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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
agricultural and biological sciences
Characterization of the novel Trypanosoma brucei inosine 5′-monophosphate dehydrogenase
Parasitology, Volume 140, No. 6, Year 2013
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Description
SUMMARY There is an alarming rate of human African trypanosomiasis recrudescence in many parts of sub-Saharan Africa. Yet, the disease has no successful chemotherapy. Trypanosoma lacks the enzymatic machinery for the de novo synthesis of purine nucleotides, and is critically dependent on salvage mechanisms. Inosine 5′-monophosphate dehydrogenase (IMPDH) is responsible for the rate-limiting step in guanine nucleotide metabolism. Here, we characterize recombinant Trypanosoma brucei IMPDH (TbIMPDH) to investigate the enzymatic differences between TbIMPDH and host IMPDH. Size-exclusion chromatography and analytical ultracentrifugation sedimentation velocity experiments reveal that TbIMPDH forms a heptamer, different from type 1 and 2 mammalian tetrameric IMPDHs. Kinetic analysis reveals calculated K m values of 30 and 1300Â μ m for IMP and NAD, respectively. The obtained K m value of TbIMPDH for NAD is approximately 20-200-fold higher than that of mammalian enzymes and indicative of a different NAD binding mode between trypanosomal and mammalian IMPDHs. Inhibition studies show K i values of 3·2Â μ m, 21 nM and 3·3 nM for ribavirin 5′-monophosphate, mycophenolic acid and mizoribine 5′-monophosphate, respectively. Our results show that TbIMPDH is different from its mammalian counterpart and thus may be a good target for further studies on anti-trypanosomal drugs. © Cambridge University Press 2013.
Authors & Co-Authors
Bessho, Tomoaki
Japan, Osaka
Osaka Metropolitan University
Morii, Shoko
Japan, Osaka
Osaka Metropolitan University
Kusumoto, Toshihide
Japan, Osaka
Osaka Metropolitan University
Shinohara, Takahiro
Japan, Osaka
Osaka Metropolitan University
Noda, Masanori
Japan, Suita
Osaka University
Uchiyama, Susumu
Japan, Suita
Osaka University
Shuto, Satoshi
Japan, Sapporo
Hokkaido University
Nishimura, Shigenori
Japan, Osaka
Osaka Metropolitan University
Djikeng, Appolinaire
Kenya, Nairobi
Biosciences Eastern and Central Africa - International Livestock Research Institute
United States, Rockville
J. Craig Venter Institute
Duszenko, Michael
Germany, Tubingen
Eberhard Karls Universität Tübingen
Martin, Samuel K.
United States, Arlington
United States Army
Inui, Takashi
Japan, Osaka
Osaka Metropolitan University
Kubata, Kilunga B.
Kenya, Nairobi
Au/nepad Agency Regional Office for Eastern and Central Africa
Statistics
Citations: 13
Authors: 13
Affiliations: 8
Identifiers
Doi:
10.1017/S0031182012002090
e-ISSN:
14698161
Research Areas
Cancer