Inhibition of the human methylmalonyl-CoA mutase by various CoA-esters.
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.
Taoka
S
S
Biochemistry Department, University of Nebraska, Lincoln 68583-0718.
Padmakumar
R
R
Lai
M T
MT
Liu
H W
HW
Banerjee
R
R
D000214:Acyl Coenzyme A / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008765:Methylmalonyl-CoA Mutase / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D012441:Saccharomyces cerevisiae; D013329:Structure-Activity Relationship
D000214:Acyl Coenzyme A; D011994:Recombinant Proteins; D008765:Methylmalonyl-CoA Mutase