{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:39:33Z","timestamp":1792787973231,"version":"4.5.0"},"reference-count":78,"publisher":"National Academy of Sciences","issue":"4","license":[{"start":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T00:00:00Z","timestamp":1737504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001409","name":"Department of Science and Technology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["CRG\/2021\/004042"],"award-info":[{"award-number":["CRG\/2021\/004042"]}],"id":[{"id":"10.13039\/501100001409","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,1,28]]},"abstract":"<jats:p>\n                    Itaconate, an abundant metabolite produced by macrophages upon interferon-\u03b3 stimulation, possesses both antibacterial and immunomodulatory properties. Despite its crucial role in immunity and antimicrobial control, its mechanism of action and dissimilation are poorly understood. Here, we demonstrate that infection of mice with\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    increases itaconate levels in lung tissues. We also show that exposure to itaconate inhibits\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    growth in vitro, in macrophages, and mice. We report that exposure to sodium itaconate (ITA) interferes with the central carbon metabolism of\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    . In addition to the inhibition of isocitrate lyase (ICL), we demonstrate that itaconate inhibits aldolase and inosine monophosphate (IMP) dehydrogenase in a concentration-dependent manner. Previous studies have shown that Rv2498c from\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    is the bona fide (S)-citramalyl-CoA lyase, but the remaining components of the pathway remain elusive. Here, we report that Rv2503c and Rv3272 possess itaconate:succinyl-CoA transferase activity, and Rv2499c and Rv3389c possess itaconyl-CoA hydratase activity. Relative to the parental and complemented strains, the \u0394Rv3389c strain of\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    was attenuated for growth in itaconate-containing medium, in macrophages, mice, and guinea pigs. The attenuated phenotype of \u0394Rv3389c strain of\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    is associated with a defect in the itaconate dissimilation and propionyl-CoA detoxification pathway. This study thus reveals that multiple metabolic enzymes are targeted by itaconate in\n                    <jats:italic>M. tuberculosis.<\/jats:italic>\n                    Furthermore, we have assigned the two remaining enzymes responsible for the degradation of itaconic acid into pyruvate and acetyl-CoA. Finally, we also demonstrate the importance of enzymes involved in the itaconate dissimilation pathway for\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    pathogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2423114122","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T10:54:23Z","timestamp":1737543263000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":24,"title":["Itaconate mechanism of action and dissimilation in\n                    <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1073","volume":"122","author":[{"given":"Manisha","family":"Priya","sequence":"first","affiliation":[{"name":"Centre for Tuberculosis Research, Tuberculosis Research Laboratory, Translational Health Science and Technology Institute, National Capital Region Biotech Science Cluster 3rd Milestone","place":["Faridabad, 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Gopal","family":"Thakur","sequence":"additional","affiliation":[{"name":"Structural Biology Laboratory, Council of Scientific and Industrial Research-Institute of Microbial Technology","place":["Chandigarh, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Mahajan","sequence":"additional","affiliation":[{"name":"Centre for Tuberculosis Research, Tuberculosis Research Laboratory, Translational Health Science and Technology Institute, National Capital Region Biotech Science Cluster 3rd Milestone","place":["Faridabad, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee","place":["Roorkee, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yashwant","family":"Kumar","sequence":"additional","affiliation":[{"name":"Centre for Tuberculosis Research, 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