Novel Interactions of Fluorinated Nucleotide Derivatives Targeting Orotidine 5′-Monophosphate Decarboxylase
نویسندگان
چکیده
منابع مشابه
The crystal structure and mechanism of orotidine 5'-monophosphate decarboxylase.
The crystal structure of Bacillus subtilis orotidine 5'-monophosphate (OMP) decarboxylase with bound uridine 5'-monophosphate has been determined by multiple wavelength anomalous diffraction phasing techniques and refined to an R-factor of 19.3% at 2.4 A resolution. OMP decarboxylase is a dimer of two identical subunits. Each monomer consists of a triosephosphate isomerase barrel and contains a...
متن کاملEnzyme Architecture: Deconstruction of the Enzyme-Activating Phosphodianion Interactions of Orotidine 5′-Monophosphate Decarboxylase
The mechanism for activation of orotidine 5'-monophosphate decarboxylase (OMPDC) by interactions of side chains from Gln215 and Try217 at a gripper loop and R235, adjacent to this loop, with the phosphodianion of OMP was probed by determining the kinetic parameters k(cat) and K(m) for all combinations of single, double, and triple Q215A, Y217F, and R235A mutations. The 12 kcal/mol intrinsic bin...
متن کاملStructural basis for the decarboxylation of orotidine 5'-monophosphate (OMP) by Plasmodium falciparum OMP decarboxylase.
Orotidine 5'-monophoshate decarboxylase (OMPDC) catalyses the decarboxylation of orotidine 5'-monophosphate (OMP) to uridine 5'-monophosphate (UMP). Here, we report the X-ray analysis of apo, substrate or product-complex forms of OMPDC from Plasmodium falciparum (PfOMPDC) at 2.7, 2.65 and 2.65 A, respectively. The structural analysis provides the substrate recognition mechanism with dynamic str...
متن کاملStructural determinants for the inhibitory ligands of orotidine-5'-monophosphate decarboxylase.
In recent years, orotidine-5'-monophosphate decarboxylase (ODCase) has gained renewed attention as a drug target. As a part of continuing efforts to design novel inhibitors of ODCase, we undertook a comprehensive study of potent, structurally diverse ligands of ODCase and analyzed their structural interactions in the active site of ODCase. These ligands comprise of pyrazole or pyrimidine nucleo...
متن کاملCatalysis by enzyme conformational change as illustrated by orotidine 5'-monophosphate decarboxylase.
An energy decomposition scheme has been used to elucidate the importance of the changes of enzyme conformational substates to the reduction of the activation barrier in enzyme-catalyzed reactions. This analysis may be illustrated by the reaction of orotidine 5'-monophosphate decarboxylase, which exhibits a remarkable rate enhancement of over 17 orders of magnitude compared to the uncatalyzed pr...
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ژورنال
عنوان ژورنال: Journal of Medicinal Chemistry
سال: 2011
ISSN: 0022-2623,1520-4804
DOI: 10.1021/jm101642g