Enzymes
UniProtKB help_outline | 3 proteins |
Reaction participants Show >> << Hide
- Name help_outline (3S)-citramalyl-CoA Identifier CHEBI:58668 Charge -5 Formula C26H37N7O20P3S InChIKeyhelp_outline XYGOWHUIVNMEIA-XBVYHAPZSA-I SMILEShelp_outline CC(C)(COP([O-])(=O)OP([O-])(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1OP([O-])([O-])=O)n1cnc2c(N)ncnc12)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@](C)(O)C([O-])=O 2D coordinates Mol file for the small molecule Search links Involved in 5 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline itaconyl-CoA Identifier CHEBI:57381 Charge -5 Formula C26H35N7O19P3S InChIKeyhelp_outline NFVGYLGSSJPRKW-CITAKDKDSA-I SMILEShelp_outline CC(C)(COP([O-])(=O)OP([O-])(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1OP([O-])([O-])=O)n1cnc2c(N)ncnc12)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(=C)C([O-])=O 2D coordinates Mol file for the small molecule Search links Involved in 2 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H2O Identifier CHEBI:15377 (CAS: 7732-18-5) help_outline Charge 0 Formula H2O InChIKeyhelp_outline XLYOFNOQVPJJNP-UHFFFAOYSA-N SMILEShelp_outline [H]O[H] 2D coordinates Mol file for the small molecule Search links Involved in 6,264 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
Cross-references
RHEA:13785 | RHEA:13786 | RHEA:13787 | RHEA:13788 | |
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Reaction direction help_outline | undefined | left-to-right | right-to-left | bidirectional |
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Publications
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An essential bifunctional enzyme in <i>Mycobacterium tuberculosis</i> for itaconate dissimilation and leucine catabolism.
Wang H., Fedorov A.A., Fedorov E.V., Hunt D.M., Rodgers A., Douglas H.L., Garza-Garcia A., Bonanno J.B., Almo S.C., de Carvalho L.P.S.
<i>Mycobacterium tuberculosis</i> (Mtb) is the etiological agent of tuberculosis. One-fourth of the global population is estimated to be infected with Mtb, accounting for ∼1.3 million deaths in 2017. As part of the immune response to Mtb infection, macrophages produce metabolites with the purpose ... >> More
<i>Mycobacterium tuberculosis</i> (Mtb) is the etiological agent of tuberculosis. One-fourth of the global population is estimated to be infected with Mtb, accounting for ∼1.3 million deaths in 2017. As part of the immune response to Mtb infection, macrophages produce metabolites with the purpose of inhibiting or killing the bacterial cell. Itaconate is an abundant host metabolite thought to be both an antimicrobial agent and a modulator of the host inflammatory response. However, the exact mode of action of itaconate remains unclear. Here, we show that Mtb has an itaconate dissimilation pathway and that the last enzyme in this pathway, Rv2498c, also participates in l-leucine catabolism. Our results from phylogenetic analysis, in vitro enzymatic assays, X-ray crystallography, and in vivo Mtb experiments, identified Mtb Rv2498c as a bifunctional β-hydroxyacyl-CoA lyase and that deletion of the <i>rv2498c</i> gene from the Mtb genome resulted in attenuation in a mouse infection model. Altogether, this report describes an itaconate resistance mechanism in Mtb and an l-leucine catabolic pathway that proceeds via an unprecedented (<i>R</i>)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) stereospecific route in nature. << Less
Proc Natl Acad Sci U S A 116:15907-15913(2019) [PubMed] [EuropePMC]
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The pathway of itaconate metabolism by liver mitochondria.
Wang S.F., Adler J., Lardy H.A.
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The human knockout gene CLYBL connects itaconate to vitamin B12.
Shen H., Campanello G.C., Flicker D., Grabarek Z., Hu J., Luo C., Banerjee R., Mootha V.K.
CLYBL encodes a ubiquitously expressed mitochondrial enzyme, conserved across all vertebrates, whose cellular activity and pathway assignment are unknown. Its homozygous loss is tolerated in seemingly healthy individuals, with reduced circulating B<sub>12</sub> levels being the only and consistent ... >> More
CLYBL encodes a ubiquitously expressed mitochondrial enzyme, conserved across all vertebrates, whose cellular activity and pathway assignment are unknown. Its homozygous loss is tolerated in seemingly healthy individuals, with reduced circulating B<sub>12</sub> levels being the only and consistent phenotype reported to date. Here, by combining enzymology, structural biology, and activity-based metabolomics, we report that CLYBL operates as a citramalyl-CoA lyase in mammalian cells. Cells lacking CLYBL accumulate citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that includes itaconate, a recently identified human anti-microbial metabolite and immunomodulator. We report that CLYBL loss leads to a cell-autonomous defect in the mitochondrial B<sub>12</sub> metabolism and that itaconyl-CoA is a cofactor-inactivating, substrate-analog inhibitor of the mitochondrial B<sub>12</sub>-dependent methylmalonyl-CoA mutase (MUT). Our work de-orphans the function of human CLYBL and reveals that a consequence of exposure to the immunomodulatory metabolite itaconate is B<sub>12</sub> inactivation. << Less
Cell 171:771-782(2017) [PubMed] [EuropePMC]
This publication is cited by 2 other entries.