3mo7 | pdb_00003mo7

Crystal structure of human orotidine 5'-monophosphate decarboxylase covalently modified by 2'-fluoro-6-iodo-UMP

spinqualitylabelsall models 3mo7, resolution 1.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3mo7 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, UFT Related: 2eaw, 2p1f, 3bgg, 3bgj, 3g3d, 3bko Gene: gi|13960142, OK/SW-cl.21, UMPS (HUMAN) Activity: Orotidine-5'-phosphate decarboxylase, with EC number 4.1.1.23 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [UMPS_HUMAN] Defects in UMPS are the cause of orotic aciduria type 1 (ORAC1) [MIM:258900]. A disorder of pyrimidine metabolism resulting in megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. A minority of cases have additional features, particularly congenital malformations and immune deficiencies. Publication Abstract from PubMed Fluorinated nucleosides and nucleotides are of considerable interest to medicinal chemists because of their antiviral, anticancer, and other biological activities. However, their direct interactions at target binding sites are not well understood. A new class of 2'-deoxy-2'-fluoro-C6-substituted uridine and UMP derivatives were synthesized and evaluated as inhibitors of orotidine 5'-monophosphate decarboxylase (ODCase or OMPDCase). These compounds were synthesized from the key intermediate, fully protected 2'-deoxy-2'-fluorouridine. Among the synthesized compounds, 2'-deoxy-2'-fluoro-6-iodo-UMP covalently inhibited human ODCase with a second-order rate constant of 0.62 +/- 0.02 M(-1) s(-1). Interestingly, the 6-cyano-2'-fluoro derivative covalently interacted with ODCase defying the conventional thinking, where its ribosyl derivative undergoes transformation into BMP by ODCase. This confirms that the 2'-fluoro moiety influences the chemistry at the C6 position of the nucleotides and thus interactions in the active site of ODCase. Molecular interactions of the 2'-fluorinated nucleotides are compared to those with the 3'-fluorinated nucleotides bound to the corresponding target enzyme, and the carbohydrate moieties were shown to bind in different conformations. Novel Interactions of Fluorinated Nucleotide Derivatives Targeting Orotidine 5'-Monophosphate Decarboxylase.,Lewis M, Meza-Avina ME, Wei L, Crandall IE, Bello AM, Poduch E, Liu Y, Paige CJ, Kain KC, Pai EF, Kotra LP J Med Chem. 2011 Mar 21. PMID:21417464 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphoribosyltransferase 3D structures Uridine 5'-monophosphate synthase 3D structures

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