria differs in several respects from other amino acid biosynthetic pathways. Histidine is derived from three precursors (Fig. 22-22): PRPP contributes five carbons, the purine ring of ATP contributes a nitrogen and a carbon, and glutamine supplies the second ring nitrogen. The key steps are condensation of ATP and PRPP, in which N-1 of the purine ring is linked to the activated C-1 of the ribose of PRPP (step in Fig. 22-22); purine ring opening that ultimately leaves N-1 and C-2 of adenine linked to the ribose (step ); and formation of the imidazole ring, a reaction in which glutamine donates a nitrogen (step ). The use of ATP as a metabolite rather than a high-energy cofactor is unusual — but not wasteful, because it dovetails with the purine biosynthetic pathway. The remnant of ATP that is released after the transfer of N-1 and C-2 is 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an intermediate of purine biosynthesis (see Fig. 22-35) that is rapidly recycled to ATP.

A figure shows how histidine is synthesized in bacteria and plants. — FIGURE 22-22 Biosynthesis of histidine in bacteria and plants. Atoms derived from PRPP and ATP are shaded light red and blue, respectively. Two of the histidine nitrogens are derived from glutamine and glutamate (green). Note that the derivative of ATP remaining after step (AICAR) is an intermediate in purine biosynthesis (see Fig. 22-35, step ), so ATP is rapidly regenerated.

FIGURE 22-22 Biosynthesis of histidine in bacteria and plants. Atoms derived from PRPP and ATP are shaded light red and blue, respectively. Two of the histidine nitrogens are derived from glutamine and glutamate (green). Note that the derivative of ATP remaining after step (AICAR) is an intermediate in purine biosynthesis (see Fig. 22-35, step ), so ATP is rapidly regenerated.

A legend shows that 1 equals A T P phosphoribosyl transferase, 2 equals pyrophosphohydrolase, 3 equals phosphoribosyl-A M P cyclohydrolase, 3 equals phosphoribosyl-A M P cyclohydrolase, 4 equals phosphoribosylformimino-5-aminoimidazole-4-carboxamide ribonucleotide isomerase, 5 equals glutamine amidotransferase, 6 equals imidazole glycerol 3-phosphate dehydratase, 7 equals L-histidinol phosphate aminotransferase, 8 equals histidinol phosphate phosphatase, and 9 equals histidinol dehydrogenase. At the top, 5-phosphoribosyl-1-pyrophosphate (P R P P) is added to A T P. P R P P is shown in a light red box as a five-membered ring with O at the top vertex, C at the right side vertex bonded to H above and to O below further bonded to a circle labeled P bonded to a circle labeled P, C at the lower right vertex bonded to H above and O H below, C at the lower left vertex bonded to H above and O H below, and C at the left side vertex bonded to H below and to C H 2 above further bonded to O bonded to a circle labeled P. A T P is shown in a blue box as a six-membered ring that shares its right side with the left side of a five-membered ring. The six-membered ring has double bonds at its upper left, lower left, and right sides; has N substituted for C at its upper left and bottom vertices, has C bonded to H at its lower left vertex, and has a top vertex bonded to N H 2 with a red pair of electrons on N. The five-membered ring shares the double bond at its left side with the six-membered ring, has a double bond at its upper right side, has N substituted for C at its upper right vertex, and has N substituted for C at its lower right vertex that is further bonded to a box labeled R i b below that is further bonded to a chain of three circles labeled P. Red arrows point from the red pair of electrons on N to the bond between the same N at the top vertex of the six-membered ring in A T P, from the double bond at the upper left side of the six-membered ring to C at the right-side vertex of P R P P, and from the bond between C at the right side vertex and O below to the same O. A downward-pointing arrow labeled 1 is accompanied by an arrow branching away to show the loss of a red box labeled P P subscript i end subscript and shows that this reaction yields italicized N end italics superscript 1 end superscript-5 prime-phosphoribosyl-A T P. The red highlighted part of the molecule is similar except that the right-side vertex is bonded to H below and to N above at the lower left vertex of the six-membered ring in the blue part of the molecule, which has rotated so that N at the upper left of the six-membered ring is now at the lower right vertex. The six-membered ring has N substituted for C at its lower left vertex that is further bonded to C at the right-side vertex of the red highlighted five-membered ring below, a left side vertex double bonded to N H, a lower right vertex of C bonded to H, a double bond at the lower right side, N substituted for C at the right side vertex, and a double bond at the top side that is the bottom side of the five-membered ring above. The five-membered ring has a double bond at its upper left side, N substituted for C at its upper left vertex, and N substituted for C at its upper right vertex that is further bonded to a box labeled R i b that is further bonded to a string of three circles labeled P. An arrow labeled 2 points right accompanied by an arrow that branches up to show the loss of P P subscript i end subscript. This yields italicized N end italics superscript 1 end superscript-5 prime-phosphoribosyl-A M P. The product is similar except that the box labeled R i b in the blue portion is now bonded to a single circle labeled P instead of three. An arrow labeled 3 points down and is joined by a curved line showing the addition of H 2 O. This yields italicized N end italics superscript 1 end superscript-5 prime-phosphoribosylformiimino-5-aminoimidazole-4-carboxamine ribonucleotide, which has a similar structure except that the six-membered ring in the blue part has lost its lower left side, N at the lower left vertex of the six-membered ring is bonded to H to the left, and C at the left side vertex of the six-membered ring is double bonded to O to the upper left and bonded to N H 2 to the left. An arrow labeled 4 points left to a yield italicized N end italics superscript 1 end superscript-5 prime-phosphoribulosyl-formimino-5-amino-imidazole-4-carboxamine ribonucleotide. The blue part of the molecule is the same but N at the lower left vertex of the partial six-membered ring in the blue art is now bonded to a vertical six-carbon chain in the red part of C bonded to H to the left and right and bonded to C below that is double bonded to O and bonded to C below that is bonded to H to the left, O H to the right, and to C below bonded to H to the left, O H to the right, and to C H 2 below bonded to O further bonded to a circle labeled P. An arrow labeled 5 points to imidazole glycerol 3-phosphate at the lower left. A curved arrow shows that a green box labeled glutamine is added and glutamate is lost. At the same point in the diagonal arrow, an arrow curves away to 5-aminoimidazole-4-carboxide ribonucleotide (A I C A R). This is a five-membered ring with double bonds at the bottom and upper left sides, N at the upper left vertex, N at the upper right vertex bonded to a box labeled R i b that is further bonded to a circle labeled P, a lower right vertex bonded to N H 2, and a lower left vertex bonded to C double bonded to O to the upper right and bonded to N H 2 to the left. An arrow points up from this molecule to text reading, to purine biosynthesis. Further down along the arrow labeled 5, an arrow branches away to show the loss of H 2 O to yield imidazole glycerol 3-phosphate. This has a red highlighted vertical five-carbon chain. The top two carbons are connected by a double bond that forms the left side of a five-membered ring with C at the upper left vertex bonded to H to the left, blue highlighted N substituted for C at the top vertex and further bonded to H, blue highlighted C H at the right side vertex, a double bond at the lower right vertex, and a green box labeled N substituted for C at the lower right vertex. The upper right vertex, upper right bond, and right side vertex are highlighted in blue. The lower left vertex is bonded to the chain below of C bonded to O H to the right, H to the left, and C below bonded to O H to the right, H to the left, and C H 2 below further bonded to a circle labeled P. An arrow labeled 6 points down to imidazole acetol 3-phosphate and is accompanied by a curved arrow showing the loss of H 2 O. The top part of the molecule with the ring is similar, but the lower left vertex of the ring is bonded to C H 2 bonded to C below that is double bonded to O to the right and bonded to C H 2 below further bonded to O bonded to a circle labeled P. Right- and left-pointing arrows labeled 7 are accompanied by a curved arrow showing the addition of a green box labeled glutamate and the loss of alpha-ketoglutarate. This yields L-histidinol phosphate, which is similar except that the lower left vertex of the chain is bonded to C H 2 below bonded to C H below bonded to N H 3 in a green box with a positive charge on N to the right and to C H 2 below further bonded to O bonded to a circle labeled P. An arrow labeled 8 points right with an arrow branching away to show the loss of P subscript i end subscript. This yields L-histidinol, which is similar except that the bottom carbon of the chain is now bonded to 2 H and O H instead of to O further bonded to a circle labeled P. An arrow labeled 9 points right to a box labeled histidine and is accompanied by a curved arrow showing the addition of 2 N A D plus and loss of 2 N A D H plus 2 H plus. Histidine is similar to the reactant except that the bottom carbon now forms C O O minus instead of being bonded to 2 H and O H.

Amino Acid Biosynthesis Is under Allosteric Regulation

As detailed in Chapter 13, the control of flux through a metabolic pathway often reflects the activity of multiple enzymes in that pathway. In the case of amino acid synthesis, regulation often takes place in part through feedback inhibition of the first reaction by the end product of the pathway. This first reaction is often catalyzed by an allosteric enzyme that plays an important role in the overall control of flux through that pathway. As an example, Figure 22-23 shows the allosteric regulation of isoleucine synthesis from threonine. The end product, isoleucine, is an allosteric inhibitor of the first reaction in the sequence. In bacteria, such allosteric modulation of amino acid synthesis contributes to the minute-to-minute adjustment of pathway activity to cellular needs.

A figure shows the allosteric regulation of the synthesis of isoleucine from threonine. — FIGURE 22-23 Allosteric regulation of isoleucine biosynthesis. The first reaction in the pathway from threonine to isoleucine is inhibited by the end product, isoleucine. This was one of the first examples of allosteric feedback inhibition to be discovered.

Allosteric regulation of an individual enzyme can be considerably more complex. An example is the remarkable set of allosteric controls exerted on glutamine synthetase of E. coli (Fig. 22-8). Six products derived from glutamine serve as negative feedback modulators of the enzyme, and the overall effects of these and other modulators are more than additive. Such regulation is called concerted inhibition.

Additional mechanisms contribute to the regulation of the amino acid biosynthetic pathways. Because the 20 common amino acids must be made in the correct proportions for protein synthesis, cells have developed ways not only of controlling the rate of synthesis of individual amino acids but also of coordinating their formation. Such coordination is especially well developed in fast-growing bacterial cells. Figure 22-24 shows how E. coli cells coordinate the synthesis of lysine, methionine, threonine, and isoleucine, all made from aspartate. Several important types of inhibition patterns are evident. The step from aspartate to aspartyl-β-phosphate is catalyzed by three isozymes, each independently controlled by different modulators. This enzyme multiplicity prevents one biosynthetic end product from shutting down key steps in a pathway when other products of the same pathway are required. The steps from aspartate β-semialdehyde to homoserine and from threonine to α-ketobutyrate (detailed in Fig. 22-17) are also catalyzed by dual, independently controlled isozymes. One isozyme for the conversion of aspartate to aspartyl-β-phosphate is allosterically inhibited by two different modulators, lysine and isoleucine, whose action is more than additive — another example of concerted inhibition. The sequence from aspartate to isoleucine undergoes multiple, overlapping negative feedback inhibitions; for example, isoleucine inhibits the conversion of threonine to α-ketobutyrate (as described above), and threonine inhibits its own formation at three points: from homoserine, from aspartate β-semialdehyde, and from aspartate (see Fig. 22-17). This overall regulatory mechanism is called sequential feedback inhibition.

A figure shows how multiple regulatory mechanisms interact in the synthesis of several amino acids derived from aspartate in italicized E. coli end italics. — FIGURE 22-24 Interlocking regulatory mechanisms in the biosynthesis of several amino acids derived from aspartate in *E. coli*. Three enzymes (A, B, C) have either two or three isozyme forms, indicated by numerical subscripts. In each case, one isozyme $(A_{2}, B_{1}, and C_{2})$ $left-parenthesis upper A Subscript 2 Baseline comma upper B Subscript 1 Baseline comma and upper C Subscript 2 Baseline right-parenthesis$ has no allosteric regulation; these isozymes are regulated by changes in the amount of enzyme synthesized. Synthesis of isozymes $A_{2}$ $upper A Subscript 2$ and $B_{1}$ $upper B Subscript 1$ is repressed when methionine levels are high, and synthesis of isozyme $C_{2}$ $upper C Subscript 2$ is repressed when isoleucine levels are high. Enzyme A is aspartokinase; B, homoserine dehydrogenase; C, threonine dehydratase.

FIGURE 22-24 Interlocking regulatory mechanisms in the biosynthesis of several amino acids derived from aspartate in *E. coli*. Three enzymes (A, B, C) have either two or three isozyme forms, indicated by numerical subscripts. In each case, one isozyme $(A_{2}, B_{1}, and C_{2})$ $left-parenthesis upper A Subscript 2 Baseline comma upper B Subscript 1 Baseline comma and upper C Subscript 2 Baseline right-parenthesis$ has no allosteric regulation; these isozymes are regulated by changes in the amount of enzyme synthesized. Synthesis of isozymes $A_{2}$ $upper A Subscript 2$ and $B_{1}$ $upper B Subscript 1$ is repressed when methionine levels are high, and synthesis of isozyme $C_{2}$ $upper C Subscript 2$ is repressed when isoleucine levels are high. Enzyme A is aspartokinase; B, homoserine dehydrogenase; C, threonine dehydratase.

Three arrows point down from a yellow box labeled aspartate to a yellow box labeled aspartyl-beta-phosphate. Each arrow has a blue oval near the top labeled from left to right as A subscript 1 end subscript, A subscript 2 end subscript, and A subscript 3 end subscript, respectively. An arrow points down from aspartyl-beta phosphate to aspartate beta-semialdehyde. Three arrows point down from aspartate beta-semialdehyde. The left-hand arrow is short and points down to a second short arrow labeled 6 steps that points down to a yellow box labeled lysine. A dashed arrow points up from lysine and branches to an arrow pointing to a red “X” in a red circle next to the top arrow of the two-arrow sequence from aspartate beta-semialdehyde to lysine before continuing up to point to a red “X” in a red circle next to arrow A subscript 1 end subscript just above aspartyl-beta-phosphate. The middle arrow pointing down from aspartate beta-semialdehyde has a blue oval labeled B subscript 1 end subscript at its top and points to a yellow box labeled homoserine below. A series of two arrows point down from homoserine to a yellow box labeled methionine and the bottom arrow in this series is labeled 3 steps. A dashed arrow points from methionine to a red “X” in a red circle next to the top arrow in the two-arrow series pointing from homoserine to methionine. The third arrow pointing down from aspartate beta-semialdehyde has a blue oval labeled B subscript 2 end subscript at its top and points down to the same yellow box labeled homoserine, from which a series of two arrows points down to a yellow box labeled threonine. From threonine, dashed arrows point to symbols showing a red “X” within a red arrow next to the top arrow of the two arrow sequence between homoserine and threonine, next to arrow B subscript 1 end subscript pointing from aspartate beta-semialdehyde to homoserine, and next to arrow A subscript 3 end subscript pointing from aspartate to aspartyl-beta-phosphate. Two arrows point down from threonine to alpha-ketobutyrate with the left-hand arrow labeled with a blue oval labeled C subscript 1 end subscript and the right-hand arrow labeled with a blue oval labeled C subscript 2 end subscript. An arrow labeled 5 steps points down from alpha-ketobutyrate to isoleucine. From isoleucine, dashed arrows point to symbols showing a red “X” within a red arrow next to the arrow labeled C subscript 1 end subscript pointing from threonine to alpha-ketobutyrate, next to the top of the arrow labeled A subscript 1 end subscript pointing from aspartate to aspartyl-beta-phosphate, and next to the top of arrow B subscript 2 end subscript pointing from aspartate beta-semialdehyde to homoserine.

Similar patterns are evident in the pathways leading to the aromatic amino acids. The first step of the early pathway to the common intermediate chorismate is catalyzed by the enzyme 2-keto-3-deoxy-d1-arabinoheptulosonate 7-phosphate (DAHP) synthase ( in Fig. 22-18). Most microorganisms and plants have three DAHP synthase isozymes. One is allosterically inhibited (feedback inhibition) by phenylalanine, another by tyrosine, and the third by tryptophan. This scheme helps the overall pathway to respond to cellular requirements for one or more of the aromatic amino acids. Additional regulation takes place after the pathway branches at chorismate. For example, the enzymes catalyzing the first two steps of the tryptophan branch are subject to allosteric inhibition by tryptophan.

SUMMARY 22.2 Biosynthesis of Amino Acids

Plants and bacteria synthesize all 20 common amino acids. Mammals can synthesize about half; the others are required in the diet (essential or conditionally essential amino acids).
Glutamate is formed by reductive amination of α-ketoglutarate and serves as the precursor of glutamine, proline, and arginine.
The carbon chain of serine is derived from 3-phosphoglycerate. Serine is a precursor of glycine; the β-carbon atom of serine is transferred to tetrahydrofolate. In microorganisms, cysteine is produced from serine and from sulfide produced by the reduction of environmental sulfate. Mammals produce cysteine from methionine and serine by a series of reactions requiring S-adenosylmethionine and cystathionine.
Alanine and aspartate (and thus asparagine) are formed from pyruvate and oxaloacetate, respectively, by transamination. Pyruvate and oxaloacetate also give rise to methionine, threonine, lysine, valine, isoleucine, and leucine via longer pathways.
The aromatic amino acids (phenylalanine, tyrosine, and tryptophan) form by a pathway in which chorismate occupies a key branch point. Tyrosine can also be formed by hydroxylation of phenylalanine (and thus is considered conditionally essential). Phosphoribosyl pyrophosphate is a precursor of tryptophan and histidine.
The pathway to histidine is interconnected with the purine synthetic pathway.
The amino acid biosynthetic pathways are subject to allosteric end-product inhibition; the regulatory enzyme is usually the first in the sequence. Regulation of the various synthetic pathways is coordinated.