Acetyl-CoA is the primary substrate that enters the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle or Krebs cycle), where a series of chemical reactions happen and reducing equivalents (nicotinamide adenine dinucleotide and FADH2) are produced.
Acetyl-CoA is synthesized in mitochondria by a number of reactions: oxidative decarboxylation of pyruvate; catabolism of some amino acids (e.g., phenylalanine, tyrosine, leucine, lysine, and tryptophan); and β-oxidation of fatty acids (see earlier). Since acetyl-CoA cannot be transported directly across the inner mitochondrial membrane to the cytosol, its carbon atoms are transferred by two transport mechanisms:
1.Transport dependent on carnitine: Carnitine participates in the transport of long-chain acyl-CoA into the mitochondria and plays a similar role in the transport of acetyl-CoA out of mitochondria. However, carnitine acetyl transferases have a minor role in acetyl-CoA transport.
2.Cytosolic generation of acetyl-CoA (citrate shuttle): This pathway is shown in Figure 16.8. Citrate synthesized from oxaloacetate and acetyl-CoA is transported from mitochondria to the cytosol via the tricarboxylate anion carrier system and cleaved to yield acetyl-CoA and oxaloacetate.
Thus, citrate not only modulates the rate of fatty acid synthesis but also provides carbon atoms for the synthesis. The oxaloacetate formed from pyruvate may eventually be converted (via malate) to glucose by the gluconeogenic pathway. The glucose oxidized via the pentose phosphate pathway augments fatty acid synthesis by providing NADPH. Pyruvate generated from oxaloacetate can enter mitochondria and be converted to oxaloacetate, which is required for the formation of citrate.
De novo synthesis of CoA is a well-conserved enzymatic pathway, in which the first and rate-limiting step corresponds to phosphorylation of vitamin B5 (or pantothenic acid). Vitamin B5 is found in high amounts in mushrooms and avocado. Accordingly, levels of vitamin B5 are associated with the subsequent metabolite CoA levels, which affect the status of protein acetylation.
Acetyl-CoA is generated either by oxidative decarboxylation of pyruvate from glycolysis, which occurs in mitochondrial matrix, by oxidation of long-chain fatty acids, or by oxidative degradation of certain amino acids such as phenylalanine, tyrosine, leucine, lysine, and tryptophan.
Amino Acids for Acetyl-CoA synthesis: