Cobamides play a paradoxical but critical role in the biology of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Although Mtb retains nearly all cobalamin (Cbl) biosynthetic genes and encodes multiple cobamide-requiring enzymes, experimental evidence indicates that Mtb is incapable of de novo Cbl synthesis under any tested conditions to date. Instead, an evolutionary shift appears to have occurred toward host dependency for biologically relevant cobamides or their precursors. This review highlights recent advances in our understanding of cobamide-related metabolism in Mtb, including: (i) the progressive erosion of de novo cobamide biosynthetic capacity across Mtb lineages; (ii) the role of host-derived cobamides in sustaining key mycobacterial metabolic pathways, including methionine synthesis and propionate catabolism; (iii) the impact of host immune pressures, including itaconate-mediated inhibition of methylmalonyl-CoA mutase; (iv) strategies employed by Mtb for cobamide and precursor acquisition; and (v) unique adaptations of Cbl-sensing riboswitches that regulate methionine synthesis, virulence-associated gene expression, and dormancy resuscitation. We also highlight unresolved questions, including possible niche-specific synthesis, utilization of alternate cobamide species, and the therapeutic potential of targeting cobamide-related metabolism. We review recent evidence of the centrality of cobamides in the metabolic flexibility of Mtb, virulence, and survival in the host environment, despite apparent loss of de novo biosynthetic capacity. Further mechanistic studies are required which may reveal vulnerabilities for the exploitation of cobamide acquisition, cobamide-related regulation, and the role of cobamides at the Mtb-host interface for innovative therapeutic interventions.
Keywords: B12 riboswitch; Vitamin B12; corrinoids; methionine synthase; methylmalonyl-CoA mutase; ribonucleotide reductase.