1. Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA
3. These authors contributed equally to this work.

Correspondence to: Christopher T. Walsh²Graham C. Walker¹ Correspondence and requests for materials should be addressed to G.C.W. (Email: gwalker@mit.edu) or C.T.W. (Email: christopher_walsh@hms.harvard.edu).

Vitamin B₁₂ (cobalamin) is among the largest known non-polymeric natural products, and the only vitamin synthesized exclusively by microorganisms¹. The biosynthesis of the lower ligand of vitamin B₁₂, 5,6-dimethylbenzimidazole (DMB), is poorly understood^{1, 2, 3}. Recently, we discovered that a Sinorhizobium meliloti gene, bluB, is necessary for DMB biosynthesis⁴. Here we show that BluB triggers the unprecedented fragmentation and contraction of the bound flavin mononucleotide cofactor and cleavage of the ribityl tail to form DMB and d-erythrose 4-phosphate. Our structural analysis shows that BluB resembles an NAD(P)H-flavin oxidoreductase, except that its unusually tight binding pocket accommodates flavin mononucleotide but not NAD(P)H. We characterize crystallographically an early intermediate along the reaction coordinate, revealing molecular oxygen poised over reduced flavin. Thus, BluB isolates and directs reduced flavin to activate molecular oxygen for its own cannibalization. This investigation of the biosynthesis of DMB provides clarification of an aspect of vitamin B₁₂ that was otherwise incomplete, and may contribute to a better understanding of vitamin B₁₂-related disease.

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