[ω-(Adenosin-5′-O-yl)alkyl)cobalamins Mimicking the Posthomolysis Intermediate of Coenzyme B12-Dependent Rearrangements: Kinetic Investigations on Methylmalonyl-CoA Mutase

L. Poppe, J. Retey

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14 Citations (Scopus)

Abstract

Coenzyme-B12 analogues carrying oligomethylene chains (C3-C7) inserted between the central Co atom and the 5′-O atom of the adenosine moiety mimicking the putative posthomolysis intermediate in coenzyme B12-dependent rearrangements were synthesized and examined for their effects on methylmalonyl-CoA mutase from Propionibacterium shermanii. All analogues proved to be inhibitors of methylmalonyl-CoA mutase and in all cases competitive inhibition with respect to coenzyme B12 was found. Inhibition constants (Ki) were determined by two independent methods and showed in both cases the predicted trend: the Ki values versus chain length had minima at the C6 analogue in which the distance is about 10 Å between the central Co atom and the 5′ carbon of the adenosine, assuming a zig-zag chain conformation. This is the postulated distance between the Co and 5′-methylene paramagnetic centers generated in the methylmalonyl-CoA-coenzyme B12 complex after homolytic cleavage of the CoC bond.

Original languageEnglish
Pages (from-to)541-546
Number of pages6
JournalArchives of Biochemistry and Biophysics
Volume316
Issue number1
DOIs
Publication statusPublished - Jan 1995

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Methylmalonyl-CoA Mutase
Vitamin B 12
Kinetics
Atoms
Adenosine
Propionibacterium
Chain length
Conformations
Carbon
cobamamide

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics
  • Biochemistry

Cite this

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title = "[ω-(Adenosin-5′-O-yl)alkyl)cobalamins Mimicking the Posthomolysis Intermediate of Coenzyme B12-Dependent Rearrangements: Kinetic Investigations on Methylmalonyl-CoA Mutase",
abstract = "Coenzyme-B12 analogues carrying oligomethylene chains (C3-C7) inserted between the central Co atom and the 5′-O atom of the adenosine moiety mimicking the putative posthomolysis intermediate in coenzyme B12-dependent rearrangements were synthesized and examined for their effects on methylmalonyl-CoA mutase from Propionibacterium shermanii. All analogues proved to be inhibitors of methylmalonyl-CoA mutase and in all cases competitive inhibition with respect to coenzyme B12 was found. Inhibition constants (Ki) were determined by two independent methods and showed in both cases the predicted trend: the Ki values versus chain length had minima at the C6 analogue in which the distance is about 10 {\AA} between the central Co atom and the 5′ carbon of the adenosine, assuming a zig-zag chain conformation. This is the postulated distance between the Co and 5′-methylene paramagnetic centers generated in the methylmalonyl-CoA-coenzyme B12 complex after homolytic cleavage of the CoC bond.",
author = "L. Poppe and J. Retey",
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T1 - [ω-(Adenosin-5′-O-yl)alkyl)cobalamins Mimicking the Posthomolysis Intermediate of Coenzyme B12-Dependent Rearrangements

T2 - Kinetic Investigations on Methylmalonyl-CoA Mutase

AU - Poppe, L.

AU - Retey, J.

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N2 - Coenzyme-B12 analogues carrying oligomethylene chains (C3-C7) inserted between the central Co atom and the 5′-O atom of the adenosine moiety mimicking the putative posthomolysis intermediate in coenzyme B12-dependent rearrangements were synthesized and examined for their effects on methylmalonyl-CoA mutase from Propionibacterium shermanii. All analogues proved to be inhibitors of methylmalonyl-CoA mutase and in all cases competitive inhibition with respect to coenzyme B12 was found. Inhibition constants (Ki) were determined by two independent methods and showed in both cases the predicted trend: the Ki values versus chain length had minima at the C6 analogue in which the distance is about 10 Å between the central Co atom and the 5′ carbon of the adenosine, assuming a zig-zag chain conformation. This is the postulated distance between the Co and 5′-methylene paramagnetic centers generated in the methylmalonyl-CoA-coenzyme B12 complex after homolytic cleavage of the CoC bond.

AB - Coenzyme-B12 analogues carrying oligomethylene chains (C3-C7) inserted between the central Co atom and the 5′-O atom of the adenosine moiety mimicking the putative posthomolysis intermediate in coenzyme B12-dependent rearrangements were synthesized and examined for their effects on methylmalonyl-CoA mutase from Propionibacterium shermanii. All analogues proved to be inhibitors of methylmalonyl-CoA mutase and in all cases competitive inhibition with respect to coenzyme B12 was found. Inhibition constants (Ki) were determined by two independent methods and showed in both cases the predicted trend: the Ki values versus chain length had minima at the C6 analogue in which the distance is about 10 Å between the central Co atom and the 5′ carbon of the adenosine, assuming a zig-zag chain conformation. This is the postulated distance between the Co and 5′-methylene paramagnetic centers generated in the methylmalonyl-CoA-coenzyme B12 complex after homolytic cleavage of the CoC bond.

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