Acetyl-CoA generation

Scheme 13 N-acetylation of lysine. Lysine attacks the acetyl group of acetyl-CoA generating an acetylated protein and CoA.

To complete the oxidation of fatty acids the acetyl units of acetyl-CoA generated in the P oxidation sequence must be oxidized to carbon dioxide and water.77 The citric acid (or tricarboxylic acid) cycle by which this oxidation is accomplished is a vital part of the metabolism of almost all aerobic creatures. It occupies a central position in metabolism because of the fact that acetyl-CoA is also an intermediate in the catabolism of carbohydrates and of many amino acids and other compounds. The cycle is depicted in detail in Fig. 10-6 and in an abbreviated form, but with more context, in Fig. 17-4. 

Formation of citrate, catalyzed by citrate synthase. A carbanion of acetyl-CoA, generated by loss of a proton to water (or to an acceptor group on the enzyme), adds to the carbonyl group of oxaloacetate. 

Lactate and pyruvate dehydrogenases generate 3 ATPs each, whereas acetyl-CoA generates 12 ATPs for a total of 18. 

The acetyl-CoA generated from citrate is then used for fatty acid biosynthesis. In the human being, only two multifunctional enzymes are involved acetyl-CoA carboxylase (also termed malonyl-CoA synthetase) and fatty acid synthetase, with a molecular weight of 500,000, and coded by a single gene. The product of the two enzymes is palmitate. Other fatty acids may be made from palmitate by chain unsaturation, or elongation, or both (see later). The initial reaction involves the carboxylation of acetyl-CoA in two steps by acetyl-CoA carboxylase. Biotin is a cofactor, and one molecule of ATP is hydrolyzed to ADP and Pc ... 

Fatty acids are activated in liver cells and converted to acetyl CoA, generating ATP. As NADH and ATP levels rise, acetyl CoA accumulates. 

B. Ketone bodies are produced in the liver from acetyl CoA generated by fatty acid oxidation. In a carnitine deficiency, fatty acids are not oxidized, so ketone bodies are not produced. 

O -glycerophosphate derived in situ from glucose. The glucose can also be converted into fatty acids from acetyl-CoA generated via glycolysis and the pyruvate dehydrogenase reaction and from NADPH obtained via the pentose phosphate pathway. 

Severe dieting stimulates massive lipolysis. The large amounts of acetyl-CoA generated in this process trigger a vastly increased synthesis of the ketone bodies. When present in such large amounts, the ketone bodies overwhelm the buffering capacity of the blood and its pH falls. 

In apicoplast FA biosynthesis, the main carbon substrate is acetyl-coenzyme A (acetyl-CoA) generated from acetate by the action of acetyl-CoA synthase or from pyruvate by the pyruvate dehydrogenase (PDH) complex. Within the plastid, pyruvate is formed by the action of... 

Not all acetyl CoA generated from P-oxidation enters the TCA cycle. In the liver, acetyl CoA generated from p-oxidation of fatty acids can also be converted to the... 

In the liver, much of the acetyl CoA generated from fatty acid oxidation is converted to the ketone bodies, acetoacetate and p-hydroxybutyrate, which enter the blood (see Fig. 23.1). In other tissues, these ketone bodies are converted to acetyl... 

In the liver, ketone bodies are synthesized in the mitochondrial matrix from acetyl CoA generated from fatty acid oxidation (Fig. 23.18). The thiolase reaction of fatty acid oxidation, which converts acetoacetyl CoA to two molecules of acetyl CoA, is a reversible reaction, although formation of acetoacetyl-CoA is not the favored direction. It can, thus, when acetyl-CoA levels are high, generate acetoacetyl CoA... 

Fig. 31.5. Conversion of pyruvate to phosphoenolpyruvate (PEP). Follow the shaded circled numbers on the diagram, starting with the precursors alanine and lactate. The first step is the conversion of alanine and lactate to pyruvate. Pyruvate then enters the mitochondria and is converted to OAA (circle 2) by pyruvate carboxylase. Pyruvate dehydrogenase has been inactivated by both the NADH and acetyl-CoA generated from fatty acid oxidation, which allows oxaloacetate production for gluconeogenesis. The oxaloacetate formed in the mitochondria is converted to either malate or aspartate to enter the cytoplasm via the malate/aspartate shuttle. Once in the cytoplasm the malate or aspartate is converted back into oxaloacetate (circle 3), and phosphoenolpyruvate carboxykinase will convert it to PEP (circle 4). The white circled numbers are alternate routes for exit of carbon from the mitochondrion using the malate/aspartate shuttle. OAA = oxaloacetate FA = fatty acid TG = triacylglycerol.

Not all acetyl CoA generated metabolically enters the citric acid cycle. Some also serve as a starting material for fatty acid biosynthesis (Section 14.7). The fatty acid components of triglycerides, for example, are synthesized using acetyl CoA. Thus, as most people are aware, the intake of excess dietary carbohydrates can lead to an increase in body fat storage. 

Fatland BL, Nikolau BJ, Wuitele ES (2005) Reverse genetic characterization of cytosolic acetyl-CoA generation by ATP-citrate lyase in Arabidopsis. Plemt CeU 17 182-203 Fukui T, Doi Y (1997) Qoning and analysis of the poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) biosynthesis genes of Aeromonas caviae. J Bacteriol 179 4821 830 Fukui T, Shiomi N, Doi Y (1998) Expression and characterization of (R)-spedfic enoyl coenzyme A hydratase involved in polyhydroxyalkanoate biosynthesis by Aeromonas caviae. J Bacteriol 180 667-673... 

Under fermentative conditions the pathway probably operates only in the turn-over of fats and the acetyl CoA generated is probably used for the synthesis of fatty acids. 

The fate of the acetyl-CoA generated during 8-oxidation is only known... 

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