Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Cobalamin, commonly known as vitamin B<sub>12</sub>, 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<sub>12</sub>-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<sub>d</sub>), binding kinetics (k<sub>on</sub>), and concentration dependence during catalysis (K<sub>M, app</sub>). 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.

Original publication

DOI

10.1016/j.biochi.2020.06.014

Type

Journal article

Journal

Biochimie

Publication Date

10/07/2020

Addresses

Department of Plant & Microbial Biology, University of California, Berkeley, CA, USA; Department of Chemistry, University of California, Berkeley, CA, USA.