Chapter 17 Fatty Acid Catabolism
The oxidation of long-chain fatty acids to acetyl-CoA is a central energy-yielding pathway in many organisms and tissues. In mammalian heart and liver, for example, it provides as much as 80% of the energetic needs under all physiological circumstances. The electrons removed from fatty acids during oxidation pass through the respiratory chain, driving ATP synthesis; the acetyl-CoA produced from the fatty acids may be completely oxidized to in the citric acid cycle, resulting in further energy conservation.
In Chapter 10 we described the properties of triacylglycerols (also called triglycerides or neutral fats) that make them especially suitable as storage fuels. The long alkyl chains of their constituent fatty acids are essentially hydrocarbons, highly reduced structures with an energy of complete oxidation more than twice that for the same weight of carbohydrate or protein. This advantage is compounded by the extreme insolubility of lipids in water; cellular triacylglycerols aggregate in lipid droplets, which do not raise the osmolarity of the cytosol, and they are unsolvated. (In storage polysaccharides, by contrast, water of solvation can account for two-thirds of the overall weight of the stored molecules.) And because of their relative chemical inertness, triacylglycerols can be stored in large quantity in cells without the risk of undesired chemical reactions with other cellular constituents.
The properties that make triacylglycerols good storage compounds, however, present problems in their role as fuels. Because they are insoluble in water, ingested triacylglycerols must be emulsified before they can be digested by water-soluble enzymes in the intestine, and triacylglycerols absorbed in the intestine or mobilized from storage tissues must be carried in the blood bound to proteins that counteract their insolubility. Also, to overcome the relative stability of the bonds in a fatty acid, the carboxyl group at C-1 is activated by attachment to coenzyme A, which allows stepwise oxidation of the fatty acyl group at the C-3, or β, position — hence the name β oxidation.
The principles we emphasize in this chapter are not new. They apply to the catabolic pathways of carbohydrates that we just studied.
Metabolites of diverse origin funnel into a few central pathways. Fatty acid catabolism and glycolysis convert quite different starting materials into the same product (acetyl-CoA). The electrons from the oxidative reactions of these pathways and of the citric acid cycle are carried by common cofactors (NAD and FAD) to the mitochondrial respiratory chain leading to oxygen, providing the energy for ATP synthesis by oxidative phosphorylation.
Evolution selects for chemical mechanisms that make useful reactions more energetically favorable, and those same mechanisms are used in different pathways. In the breakdown of fatty acids we see the activation of a carboxylic acid by its conversion to a thioester, as we saw with acetyl-CoA in the citric acid cycle. To break the bonds in the long chain of relatively inert groups in fatty acids, a carbonyl group is created adjacent to the group, as we saw in the reactions of the citric acid cycle.
Allosteric mechanisms and posttranslational regulation (protein phosphorylation) coordinate metabolic processes within a cell. Hormones and growth factors coordinate metabolic activities among tissues and organs. Reciprocal regulation of catabolic and anabolic pathways prevents the inefficiency of futile cycling.
When a process lacks a critical component — an enzyme, a cofactor, or a regulatory agent — the resulting loss of homeostasis may cause disease across a spectrum of severity. Defects in fatty acid breakdown are no exception.
The liver plays a unique role in whole-body metabolism. When glucose is unavailable, the liver makes glucose by gluconeogenesis and releases it to the blood for distribution to other tissues, including the brain. During starvation, the liver processes fatty acids into ketone bodies, which, unlike fatty acids, can cross the blood brain barrier and fuel the brain.
Metabolites of diverse origin funnel into a few central pathways. Fatty acid catabolism and glycolysis convert quite different starting materials into the same product (acetyl-CoA). The electrons from the oxidative reactions of these pathways and of the citric acid cycle are carried by common cofactors (NAD and FAD) to the mitochondrial respiratory chain leading to oxygen, providing the energy for ATP synthesis by oxidative phosphorylation.
Evolution selects for chemical mechanisms that make useful reactions more energetically favorable, and those same mechanisms are used in different pathways. In the breakdown of fatty acids we see the activation of a carboxylic acid by its conversion to a thioester, as we saw with acetyl-CoA in the citric acid cycle. To break the bonds in the long chain of relatively inert groups in fatty acids, a carbonyl group is created adjacent to the group, as we saw in the reactions of the citric acid cycle.
Allosteric mechanisms and posttranslational regulation (protein phosphorylation) coordinate metabolic processes within a cell. Hormones and growth factors coordinate metabolic activities among tissues and organs. Reciprocal regulation of catabolic and anabolic pathways prevents the inefficiency of futile cycling.
When a process lacks a critical component — an enzyme, a cofactor, or a regulatory agent — the resulting loss of homeostasis may cause disease across a spectrum of severity. Defects in fatty acid breakdown are no exception.
The liver plays a unique role in whole-body metabolism. When glucose is unavailable, the liver makes glucose by gluconeogenesis and releases it to the blood for distribution to other tissues, including the brain. During starvation, the liver processes fatty acids into ketone bodies, which, unlike fatty acids, can cross the blood brain barrier and fuel the brain.