The effect of vitamin B₁₂ deprivation on the enzymes of fatty acid synthesis

The enzymes of fatty acid synthesis from liver and brain in normal and B₁₂ deprived rats were studied. Both total and specific activities of fatty acid synthetase and acetyl coenzyme A carboxylase were 2 to 5 fold greater in B₁₂ deprivation than in the normal state. The presence of excess activators in the B₁₂ deprived rat or an excess inhibitor in the normal rat was not found by serial admixtures of the respective cytosol preparations or by partial purification of the enzymes. Since B₁₂ deficiency is associated with an increase in the tissue concentrations of propionic and methylmalonic acid, the effect of the coenzyme A derivatives of these acids on fatty acid synthetase and acetyl CoA carboxylase activity was studied. Propionyl CoA was a substrate for fatty acid synthetase, while methylmalonyl CoA markedly inhibited synthetase activity. Methylmalonyl CoA markedly inhibited acetyl CoA carboxylase activity. Propionyl CoA was shown to be a substrate for acetyl CoA carboxylase, competing with acetyl CoA, and the product synthesized was methylmalonyl CoA. Thus, in vitamin B₁₂ deprivation propionyl CoA competes with acetyl CoA as substrate providing a mechanism for odd chain fatty acid production, and its product, methylmalonyl CoA, may function as an inhibitor of the enzymes of fatty acid synthesis.