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Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase.

Authors
  • Sokolovskaya, Olga M1
  • Plessl, Tanja2
  • Bailey, Henry3
  • Mackinnon, Sabrina3
  • Baumgartner, Matthias R2
  • Yue, Wyatt W3
  • Froese, D Sean2
  • Taga, Michiko E4
  • 1 Department of Plant & Microbial Biology, University of California, Berkeley, CA, USA; Department of Chemistry, University of California, Berkeley, CA, USA.
  • 2 Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, Switzerland. , (Switzerland)
  • 3 Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, UK.
  • 4 Department of Plant & Microbial Biology, University of California, Berkeley, CA, USA. Electronic address: [email protected]
Type
Published Article
Journal
Biochimie
Publication Date
Apr 01, 2021
Volume
183
Pages
35–43
Identifiers
DOI: 10.1016/j.biochi.2020.06.014
PMID: 32659443
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Cobalamin, commonly known as vitamin B12, is an essential micronutrient for humans because of its role as an enzyme cofactor. Cobalamin is one of over a dozen structurally related compounds - cobamides - that are found in certain foods and are produced by microorganisms in the human gut. Very little is known about how different cobamides affect B12-dependent metabolism in human cells. Here, we test in vitro how diverse cobamide cofactors affect the function of methylmalonyl-CoA mutase (MMUT), one of two cobalamin-dependent enzymes in humans. We find that, although cobalamin is the most effective cofactor for MMUT, multiple cobamides support MMUT function with differences in binding affinity (Kd), binding kinetics (kon), and concentration dependence during catalysis (KM, app). Additionally, we find that six disease-associated MMUT variants that cause cobalamin-responsive impairments in enzymatic activity also respond to other cobamides, with the extent of catalytic rescue dependent on the identity of the cobamide. Our studies challenge the exclusive focus on cobalamin in the context of human physiology, indicate that diverse cobamides can support the function of a human enzyme, and suggest future directions that will improve our understanding of the roles of different cobamides in human biology. Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

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