5vxo

Crystal Structure Analysis of human CLYBL in complex with propionyl-CoA

spinqualitylabelsall models 5vxo, resolution 2.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5vxo is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1VU, EDO, PEG, PG4, PGE, PO4 Related: 5vxc Gene: CLYBL, CLB (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CLYBL_HUMAN] Mitochondrial malate and beta-methylmalate synthase, which may be involved in vitamin B12 metabolism (Probable). Acts both as a malate synthase, converting glyoxylate and acetyl-CoA to malate. Also acts as a beta-methylmalate synthase by mediating conversion of glyoxylate and propionyl-CoA to beta-methylmalate (PubMed:24334609). Publication Abstract from PubMed 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 B12 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 B12 metabolism and that itaconyl-CoA is a cofactor-inactivating, substrate-analog inhibitor of the mitochondrial B12-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 B12 inactivation. The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12.,Shen H, Campanello GC, Flicker D, Grabarek Z, Hu J, Luo C, Banerjee R, Mootha VK Cell. 2017 Nov 2;171(4):771-782.e11. doi: 10.1016/j.cell.2017.09.051. Epub 2017, Oct 19. PMID:29056341 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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