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

Lookup NU author(s): Dr Sabrina MackinnonORCiD, Professor Wyatt YueORCiD

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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 (K_d), binding kinetics (k_on), and concentration dependence during catalysis (K_{M, 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.

Publication metadata

Author(s): Sokolovskaya OM, Plessl T, Bailey H, Mackinnon S, Baumgartner MR, Yue WW, Froese DS, Taga ME

Publication type: Article

Publication status: Published

Journal: Biochimie

Year: 2021

Volume: 183

Pages: 35-43

Print publication date: 01/04/2021

Online publication date: 10/07/2020

Acceptance date: 30/06/2020

ISSN (print): 0300-9084

ISSN (electronic): 1638-6183

Publisher: Elsevier Masson

URL: https://doi.org/10.1016/j.biochi.2020.06.014

DOI: 10.1016/j.biochi.2020.06.014

PubMed id: 32659443

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