Crystal structures and inhibition of Trypanosoma brucei hypoxanthine-guanine phosphoribosyltransferase

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F16%3A00465607" target="_blank" >RIV/61388963:_____/16:00465607 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/60077344:_____/16:00465607

Výsledek na webu

<a href="http://www.nature.com/articles/srep35894" target="_blank" >http://www.nature.com/articles/srep35894</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/srep35894" target="_blank" >10.1038/srep35894</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Crystal structures and inhibition of Trypanosoma brucei hypoxanthine-guanine phosphoribosyltransferase

Popis výsledku v původním jazyce

Human African Trypanosomiasis (HAT) is a life-threatening infectious disease caused by the protozoan parasite, Trypanosoma brucei (Tbr). Due to the debilitating side effects of the current therapeutics and the emergence of resistance to these drugs, new medications for this disease need to be developed. One potential new drug target is 6-oxopurine phosphoribosyltransferase (PRT), an enzyme central to the purine salvage pathway and whose activity is critical for the production of the nucleotides (GMP and IMP) required for DNA/RNA synthesis within this protozoan parasite. Here, the first crystal structures of this enzyme have been determined, these in complex with GMP and IMP and with three acyclic nucleoside phosphonate (ANP) inhibitors. The K-i values for GMP and IMP are 30.5 mu M and 77 mu M, respectively. Two of the ANPs have K-i values considerably lower than for the nucleotides, 2.3 mu M (with guanine as base) and 15.8 mu M (with hypoxanthine as base). The crystal structures show that when two of the ANPs bind, they induce an unusual conformation change to the loop where the reaction product, pyrophosphate, is expected to bind. This and other structural differences between the Tbr and human enzymes suggest selective inhibitors for the Tbr enzyme can be designed.

Název v anglickém jazyce

Crystal structures and inhibition of Trypanosoma brucei hypoxanthine-guanine phosphoribosyltransferase

Popis výsledku anglicky

Human African Trypanosomiasis (HAT) is a life-threatening infectious disease caused by the protozoan parasite, Trypanosoma brucei (Tbr). Due to the debilitating side effects of the current therapeutics and the emergence of resistance to these drugs, new medications for this disease need to be developed. One potential new drug target is 6-oxopurine phosphoribosyltransferase (PRT), an enzyme central to the purine salvage pathway and whose activity is critical for the production of the nucleotides (GMP and IMP) required for DNA/RNA synthesis within this protozoan parasite. Here, the first crystal structures of this enzyme have been determined, these in complex with GMP and IMP and with three acyclic nucleoside phosphonate (ANP) inhibitors. The K-i values for GMP and IMP are 30.5 mu M and 77 mu M, respectively. Two of the ANPs have K-i values considerably lower than for the nucleotides, 2.3 mu M (with guanine as base) and 15.8 mu M (with hypoxanthine as base). The crystal structures show that when two of the ANPs bind, they induce an unusual conformation change to the loop where the reaction product, pyrophosphate, is expected to bind. This and other structural differences between the Tbr and human enzymes suggest selective inhibitors for the Tbr enzyme can be designed.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

CC - Organická chemie

OECD FORD obor

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Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Scientific Reports

ISSN

2045-2322

e-ISSN

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Svazek periodika

6

Číslo periodika v rámci svazku

Oct 27

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

14

Strana od-do

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Kód UT WoS článku

000386762800001

EID výsledku v databázi Scopus

2-s2.0-84992671908