Abstract
Inosine 5'-monophosphate dehydrogenase (IMPDH) represents a potential antimicrobial drug target. The crystal structure of recombinant Pseudomonas aeruginosa IMPDH has been determined to a resolution of 2.25 Å. The structure is a homotetramer of subunits dominated by a (β/α)8-barrel fold, consistent with other known structures of IMPDH. Also in common with previous work, the cystathionine β-synthase domains, residues 92-204, are not present in the model owing to disorder. However, unlike the majority of available structures, clearly defined electron density exists for a loop that creates part of the active site. This loop, composed of residues 297-315, links α8 and β9 and carries the catalytic Cys304. P. aeruginosa IMPDH shares a high level of sequence identity with bacterial and protozoan homologues, with residues involved in binding substrate and the NAD+ cofactor being conserved. Specific differences that have been proven to contribute to selectivity against the human enzyme in a study of Cryptosporidium parvum IMPDH are also conserved, highlighting the potential value of IMPDH as a drug target.
Highlights
Inosine 50-monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) catalyzes the first committed reaction in de novo guanine-nucleotide biosynthesis
Guanine nucleotides are essential for signal transduction and DNA/RNA synthesis and IMPDH plays a pivotal role in the growth and proliferation of both prokaryotic and eukaryotic cells (Hedstrom, 2009)
Recombinant PaIMPDH was produced in E. coli BL21 (DE3) pLysS cells (Stratagene) at 310 K in LB medium supplemented with 100 mg mlÀ1 ampicillin
Summary
Inosine 50-monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) catalyzes the first committed reaction in de novo guanine-nucleotide biosynthesis This enzyme converts inosine 50-monophosphate (IMP) to xanthosine 50-monophosphate (XMP), which can be converted to guanosine 50-monophosphate (GMP) by GMP synthetase. Progress has been made in developing highly potent inhibitors of the enzyme from C. parvum, which display antiparasitic efficacy against Toxoplasma gondii (Gorla et al, 2012). These researchers have addressed the issue of selectivity over the human homologue and a selectivity of greater than 1000-fold has been attained for the microbial enzymes. Comparisons with the structures of the enzyme from C. parvum (CpIMPDH) and Homo sapiens suggests that it may be possible to selectively inhibit the bacterial IMPDH over that of the host
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