| RRC ID |
74541
|
| Author |
Bessho T, Okada T, Kimura C, Shinohara T, Tomiyama A, Imamura A, Kuwamura M, Nishimura K, Fujimori K, Shuto S, Ishibashi O, Kubata BK, Inui T.
|
| Title |
Novel Characteristics of Trypanosoma brucei Guanosine 5'-monophosphate Reductase Distinct from Host Animals.
|
| Journal |
PLoS Negl Trop Dis
|
| Abstract |
The metabolic pathway of purine nucleotides in parasitic protozoa is a potent drug target for treatment of parasitemia. Guanosine 5'-monophosphate reductase (GMPR), which catalyzes the deamination of guanosine 5'-monophosphate (GMP) to inosine 5'-monophosphate (IMP), plays an important role in the interconversion of purine nucleotides to maintain the intracellular balance of their concentration. However, only a few studies on protozoan GMPR have been reported at present. Herein, we identified the GMPR in Trypanosoma brucei, a causative protozoan parasite of African trypanosomiasis, and found that the GMPR proteins were consistently localized to glycosomes in T. brucei bloodstream forms. We characterized its recombinant protein to investigate the enzymatic differences between GMPRs of T. brucei and its host animals. T. brucei GMPR was distinct in having an insertion of a tandem repeat of the cystathionine β-synthase (CBS) domain, which was absent in mammalian and bacterial GMPRs. The recombinant protein of T. brucei GMPR catalyzed the conversion of GMP to IMP in the presence of NADPH, and showed apparent affinities for both GMP and NADPH different from those of its mammalian counterparts. Interestingly, the addition of monovalent cations such as K+ and NH4+ to the enzymatic reaction increased the GMPR activity of T. brucei, whereas none of the mammalian GMPR's was affected by these cations. The monophosphate form of the purine nucleoside analog ribavirin inhibited T. brucei GMPR activity, though mammalian GMPRs showed no or only a little inhibition by it. These results suggest that the mechanism of the GMPR reaction in T. brucei is distinct from that in the host organisms. Finally, we demonstrated the inhibitory effect of ribavirin on the proliferation of trypanosomes in a dose-dependent manner, suggesting the availability of ribavirin to develop a new therapeutic agent against African trypanosomiasis.
|
| Volume |
10(1)
|
| Pages |
e0004339
|
| Published |
2016-1-1
|
| DOI |
10.1371/journal.pntd.0004339
|
| PII |
PNTD-D-15-01486
|
| PMID |
26731263
|
| PMC |
PMC4701174
|
| MeSH |
Amino Acid Sequence
Animals
Antimetabolites / pharmacology
GMP Reductase / genetics
GMP Reductase / metabolism*
Gene Expression Regulation, Enzymologic
Hydrogen-Ion Concentration
Molecular Sequence Data
Recombinant Proteins
Ribavirin / pharmacology
Species Specificity
Temperature
Trypanocidal Agents / pharmacology
Trypanosoma brucei brucei / enzymology*
Trypanosoma brucei brucei / genetics
Trypanosoma brucei brucei / metabolism
|
| IF |
3.885
|
| Resource |
| Pathogenic eukaryotic microorganisms |
Trypanosoma brucei brucei GUTat 3.1 |
