Cofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme

ABSTRACT Cobamides, a uniquely diverse family of enzyme cofactors related to vitamin B12, are produced exclusively by bacteria and archaea but used in all domains of life. While it is widely accepted that cobamide-dependent organisms require specific cobamides for their metabolism, the biochemical m...

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Autores principales:	Olga M. Sokolovskaya, Kenny C. Mok, Jong Duk Park, Jennifer L. A. Tran, Kathryn A. Quanstrom, Michiko E. Taga
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Sinorhizobium meliloti chemical diversity cobalamin cobamides enzyme selectivity Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/674954d760e44c9289ab047d2dccba1c
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spelling	oai:doaj.org-article:674954d760e44c9289ab047d2dccba1c2021-11-15T15:59:41ZCofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme10.1128/mBio.01303-192150-7511https://doaj.org/article/674954d760e44c9289ab047d2dccba1c2019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01303-19https://doaj.org/toc/2150-7511ABSTRACT Cobamides, a uniquely diverse family of enzyme cofactors related to vitamin B12, are produced exclusively by bacteria and archaea but used in all domains of life. While it is widely accepted that cobamide-dependent organisms require specific cobamides for their metabolism, the biochemical mechanisms that make cobamides functionally distinct are largely unknown. Here, we examine the effects of cobamide structural variation on a model cobamide-dependent enzyme, methylmalonyl coenzyme A (CoA) mutase (MCM). The in vitro binding affinity of MCM for cobamides can be dramatically influenced by small changes in the structure of the lower ligand of the cobamide, and binding selectivity differs between bacterial orthologs of MCM. In contrast, variations in the lower ligand have minor effects on MCM catalysis. Bacterial growth assays demonstrate that cobamide requirements of MCM in vitro largely correlate with in vivo cobamide dependence. This result underscores the importance of enzyme selectivity in the cobamide-dependent physiology of bacteria. IMPORTANCE Cobamides, including vitamin B12, are enzyme cofactors used by organisms in all domains of life. Cobamides are structurally diverse, and microbial growth and metabolism vary based on cobamide structure. Understanding cobamide preference in microorganisms is important given that cobamides are widely used and appear to mediate microbial interactions in host-associated and aquatic environments. Until now, the biochemical basis for cobamide preferences was largely unknown. In this study, we analyzed the effects of the structural diversity of cobamides on a model cobamide-dependent enzyme, methylmalonyl-CoA mutase (MCM). We found that very small changes in cobamide structure could dramatically affect the binding affinity of cobamides to MCM. Strikingly, cobamide-dependent growth of a model bacterium, Sinorhizobium meliloti, largely correlated with the cofactor binding selectivity of S. meliloti MCM, emphasizing the importance of cobamide-dependent enzyme selectivity in bacterial growth and cobamide-mediated microbial interactions.Olga M. SokolovskayaKenny C. MokJong Duk ParkJennifer L. A. TranKathryn A. QuanstromMichiko E. TagaAmerican Society for MicrobiologyarticleSinorhizobium melilotichemical diversitycobalamincobamidesenzyme selectivityMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Sinorhizobium meliloti chemical diversity cobalamin cobamides enzyme selectivity Microbiology QR1-502
spellingShingle	Sinorhizobium meliloti chemical diversity cobalamin cobamides enzyme selectivity Microbiology QR1-502 Olga M. Sokolovskaya Kenny C. Mok Jong Duk Park Jennifer L. A. Tran Kathryn A. Quanstrom Michiko E. Taga Cofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme
description	ABSTRACT Cobamides, a uniquely diverse family of enzyme cofactors related to vitamin B12, are produced exclusively by bacteria and archaea but used in all domains of life. While it is widely accepted that cobamide-dependent organisms require specific cobamides for their metabolism, the biochemical mechanisms that make cobamides functionally distinct are largely unknown. Here, we examine the effects of cobamide structural variation on a model cobamide-dependent enzyme, methylmalonyl coenzyme A (CoA) mutase (MCM). The in vitro binding affinity of MCM for cobamides can be dramatically influenced by small changes in the structure of the lower ligand of the cobamide, and binding selectivity differs between bacterial orthologs of MCM. In contrast, variations in the lower ligand have minor effects on MCM catalysis. Bacterial growth assays demonstrate that cobamide requirements of MCM in vitro largely correlate with in vivo cobamide dependence. This result underscores the importance of enzyme selectivity in the cobamide-dependent physiology of bacteria. IMPORTANCE Cobamides, including vitamin B12, are enzyme cofactors used by organisms in all domains of life. Cobamides are structurally diverse, and microbial growth and metabolism vary based on cobamide structure. Understanding cobamide preference in microorganisms is important given that cobamides are widely used and appear to mediate microbial interactions in host-associated and aquatic environments. Until now, the biochemical basis for cobamide preferences was largely unknown. In this study, we analyzed the effects of the structural diversity of cobamides on a model cobamide-dependent enzyme, methylmalonyl-CoA mutase (MCM). We found that very small changes in cobamide structure could dramatically affect the binding affinity of cobamides to MCM. Strikingly, cobamide-dependent growth of a model bacterium, Sinorhizobium meliloti, largely correlated with the cofactor binding selectivity of S. meliloti MCM, emphasizing the importance of cobamide-dependent enzyme selectivity in bacterial growth and cobamide-mediated microbial interactions.
format	article
author	Olga M. Sokolovskaya Kenny C. Mok Jong Duk Park Jennifer L. A. Tran Kathryn A. Quanstrom Michiko E. Taga
author_facet	Olga M. Sokolovskaya Kenny C. Mok Jong Duk Park Jennifer L. A. Tran Kathryn A. Quanstrom Michiko E. Taga
author_sort	Olga M. Sokolovskaya
title	Cofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme
title_short	Cofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme
title_full	Cofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme
title_fullStr	Cofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme
title_full_unstemmed	Cofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme
title_sort	cofactor selectivity in methylmalonyl coenzyme a mutase, a model cobamide-dependent enzyme
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/674954d760e44c9289ab047d2dccba1c
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Cofactor Selectivity in Methylmalonyl Coenzyme A Mutase, a Model Cobamide-Dependent Enzyme

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