title: Assessing the reversibility of the anaplerotic reactions of the propionyl-CoA pathway in heart and liver.
abstract: While a number of studies underline the importance of anaplerotic pathways for hepatic biosynthetic functions and cardiac contractile activity, much remains to be learned about the sites and regulation of anaplerosis in these tissues. As part of a study on the regulation of anaplerosis from propionyl-CoA precursors in rat livers and hearts, we investigated the degree of reversibility of the reactions of the propionyl-CoA pathway. Label was introduced into the pathway via NaH13CO3, [U-13C3]propionate, or [U-13C3]lactate + [U-13C3]pyruvate, under various concentrations of propionate. The mass isotopomer distributions of propionyl-CoA, methylmalonyl-CoA, and succinyl-CoA revealed that, in intact livers and hearts, (i) the propionyl-CoA carboxylase reaction is slightly reversible only at low propionyl-CoA flux, (ii) the methylmalonyl-CoA racemase reaction keeps the methylmalonyl-CoA enantiomers in isotopic equilibrium under all conditions tested, and (iii) the methylmalonyl-CoA mutase reaction is reversible, but its reversibility decreases as the flow of propionyl-CoA increases. The thermodynamic dis-equilibrium of the combined reactions of the propionyl-CoA pathway explains the effectiveness of anaplerosis from propionyl-CoA precursors such as heptanoate.
authors.affiliation: Department of Biochemistry, Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Aneta E
authors.initials: AE
authors.lastname: Reszko
authors.forename: Takhar
authors.initials: T
authors.lastname: Kasumov
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Pierce
authors.forename: France
authors.initials: F
authors.lastname: David
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
authors.forename: Henri
authors.initials: H
authors.lastname: Brunengraber
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D002247:Carbon Isotopes; D007553:Isotope Labeling / Q000379:methods; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008765:Methylmalonyl-CoA Mutase / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D011422:Propionates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000214:Acyl Coenzyme A; D002247:Carbon Isotopes; D011422:Propionates; C009061:propionyl-coenzyme A; D008765:Methylmalonyl-CoA Mutase