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Although\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      retains nearly all cobalamin (Cbl) biosynthetic genes and encodes multiple cobamide-requiring enzymes, experimental evidence indicates that\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      is incapable of\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      , including: (i) the progressive erosion of\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      cobamide biosynthetic capacity across\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      , virulence, and survival in the host environment, despite apparent loss of\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      -host interface for innovative therapeutic interventions.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jb.00204-25","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T14:00:49Z","timestamp":1762869649000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Cobamide metabolism, regulation, and adaptation in\n                    <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1128","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5466-1726","authenticated-orcid":true,"given":"Terry","family":"Kipkorir","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00a0jsq62","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infection Biology, The London School of Hygiene and Tropical Medicine","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3507-5857","authenticated-orcid":true,"given":"Rendani D.","family":"Mbau","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05bk57929","id-type":"ROR","asserted-by":"publisher"}],"name":"SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4146-0930","authenticated-orcid":true,"given":"Digby F.","family":"Warner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Molecular Mycobacteriology Research Unit, Division of Medical Microbiology, Department of Pathology, University of Cape Town","place":["Cape Town, South Africa"]},{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Infectious Disease and Molecular Medicine, University of Cape Town","place":["Cape Town, South Africa"]},{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Wellcome Discovery Research Platform for Infection, CIDRI-Africa, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0617-6897","authenticated-orcid":true,"given":"Gopinath","family":"Krishnamoorthy","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01hcx6992","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9012-3634","authenticated-orcid":true,"given":"Atica","family":"Moosa","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Molecular Mycobacteriology Research Unit, Division of Medical Microbiology, Department of Pathology, University of Cape Town","place":["Cape Town, South Africa"]},{"id":[{"id":"https:\/\/ror.org\/03p74gp79","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Infectious Disease and Molecular Medicine, University of Cape Town","place":["Cape Town, South Africa"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/ecosalplus.3.6.3.8"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00253-001-0902-7"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1039\/b108967f"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1006\/bioo.1998.1125"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST0330806"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2008.11.005"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12934-017-0631-y"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41396-018-0304-9"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-10-78"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/advances\/nmac030"},{"key":"e_1_3_2_12_2","first-page":"309","volume-title":"In Methods in Enzymology","author":"Mascarenhas R","year":"2022","unstructured":"Mascarenhas R, Gouda H, Ruetz M, Banerjee R. 2022. 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