Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 34, Pages 10792-10797Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1509132112
Keywords
vitamin B-12; cobalamin; cobamide; 5,6-dimethylbenzimidazole; biosynthesis
Categories
Funding
- National Science Foundation [MCB1122046]
- Hellman Family Faculty Fund award
- Robert A. Welch Foundation [A-0034]
- Direct For Biological Sciences [1122046] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience [1122046] Funding Source: National Science Foundation
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Vitamin B-12 (cobalamin) is required by humans and other organisms for diverse metabolic processes, although only a subset of prokaryotes is capable of synthesizing B-12 and other cobamide cofactors. The complete aerobic and anaerobic pathways for the de novo biosynthesis of B-12 are known, with the exception of the steps leading to the anaerobic biosynthesis of the lower ligand, 5,6-dimethylbenzimidazole (DMB). Here, we report the identification and characterization of the complete pathway for anaerobic DMB biosynthesis. This pathway, identified in the obligate anaerobic bacterium Eubacterium limosum, is composed of five previously uncharacterized genes, bzaABCDE, that together direct DMB production when expressed in anaerobically cultured Escherichia coli. Expression of different combinations of the bza genes revealed that 5-hydroxybenzimidazole, 5-methoxybenzimidazole, and 5-methoxy-6-methylbenzimidazole, all of which are lower ligands of cobamides produced by other organisms, are intermediates in the pathway. The bza gene content of several bacterial and archaeal genomes is consistent with experimentally determined structures of the benzimidazoles produced by these organisms, indicating that these genes can be used to predict cobamide structure. The identification of the bza genes thus represents the last remaining unknown component of the biosynthetic pathway for not only B-12 itself, but also for three other cobamide lower ligands whose biosynthesis was previously unknown. Given the importance of cobamides in environmental, industrial, and human-associated microbial metabolism, the ability to predict cobamide structure may lead to an improved ability to understand and manipulate microbial metabolism.
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