Cryptosporidium parvum IMP Dehydrogenase

Umejiego, Nwakaso N.; Li, Catherine; Riera, Thomas V.; Hedstrom, Lizbeth; Striepen, Boris

doi:10.1074/jbc.m407121200

Cited by 89 publications

(57 citation statements)

References 44 publications

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“…(5), suggesting that C. parvum obtained its IMPDH gene by horizontal transfer [22, 65]. As expected, the recombinant Cp IMPDH has the high values of K m for IMP and NAD + and resistance to MPA typical of prokaryotic IMPDHs (Table 1 ; [66]).…”

Section: Prokaryotic-specific Impdh Inhibitorsmentioning

confidence: 74%

The Antibiotic Potential of Prokaryotic IMP Dehydrogenase Inhibitors

Hedstrom

Liechti²,

Goldberg³

et al. 2011

CMC

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Inosine 5′-monophosphate dehydrogenase (IMPDH) catalyzes the first committed step of guanosine 5′-monophosphate (GMP) biosynthesis, and thus regulates the guanine nucleotide pool, which in turn governs proliferation. Human IMPDHs are validated targets for immunosuppressive, antiviral and anticancer drugs, but as yet microbial IMPDHs have not been exploited in antimicrobial chemotherapy. Selective inhibitors of IMPDH from Cryptosporidium parvum have recently been discovered that display anti-parasitic activity in cell culture models of infection. X-ray crystal structure and mutagenesis experiments identified the structural features that determine inhibitor susceptibility. These features are found in IMPDHs from a wide variety of pathogenic bacteria, including select agents and multiply drug resistant strains. A second generation inhibitor displays antibacterial activity against Helicobacter pylori, demonstrating the antibiotic potential of IMPDH inhibitors.

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Section: Prokaryotic-specific Impdh Inhibitorsmentioning

confidence: 74%

The Antibiotic Potential of Prokaryotic IMP Dehydrogenase Inhibitors

Hedstrom

Liechti²,

Goldberg³

et al. 2011

CMC

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“…Remarkably, these DPU inhibitors of Mt-GuaB2 have mechanistic and structural precedent in several compounds identified through high-throughput screening of Cryptosporidium parvum IMPDH (Macpherson et al, 2010). Despite the protozoan nature of C. parvum, its IMPDH has long been thought to have been acquired via gene transfer from a bacterial source (Striepen et al, 2002;Umejiego et al, 2004). Observing the structure of C. parvum IMPDH with one of these inhibitors (inhibitor C64, PDB code 3KHJ) reveals a novel interaction with the enzyme, which partially stacks against the purine ring of IMP.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel diphenyl urea inhibitors of Mt-GuaB2 active against Mycobacterium tuberculosis

et al. 2011

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In contrast with most bacteria, which harbour a single inosine monophosphate dehydrogenase (IMPDH) gene, the genomic sequence of Mycobacterium tuberculosis H37Rv predicts three genes encoding IMPDH: guaB1, guaB2 and guaB3. These three genes were cloned and expressed in Escherichia coli to evaluate functional IMPDH activity. Purified recombinant Mt-GuaB2, which uses inosine monophosphate as a substrate, was identified as the only active GuaB orthologue in M. tuberculosis and showed optimal activity at pH 8.5 and 37 6C. Mt-GuaB2 was inhibited significantly in vitro by a panel of diphenyl urea-based derivatives, which were also potent anti-mycobacterial agents against M. tuberculosis and Mycobacterium smegmatis, with MICs in the range of 0.2-0.5 mg ml "1 . When Mt-GuaB2 was overexpressed on a plasmid in trans in M. smegmatis, a diphenyl urea analogue showed a 16-fold increase in MIC. Interestingly, when Mt-GuaB orthologues (Mt-GuaB1 and 3) were also overexpressed on a plasmid in trans in M. smegmatis, they also conferred resistance, suggesting that although these Mt-GuaB orthologues were inactive in vitro, they presumably titrate the effect of the inhibitory properties of the active compounds in vivo.

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“…1). Its enzymatic activity has already been proven in many protozoan parasites (9)(10)(11)(12)(13)(14). The antiprotozoan activities of MPA against Babesia spp.…”

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confidence: 99%

Mycophenolic Acid and Its Derivatives as Potential Chemotherapeutic Agents Targeting Inosine Monophosphate Dehydrogenase in Trypanosoma congolense

Suganuma

Sarwono

Mitsuhashi

et al. 2016

Antimicrob Agents Chemother

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e This study aimed to evaluate the trypanocidal activity of mycophenolic acid (MPA) and its derivatives for Trypanosoma congolense. The proliferation of T. congolense was completely inhibited by adding <1 M MPA and its derivatives. In addition, the IMP dehydrogenase in T. congolense was molecularly characterized as the target of these compounds. The results suggest that MPA and its derivatives have the potential to be new candidates as novel trypanocidal drugs.T rypanosoma congolense causes animal African trypanosomiasis (AAT) in livestock. The lack of effective vaccines makes the use of chemotherapeutic agents the most effective measure for controlling AAT. Limited numbers of commercial drugs have long been used to treat AAT. The emergence of drug-resistant trypanosomes and cases of drug-refractory trypanosomiasis have been reported (1-4), underscoring the need for development of new drugs.A candidate target for drug development is IMP dehydrogenase (IMPDH). This enzyme is very important in the Trypanosoma spp. because it lacks a de novo purine synthesis pathway, which makes the purine nucleotide synthesis in these parasites solely dependent on a salvage pathway in the glycosomes (5-7). IMPDH converts IMP into XMP through this pathway, which is a rate-limiting step in the metabolism of guanine nucleotides (8). Mycophenolic acid (MPA), compound 1, is a well-known IMPDH inhibitor (Fig. 1). Its enzymatic activity has already been proven in many protozoan parasites (9-14). The antiprotozoan activities of MPA against Babesia spp. were reported in in vivo and in vitro studies (9, 15). Thus, the activity of MPA against IMPDH

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Cryptosporidium parvum IMP Dehydrogenase

Cited by 89 publications

References 44 publications

The Antibiotic Potential of Prokaryotic IMP Dehydrogenase Inhibitors

The Antibiotic Potential of Prokaryotic IMP Dehydrogenase Inhibitors

Identification of novel diphenyl urea inhibitors of Mt-GuaB2 active against Mycobacterium tuberculosis

Mycophenolic Acid and Its Derivatives as Potential Chemotherapeutic Agents Targeting Inosine Monophosphate Dehydrogenase in Trypanosoma congolense

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