Cloning, Sequencing, and Structural Analysis of the DNA Encoding Inosine Monophosphate Dehydrogenase (EC 1.1.1.205) from Tritrichomonas foetus

Beck, Joanne T.; Zhao, Sheng; Wang, C. C.

doi:10.1006/expr.1994.1010

Cited by 20 publications

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“…Specific inhibitors of IMP dehydrogenase, e.g., MPA, have been of therapeutic importance as drugs with antiviral and antitumor activities (53) and have been discussed as potential chemotherapeutic agents for protozoan infections (5). Resistance to MPA in some kinetoplastid protozoans involves interesting mechanisms of chromosomal and extrachromosomal IMP dehydrogenase gene amplification (56,57).…”

Section: Discussionmentioning

confidence: 99%

“…This conversion of IMP to XMP is the rate-limiting step in the biosynthetic pathway of guanine nucleotides, at least in mammals (26). While genes encoding IMP dehydrogenases have been isolated from archaea (11), protozoa (5,54,55), bacteria (2,3,16,31,36,47,49), plants (12), invertebrates (46), and mammals (10,13,39,50), the only fungal sequences known are those encoding the putative IMP dehydrogenase genes sequenced in the Saccharomyces cerevisiae genome project (14,27,28). The polymorphic fungus Candida albicans is an opportunistic pathogen in immunocompromised individuals, causing oral and vaginal candidiasis as well as disseminated infections in neutropenic patients.…”

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Overexpression of a cloned IMP dehydrogenase gene of Candida albicans confers resistance to the specific inhibitor mycophenolic acid

1997

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An IMP dehydrogenase gene was isolated from Candida albicans on a ϳ2.9-kb XbaI genomic DNA fragment. The putative Candida IMP dehydrogenase gene (IMH3) encodes a protein of 521 amino acids with extensive sequence similarity to the IMP dehydrogenases of Saccharomyces cerevisiae and various other organisms. Like the S. cerevisiae IMH3 sequence characterized in the genome sequencing project, the open reading frame of the C. albicans IMH3 gene is interrupted by a small intron (248 bp) with typical exon-intron boundaries and a consensus S. cerevisiae branchpoint sequence. IMP dehydrogenase mRNAs are detected in both the yeast and hyphal forms of C. albicans as judged by Northern hybridization. Growth of wild-type (sensitive) C. albicans cells is inhibited at 1 g of mycophenolic acid (MPA), a specific inhibitor of IMP dehydrogenases, per ml, whereas transformants hosting a plasmid with the IMH3 gene are resistant to MPA levels of up to at least 40 g/ml. The resistance of cells to MPA is gene dosage dependent and suggests that IMH3 can be used as a dominant selection marker in C. albicans.IMP dehydrogenase (EC 1.1.1.205) is the key enzyme in the de novo biosynthesis of GMP, catalyzing the NAD-dependent oxidation of IMP to XMP. This conversion of IMP to XMP is the rate-limiting step in the biosynthetic pathway of guanine nucleotides, at least in mammals (26). While genes encoding IMP dehydrogenases have been isolated from archaea (11), protozoa (5, 54, 55), bacteria (2,3,16,31,36,47,49), plants (12), invertebrates (46), and mammals (10, 13, 39, 50), the only fungal sequences known are those encoding the putative IMP dehydrogenase genes sequenced in the Saccharomyces cerevisiae genome project (14,27,28). The polymorphic fungus Candida albicans is an opportunistic pathogen in immunocompromised individuals, causing oral and vaginal candidiasis as well as disseminated infections in neutropenic patients. Genetic manipulations of this diploid microorganism have been hampered by the apparent absence of a haploid phase and the dependence of marker systems on the spontaneous occurrence of auxotrophic mutants. Thus, the identification of the IMH3 gene in C. albicans suggested to us that mycophenolic acid (MPA), a specific inhibitor of IMP dehydrogenases, might be used to develop a dominant selectable marker system in Candida. In several other organisms, it has been shown that amplification of an IMP dehydrogenase gene can confer MPA resistance in a gene-dosage-dependent manner by overexpression of the enzyme (9,20,23,25,54). We report the cloning and sequencing of a DNA fragment of C. albicans with a coding region for a protein with high amino acid similarity and identity to known IMP dehydrogenases. Transformation of C.albicans by using a multicopy plasmid vector yielded transformants resistant to the specific IMP dehydrogenase inhibitor MPA. Culturing of transformant cells in the presence of MPA stabilized replicative plasmids, suggesting the feasibility of using IMH3 as a dominant selection marker for genetic studies in C. alb...

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Section: Discussionmentioning

confidence: 99%

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Overexpression of a cloned IMP dehydrogenase gene of Candida albicans confers resistance to the specific inhibitor mycophenolic acid

1997

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“…1 As one of the purine salvage enzymes, GMPR catalyzes the irreversible reductive deamination of GMP to IMP (GMPCNADPHC H C /IMPCNH 3 CNADP C ) and participates in the re-utilization of free intracellular bases and purine nucleosides. 2 The GMP reductases exist in various organisms including Tritrichomonas foetus, 3 Escherichia coli, 4 Bos taurus, 5 and Homo Sapiens; 6 the amino acid sequence is similar across species. In humans, two isoenzymes of GMP reductase have been identified: hGMPR1 and hGMPR2.…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure of Human Guanosine Monophosphate Reductase 2 (GMPR2) in Complex with GMP

Wei

Zheng

et al. 2006

Journal of Molecular Biology

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“…As detailed in the introduction, the transfer of Cryptosporidium IMPDH is well documented and supported by phylogenetic as well as biochemical data [359,360]. Like the enzymes of eubacteria, Cryptosporidium and the kinetoplastid IMPDH P , Tritrichomonas foetus IMPDH it is quite resistant to mycophenolic acid and its similarity to bacterial IMPDH had been noticed earlier [379]. Our searches failed to detect an IMPDH gene in the genome of the related parasite Trichomonas vaginalis, though biochemical studies suggested the presence of this enzyme [380].…”

Section: Discussionmentioning

confidence: 78%

The early evolution of meiotic genes

Malik¹

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Thesis Supervisor: Associate Professor John M. Logsdon Jr.Meiosis is a hallmark of eukaryotes. However, to demonstrate that homologous sexual processes are pan-eukaryotic, it is necessary to compare the molecular machinery of meiotic recombination across diverse eukaryotic groups, especially protists. The homologs of 34 meiotic genes encoding components of the meiotic recombination machinery, sister chromatid cohesion and synaptonemal complexes were identified in the genomes of diverse eukaryotes and verified by phylogenetic analyses. Twelve of these genes function only in meiosis in model organisms Hop1, Hop2, Mnd1, Dmc1, Msh4, Msh5, Mer3, Zip1, Zip4 and Rec8). Homologs of meiosis-specific genes were identified in several organisms previously considered to be asexual, indicating that they are derived from sexual lineages, and may have as-yet-unobserved meiosis. The putatively early-diverged protists Trichomonas and Giardia have orthologs of eight and six of the meiosis-specific genes, respectively. Using degenerate PCR, additional meiosis-specific genes were identified in Naegleria, Acanthamoeba, Amphidinium and other protists. All of the meiotic genes are conserved in animals, fungi and plants; most of the meiotic genes (including the meiosis-specific genes) are also broadly conserved among protist lineages. These data indicate that the molecular machinery for meiotic recombination evolved once, early during eukaryotic evolution, prior to the divergence of major eukaryotic lineages. Thus, the eukaryotic cenancestor likely had each component of this "meiosis detection toolkit". Many of the 34 meiotic genes -including ten meiosis-specific genes -evolved by gene duplications early during eukaryotic evolution, revealing that gene duplication has been a pervasive evolutionary force in the evolution of the meiotic machinery. Abstract Approved: ____________________________________ Thesis Supervisor ____________________________________ ii To my grandmothers, Bano-bai Mazher Master binte Imran-bhai Shamsi and the late Zainab-bai Gulamali Malik binte Noman-bhai Rangwala, and to my mother, Nafisa Hatim Malik binte Mazher-bhai Master. iii ACKNOWLEDGMENTS I would like to express my gratitude towards the many people who contributed towards my growth as a scientist while I have pursued this degree, from Emory University to the University of Iowa. First and foremost, I would like to thank my thesis advisor, John Logsdon, for his time, advice, many discussions, and for giving me the opportunity to work with him on the projects culminating in this thesis. I also feel fortunate that John has sent me to present my work at a conference almost every year, and really helped me to network with other scientists. I am grateful to my other thesis advisory committee members, Bryant McAllister, Bob Malone, Debashish Bhattacharya and Chris Brochu, for their time, constructive criticism and helpful advice. I am indebted to Mark Farmer and David Patterson for illustrative discussions about protists. I am thankful to Chris Beck, Sonia Altiz...

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Cloning, Sequencing, and Structural Analysis of the DNA Encoding Inosine Monophosphate Dehydrogenase (EC 1.1.1.205) from Tritrichomonas foetus

Cited by 20 publications

References 0 publications

Overexpression of a cloned IMP dehydrogenase gene of Candida albicans confers resistance to the specific inhibitor mycophenolic acid

Overexpression of a cloned IMP dehydrogenase gene of Candida albicans confers resistance to the specific inhibitor mycophenolic acid

Crystal Structure of Human Guanosine Monophosphate Reductase 2 (GMPR2) in Complex with GMP

The early evolution of meiotic genes

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