[OMEGA-(ADENOSIN-5'-O-YL)ALKYL]COBALAMINS MIMICKING THE POSTHOMOLYSISINTERMEDIATE OF COENZYME B-12-DEPENDENT REARRANGEMENTS - KINETIC INVESTIGATIONS ON METHYLMALONYL-COA MUTASE

Coenzyme-B-12 analogues carrying oligomethylene chains (C-3-C-7) inser ted between the central Co atom and the 5'-0 atom of the adenosine moi ety mimicking the putative posthomolysis intermediate in coenzyme B-12 -dependent rearrangements were synthesized and examined for their effe cts on methylmalonyl-CoA mutase from Propionibacterium shermanii. All analogues proved to be inhibitors of methylmalonyl-CoA mutase and in a ll cases competitive inhibition with respect to coenzyme B-12 was foun d. Inhibition constants (K-i) were determined by two independent metho ds and showed in both cases the predicted trend: the K-i values versus chain length had minima at the C-6 analogue in which the distance is about 10 Angstrom between the central Co atom and the 5' carbon of the adenosine, assuming a zig-zag chain conformation. This is the postula ted distance between the Co and 5'-methylene paramagnetic centers gene rated in the methylmalonyl-CoA-coenzyme B-12 complex after homolytic c leavage of the Co-C bond. (C) 1995 Academic Press, Inc.