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.