Inhibition of the human methylmalonyl-CoA mutase by various CoA-esters
| Autor: | Shinichi Taoka, Ming-Tain Lai, Raghavakaimal Padmakumar, Ruma Banerjee, Hung-Wen Liu |
|---|---|
| Rok vydání: | 1994 |
| Předmět: |
chemistry.chemical_classification
Stereochemistry Protein subunit Methylmalonyl-CoA mutase Kinetics Methylmalonyl-CoA Mutase Substrate (chemistry) Mixed inhibition Saccharomyces cerevisiae Cell Biology Biochemistry Recombinant Proteins Structure-Activity Relationship chemistry.chemical_compound Mutase Enzyme chemistry Humans Acyl Coenzyme A Carboxylate Molecular Biology |
| Zdroj: | Journal of Biological Chemistry. 269:31630-31634 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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