Priya Manisha, Gupta Sonu Kumar, Koundal Anil, Kapoor Srajan, Tiwari Snigdha, Kidwai Saqib, Sorio de Carvalho Luiz Pedro, Thakur Krishan Gopal, Mahajan Dinesh, Sharma Deepak, Kumar Yashwant, Singh Ramandeep
Centre for Tuberculosis Research, Tuberculosis Research Laboratory, Translational Health Science and Technology Institute, National Capital Region Biotech Science Cluster 3rd Milestone, Faridabad, Haryana 121001, India.
Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India.
Proc Natl Acad Sci U S A. 2025 Jan 28;122(4):e2423114122. doi: 10.1073/pnas.2423114122. Epub 2025 Jan 22.
Itaconate, an abundant metabolite produced by macrophages upon interferon-γ 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 increases itaconate levels in lung tissues. We also show that exposure to itaconate inhibits growth in vitro, in macrophages, and mice. We report that exposure to sodium itaconate (ITA) interferes with the central carbon metabolism of . 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 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 ΔRv3389c strain of was attenuated for growth in itaconate-containing medium, in macrophages, mice, and guinea pigs. The attenuated phenotype of ΔRv3389c strain of 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 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 pathogenesis.
衣康酸是巨噬细胞在γ-干扰素刺激下产生的一种丰富代谢产物，具有抗菌和免疫调节特性。尽管它在免疫和抗菌控制中起着关键作用，但其作用机制和异化过程却知之甚少。在此，我们证明用[具体感染物]感染小鼠会增加肺组织中的衣康酸水平。我们还表明，暴露于衣康酸会在体外、巨噬细胞和小鼠体内抑制[具体病原体]的生长。我们报告称，暴露于衣康酸钠（ITA）会干扰[具体病原体]的中心碳代谢。除了抑制异柠檬酸裂解酶（ICL）外，我们还证明衣康酸以浓度依赖的方式抑制醛缩酶和肌苷单磷酸（IMP）脱氢酶。先前的研究表明，来自[具体病原体]的Rv2498c是真正的（S）-柠康酸辅酶A裂解酶，但该途径的其余成分仍不清楚。在此，我们报告Rv2503c和Rv3272具有衣康酸：琥珀酰辅酶A转移酶活性，而Rv2499c和Rv3389c具有衣康酰辅酶A水合酶活性。相对于亲本菌株和互补菌株，[具体病原体]的ΔRv3389c菌株在含衣康酸的培养基中、巨噬细胞、小鼠和豚鼠体内的生长减弱。[具体病原体]的ΔRv3389c菌株的减弱表型与衣康酸异化和丙酰辅酶A解毒途径中的缺陷有关。因此，本研究揭示了衣康酸在[具体病原体]中靶向多种代谢酶。此外，我们还确定了负责将衣康酸降解为丙酮酸和乙酰辅酶A的另外两种酶。最后，我们还证明了参与衣康酸异化途径的酶对[具体病原体]致病性的重要性。
