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.

Figure 16.8. Cytoplasmic generation of acetyl-CoA via citrate transport and related reactions. PPP=pentose phosphate pathway; FAS=fatty acid synthase; —⊖→=negative allosteric modifier; —⊕→=positive allosteric modifier.

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:

  1. Phenylalanine: Phenylalanine is a precursor for the neurotransmitters tyrosine, dopamine, epinephrine and norepinephrine. It plays an integral role in the structure and function of proteins and enzymes and the production of other amino acids. ( Pumpkin seeds, Tempeh, hemp seeds, buckwheat,  almonds )
  2. Tryptophan: Though often associated with causing drowsiness, tryptophan has many other functions. It’s needed to maintain proper nitrogen balance and is a precursor to serotonin, a neurotransmitter that regulates your appetite, sleep and mood. (Sesame seeds, seaweed, buckwheat, tempeh, mushrooms, leafy veg, walnuts)
  3. Leucine: Like valine, leucine is a branched-chain amino acid that is critical for protein synthesis and muscle repair. It also helps regulate blood sugar levels, stimulates wound healing and produces growth hormones. (Tempeh, buckwheat, legumes)
  4. Lysine: Lysine plays major roles in protein synthesis, hormone and enzyme production and the absorption of calcium. It’s also important for energy production, immune function and the production of collagen and elastin. (Pumpkin, tempeh, buckwheat)
  5. Tyrosine: Pumkin seeds, chocolate, Spirulina.