Enzymes Of Fatty Acid Oxidation And Ketogenesis

Fatty acids, the precursors of ketone bodies, exist in a variety of chain lengths, from long-chain fatty acids, e.g., palmitate, through medium-chain fatty acids, e.g., octanoate, to short-chain fatty acids, e.g., butanoate. All such fatty acids can be catabolized in the mitochondria of hepatocytes by P-oxidation (1) (Fig. 1), whereby 2-carbon units are progressively removed from the fatty acid chain. The 2-carbon units generated are in the form of the ubiquitous cellular molecule, acetyl-coenzyme A (CoA) (Fig. 1). The ketone body acetoacetate is then formed by the condensation of acetyl-CoA, followed by the removal of the CoA moiety. Subsequently the ketone body 3-hydroxybutyrate is formed on reduction of acetoacetate, which in turn is dependent on reduced nicotinamide adenine dinucleotide (NADH). In addition, under conditions of high rates of ketogenesis, the ketone body acetone is formed spontaneously. A series of enzymes, upstream of acetyl-CoA, is responsible for catalyzing the breakdown of fatty acids of differing chain lengths. Subsequently, two enzymes downstream of acetyl-CoA are responsible for the formation of the first ketone body, acetoacetate. All such enzymes must be present for fatty acid oxidation and ketogen-esis (FAOK) to be executed, as evidenced by the potentially lethal effects of inborn errors of FAOK (4). However, only certain enzymes appear to have a major regulatory role in the flux of fatty acids to ketone bodies (3). This is because such enzymes catalyze key branch-

Fig. 1. Oxidation and ketogenesis of the 16-carbon fatty acid palmitate in the hepatocyte: B, blood; C, cytosol of hepatocyte; M, mitochondria of hepatocyte. Key branch-point steps of FAOK are catalyzed by the following enzymes: ACS1, entrapping palmitate in the hepatocyte for the oxidation pathway; CPT, committing palmitate to entry into the mitochondria, away from metabolism in the cytosol; and HMGCS2, committing acetyl-CoA to ketogenesis, away from complete oxidation to CO2 by the Krebs cycle.

Fig. 1. Oxidation and ketogenesis of the 16-carbon fatty acid palmitate in the hepatocyte: B, blood; C, cytosol of hepatocyte; M, mitochondria of hepatocyte. Key branch-point steps of FAOK are catalyzed by the following enzymes: ACS1, entrapping palmitate in the hepatocyte for the oxidation pathway; CPT, committing palmitate to entry into the mitochondria, away from metabolism in the cytosol; and HMGCS2, committing acetyl-CoA to ketogenesis, away from complete oxidation to CO2 by the Krebs cycle.

point steps in the commitment toward FAOK, at the expense of other competing pathways (Fig. 1). Such enzymes include long-chain fatty acyl-CoA synthetase 1 (ACS1), carnitine palmitoyl transferase (CPT) and mitochondrial 3-hydroxy-3-methylglutaryl-CoA syn-thetase (HMGCS2), the critical enzyme of ketogenesis from acetyl-CoA.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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