Coenzyme A metabolism in vitamin B-12-deficient rats.
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, methyl-malonyl-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 microM) by 27% in the hepatocyte system. When butyrate (1 mM) was provided as substrate, propionate (10 mM) increased [14C]CoA formation by 63%.(ABSTRACT TRUNCATED AT 250 WORDS)
Brass
E P
EP
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Tahiliani
A G
AG
Allen
R H
RH
Stabler
S P
SP
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003065:Coenzyme A / Q000096:biosynthesis / Q000378:metabolism*; D004032:Diet; D006879:Hydroxocobalamin; D006885:Hydroxybutyrates / Q000097:blood; D008099:Liver / Q000201:enzymology; D008297:Male; D008764:Methylmalonic Acid / Q000097:blood; D009132:Muscles / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D014806:Vitamin B 12 Deficiency / Q000378:metabolism*
D001786:Blood Glucose; D006885:Hydroxybutyrates; D008764:Methylmalonic Acid; D006879:Hydroxocobalamin; D003065:Coenzyme A