Taxonomic distribution of proteins containing IMPDH domains

The IMPDH domain within your query sequence starts at position 28 and ends at position 504, and its E-value is 7.39e-260.

Characteristics and crystal structure of bacterial inosine-5'-monophosphatedehydrogenase.

Zhang R, Evans G, Rotella FJ, Westbrook EM, Beno D, Huberman E, Joachimiak A, Collart FR
Biochemistry. 1999; 38: 4691-700

IMP dehydrogenase (IMPDH) is an essential enzyme that catalyzes the first stepunique to GTP synthesis. To provide a basis for the evaluation of IMPDHinhibitors as antimicrobial agents, we have expressed and characterized IMPDHfrom the pathogenic bacterium Streptococcus pyogenes. Our results show that thebiochemical and kinetic characteristics of S. pyogenes IMPDH are similar to otherbacterial IMPDH enzymes. However, the lack of sensitivity to mycophenolic acidand the Km for NAD (1180 microM) exemplify some of the differences between thebacterial and mammalian IMPDH enzymes, making it an attractive target forantimicrobial agents. To evaluate the basis for these differences, we determined the crystal structure of the bacterial enzyme at 1.9 A with substrate bound inthe catalytic site. The structure was determined usingselenomethionine-substituted protein and multiwavelength anomalous (MAD) analysisof data obtained with synchrotron radiation from the undulator beamline (19ID) ofthe Structural Biology Center at Argonne's Advanced Photon Source. S. pyogenesIMPDH is a tetramer with its four subunits related by a crystallographic 4-foldaxis. The protein is composed of two domains: a TIM barrel domain that embodiesthe catalytic framework and a cystathione beta-synthase (CBS) dimer domain of so far unknown function. Using information provided by sequence alignments and thecrystal structure, we prepared several site-specific mutants to examine the role of various active site regions in catalysis. These variants implicate the active site flap as an essential catalytic element and indicate there are significantdifferences in the catalytic environment of bacterial and mammalian IMPDHenzymes. Comparison of the structure of bacterial IMPDH with the known partialstructures from eukaryotic organisms will provide an explanation of theirdistinct properties and contribute to the design of specific bacterial IMPDHinhibitors.

Crystal structure of Tritrichomonas foetus inosine-5'-monophosphate dehydrogenaseand the enzyme-product complex.

Whitby FG, Luecke H, Kuhn P, Somoza JR, Huete-Perez JA, Phillips JD, Hill CP, Fletterick RJ, Wang CC
Biochemistry. 1997; 36: 10666-74

Inosine-5'-monophosphate dehydrogenase (IMPDH) is an attractive drug target forthe control of parasitic infections. The enzyme catalyzes the oxidation ofinosine monophosphate (IMP) to xanthosine monophosphate (XMP), the committed stepin de novo guanosine monophosphate (GMP) biosynthesis. We have determined thecrystal structures of IMPDH from the protozoan parasite Tritrichomonas foetus in the apo form at 2.3 A resolution and the enzyme-XMP complex at 2.6 A resolution. Each monomer of this tetrameric enzyme is comprised of two domains, the largestof which includes an eight-stranded parallel beta/alpha-barrel that contains the enzyme active site at the C termini of the barrel beta-strands. A second domain, comprised of residues 102-220, is disordered in the crystal. IMPDH is expected tobe active as a tetramer, since the active site cavity is formed by strands fromadjacent subunits. An intrasubunit disulfide bond, seen in the crystal structure,may stabilize the protein in a less active form, as high concentrations ofreducing agent have been shown to increase enzyme activity. Disorder at theactive site suggests that a high degree of flexibility may be inherent in thecatalytic function of IMPDH. Unlike IMPDH from other species, the T. foetusenzyme has a single arginine that is largely responsible for coordinating thesubstrate phosphate in the active site. This structural uniqueness may facilitatestructure-based identification and design of compounds that specifically inhibit the parasite enzyme.