Inhibition of the human methylmalonyl-CoA mutase by various CoA-esters

J Biol Chem. 1994 Dec 16;269(50):31630-4.


Human methylmalonyl-CoA mutase is inhibited by ethylmalonyl-CoA, cyclopropylcarbonyl-CoA carboxylate, and methylenecyclopropylacetyl-CoA, which are substrate, intermediate, and product analogs, respectively. The mode of inhibition by each analog is reversible and mixed with respect to the substrate, methylmalonyl-CoA. This implies that the inhibitors are able to bind to both free enzyme and to the enzyme-substrate complex, although with affinities that are 4.5- to 10-fold different for the two species. The Ki1 for the cyclopropylcarbonyl-CoA carboxylate (0.26 +/- 0.07 mM), is 4-fold greater than the Km(app) measured for the substrate, methylmalonyl-CoA. Additionally, ethylmalonyl-CoA functions as an alternate substrate and is metabolized to methylsuccinyl-CoA. The human mutase is a homodimer that binds 1 mol of cobalamin per subunit. So, the observed mixed inhibition kinetics by substrate analogs is curious. Our finding that methylenecyclopropylacetyl-CoA, the causative agent of Jamaican "vomiting sickness," inhibits methylmalonyl-CoA mutase, while interesting, is probably not physiologically important because of the relatively high inhibition constants (Ki1 = 0.47 +/- 0.12 mM and Ki2 = 2 +/- 0.34 mM) observed with this compound.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acyl Coenzyme A / chemistry
  • Acyl Coenzyme A / pharmacology*
  • Humans
  • Kinetics
  • Methylmalonyl-CoA Mutase / antagonists & inhibitors*
  • Recombinant Proteins
  • Saccharomyces cerevisiae
  • Structure-Activity Relationship


  • Acyl Coenzyme A
  • Recombinant Proteins
  • Methylmalonyl-CoA Mutase