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Nucleotide Biosynthesis (nucleotide + biosynthesis)
Selected AbstractsInosine monophosphate dehydrogenase (IMPDH) as a target in drug discoveryMEDICINAL RESEARCH REVIEWS, Issue 2 2008Qingning Shu Abstract Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme of de novo purine nucleotide biosynthesis and is viewed as an important target in the quest for discovery of drugs in the antiviral, antibacterial and anticancer therapeutic areas. This review focuses on the medicinal chemistry, drug discovery and chemical biology of IMPDH. Examples of IMP and cofactor site-directed inhibitors, allosteric inhibitors and isoform-selective inhibitors are presented. Comparison of IMPDHs from different organisms is also made to facilitate the design of species-selective IMPDH inhibitors for drug discovery. Special emphasis in the review is placed on IMPDH from Mycobacterium tuberculosis. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 2, 219,232, 2008 [source] The CBS subdomain of inosine 5,-monophosphate dehydrogenase regulates purine nucleotide turnoverMOLECULAR MICROBIOLOGY, Issue 2 2008Maxim Pimkin Summary Inosine 5,-monophosphate dehydrogenase (IMPDH) catalyses the rate-limiting step in guanine nucleotide biosynthesis. IMPDH has an evolutionary conserved CBS subdomain of unknown function. The subdomain can be deleted without impairing the in vitro IMPDH catalytic activity and is the site for mutations associated with human retinitis pigmentosa. A guanine-prototrophic Escherichia coli strain, MP101, was constructed with the subdomain sequence deleted from the chromosomal gene for IMPDH. The ATP content was substantially elevated in MP101 whereas the GTP content was slighty reduced. The activities of IMPDH, adenylosuccinate synthetase and GMP reductase were two to threefold lower in MP101 crude extracts compared with the BW25113 wild-type strain. Guanine induced a threefold reduction in the MP101 ATP pool and a fourfold increase in the GTP pool within 10 min of addition to growing cells; this response does not result from the reduced IMPDH activity or starvation for guanylates. In vivo kinetic analysis using 14-C tracers and 33-P pulse-chasing revealed mutation-associated changes in purine nucleotide fluxes and turnover rates. We conclude that the CBS subdomain of IMPDH may coordinate the activities of the enzymes of purine nucleotide metabolism and is essential for maintaining the normal ATP and GTP pool sizes in E. coli. [source] Identification of protein differences between two clinical isolates of Streptococcus mutans by proteomic analysisMOLECULAR ORAL MICROBIOLOGY, Issue 2 2008L. H. Guo Introduction:,Streptococcus mutans is generally considered to be the principal etiological agent for dental caries. Different strains of S. mutans may display different virulence mechanisms, so the isolation of the differential proteins is illuminating. Methods:,S. mutans strains 9-1 and 9-2, which both colonized the same oral cavity, were selected after screening for the possession of suspected virulence traits. The soluble cellular proteins were extracted from steady-state planktonic cells of strains 9-1 and 9-2 and were analyzed using high-resolution two-dimensional gel electrophoresis. Then, replicate maps of proteins from the two strains were generated. Proteins expressed only in strain 9-1 or 9-2 were excised and digested with trypsin by using an in-gel protocol. Tryptic digests were analyzed using matrix-assisted laser desorption/ionization time of flight mass spectrometry, by which peptide mass fingerprints were generated, and these were used to assign putative functions according to their homology with the translated sequences in the S. mutans genomic database. Results:, There were 12 proteins only expressed in strain 9-1 and three proteins only expressed in strain 9-2. They were involved in protein biosynthesis, protein folding, cell wall biosynthesis, fatty acid biosynthesis, nucleotide biosynthesis, repair of DNA damage, carbohydrate metabolism, signal transduction, and translation. Conclusion:, The identification of proteins differentially expressed between strains 9-1 and 9-2 provides new information concerning the mechanisms of cariogenesis. [source] Structure of Escherichia coli uridine phosphorylase at 2.0,ÅACTA CRYSTALLOGRAPHICA SECTION D, Issue 1 2003F. Temple Burling The 2.0,Å crystal structure has been determined for Escherichia coli uridine phosphorylase (UP), an essential enzyme in nucleotide biosynthesis that catalyzes the phosphorolytic cleavage of the C,N glycosidic bond of uridine to ribose-1-phosphate and uracil. The structure determination of two independent monomers in the asymmetric unit revealed the residue composition and atomic details of the apo configurations of each active site. The native hexameric UP enzyme was revealed by applying threefold crystallographic symmetry to the contents of the asymmetric unit. The 2.0,Å model reveals a closer structural relationship to other nucleotide phosphorylase enzymes than was previously appreciated. [source] Structure of purine nucleoside phosphorylase (DeoD) from Bacillus anthracisACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 5 2005Rosa Grenha Protein structures from the causative agent of anthrax (Bacillus anthracis) are being determined as part of a structural genomics programme. Amongst initial candidates for crystallographic analysis are enzymes involved in nucleotide biosynthesis, since these are recognized as potential targets in antibacterial therapy. Purine nucleoside phosphorylase is a key enzyme in the purine-salvage pathway. The crystal structure of purine nucleoside phosphorylase (DeoD) from B. anthracis has been solved by molecular replacement at 2.24,Å resolution and refined to an R factor of 18.4%. This is the first report of a DeoD structure from a Gram-positive bacterium. [source] | ||||||||||