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Coenzyme A Metabolism in Vitamin B-12—Deficient Rats¹

Eric P. Brass^*,2, Arun G. Tahiliani, Robert H. Allen^* and Sally P. Stabler^*

^* Department of Medicine Department of Pharmacology, University of Colorado Health Sciences Center, Denver, CO 80262 Weis Center for Research, Danville, PA 17822

Vitamin B-12 (cobalamin) deficiency results in decreased L-methylmalonyl-coenzyme A (CoA) mutase activity. The consequence of this defect on the cellular CoA pool was studied in rats with functional vitamin B-12 deficiency induced by administration of the cobalamin analogue hydroxy-cobalamin [c-lactam] or by dietary vitamin B-12 deficiency. Both types of vitamin B-12 deficiency were associated with methylmalonic acidemia (100–300-fold increases in plasma methylmalonic acid concentration compared with controls), but overall fuel homeostasis was intact. Liver from rats treated with hydroxy-cobalamin [c-lactam] contained a threefold greater concentration of total CoA (free CoA plus all acyl-CoA) compared with saline-treated rats. Fractionation of the CoA pool revealed higher levels of CoA, propionyl-CoA, methylmalonyl-CoA, acid-insoluble CoA, as well as total CoA in the rats treated with hydroxy-cobalamin [c-lactam] compared with controls. Similar increases in liver CoA content were seen in dietary vitamin B-12 deficiency in both the fed and fasted states. To examine the hypothesis that sequestration of hepatic CoA as propionyl-CoA and methylmalonyl-CoA could increase CoA biosynthesis, the effect of propionate on CoA biosynthesis was studied in hepatocytes isolated from control rats. Propionate (1 mM) increased the formation of ¹⁴C-CoA from [¹⁴C]pantothenate (10 µM) by 27% in the hepatocyte system. When butyrate (1 mM) was provided as substrate, propionate (10 mM) increased [¹⁴C]CoA formation by 63%. -Ketobutyrate, which is decarboxylated to propionyl-CoA, also increased hepatocyte [¹⁴C]pantothenate metabolism. Thus, vitamin B-12 deficiency is associated with hepatic accumulation of propionyl-CoA and methylmalonyl-CoA, and an increase in hepatic total CoA content. This increase in total CoA content may result from enhanced biosynthesis of CoA because cellular CoA is sequestered as poorly metabolized acyl-CoA. The increase in CoA biosynthesis may be an important compensatory mechanism to maintain cellular metabolism under conditions of acyl-CoA accretion.

KEY WORDS: • vitamin B-12 • coenzyme A • propionate • pantothenate • rats

¹ Supported by National Institutes of Health grants DK 36069 (EPB) and DK 37165 (SPS).

² Author to whom reprint requests should be addressed.

Manuscript received 30 May 1989. Revision accepted 3 October 1989.

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