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Naturally occurring cobalamin (B$_{12}$) analogs can function as cofactors for human methylmalonyl-CoA mutase


Sokolovskaya, Olga M; Plessl, Tanja; Bailey, Henry; Mackinnon, Sabrina; Baumgartner, Matthias R; Yue, Wyatt W; Froese, D Sean; Taga, Michiko E (2020). Naturally occurring cobalamin (B$_{12}$) analogs can function as cofactors for human methylmalonyl-CoA mutase. Biochimie:Epub ahead of print.

Abstract

Cobalamin, commonly known as vitamin B$_{12}$, 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 B$_{12}$-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.

Abstract

Cobalamin, commonly known as vitamin B$_{12}$, 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 B$_{12}$-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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Biochemistry
Language:English
Date:10 July 2020
Deposited On:06 Nov 2020 10:02
Last Modified:07 Nov 2020 21:00
Publisher:Elsevier
ISSN:0300-9084
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.biochi.2020.06.014
PubMed ID:32659443

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