6ufp | pdb_00006ufp

Structure of proline utilization A with the FAD covalently modified by L-thiazolidine-2-carboxylate and three cysteines (Cys46, Cys470, Cys638) modified to S,S-(2-HYDROXYETHYL)THIOCYSTEINE

spinqualitylabelsall models 6ufp, resolution 1.74Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ufp is a 2 chain structure with sequence from Sinorhizobium meliloti SM11. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.737Å Ligands: CME, FDA, FMT, NAD, PEG, SO4, T2C Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function F7X6I3_SINMM Oxidizes proline to glutamate for use as a carbon and nitrogen source.[PIRNR:PIRNR000197] Publication Abstract from PubMed Proline dehydrogenase (PRODH) catalyzes the first step of proline catabolism, the FAD-dependent 2-electron oxidation of L-proline to 1-pyrroline-5-carboxylate. PRODH has emerged as a possible cancer therapy target, and thus the inhibition of PRODH is of interest. Here we show that the proline analog thiazolidine-2-carboxylate (T2C) is a mechanism-based inactivator of PRODH. Structures of the bifunctional proline catabol-ic enzyme proline utilization A (PutA) determined from crystals grown in the presence of T2C feature strong electron density for a 5-membered ring species resembling L-T2C covalently bound to the N5 of the FAD in the PRODH domain. The modified FAD exhibits a large butterfly bend angle, indicating that the FAD is locked into the 2-electron reduced state. Reduction of the FAD is consistent with the crystals lacking the distinctive yellow color of the oxidized enzyme and stopped-flow kinetic data showing that T2C is a sub-strate for the PRODH domain of PutA. A mechanism is proposed in which PRODH catalyzes the oxidation of T2C at the C atom adjacent to the S atom of the thiazolidine ring (C5). Then, the N5 atom of the reduced FAD attacks the C5 of the oxidized T2C species, resulting in the covalent adduct observed in the crystal structure. To our knowledge, this is the first report of T2C inactivating (or inhibiting) PRODH or any other flavoenzyme. These results may inform the design of new mechanism-based inactivators of PRODH for use as chemical probes to study the roles of proline metabolism in cancer. Covalent Modification of the Flavin in Proline Dehydrogenase by Thiazolidine-2-Carboxylate.,Campbell AC, Becker DF, Gates KS, Tanner JJ ACS Chem Biol. 2020 Mar 11. doi: 10.1021/acschembio.9b00935. PMID:32159324 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Proline utilization A

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