Chagas disease, caused by the parasitic protozoan
Trypanosoma cruzi
, affects over 8 million people
worldwide. Current antiparasitic treatments for Chagas disease are
ineffective in treating advanced, chronic stages of the disease, and
are noted for their toxicity. Like most parasitic protozoa,
T. cruzi
is unable to synthesize purines
de novo
, and relies on the salvage of preformed purines
from the host. Hypoxanthine–guanine phosphoribosyltransferases
(HGPRTs) are enzymes that are critical for the salvage of preformed
purines, catalyzing the formation of inosine monophosphate (IMP) and
guanosine monophosphate (GMP) from the nucleobases hypoxanthine and
guanine, respectively. Due to the central role of HGPRTs in purine
salvage, these enzymes are promising targets for the development of
new treatment methods for Chagas disease. In this study, we characterized
two gene products in the
T. cruzi
CL
Brener strain that encodes enzymes with functionally identical HGPRT
activities
in vitro
: TcA (TcCLB.509693.70) and TcC
(TcCLB.506457.30). The TcC isozyme was kinetically characterized to
reveal mechanistic details on catalysis, including identification
of the rate-limiting step(s) of catalysis. Furthermore, we identified
and characterized inhibitors of
T. cruzi
HGPRTs originally developed as transition-state analogue inhibitors
(TSAIs) of
Plasmodium falciparum
hypoxanthine–guanine–xanthine
phosphoribosyltransferase (
Pf
HGXPRT), where the most
potent compound bound to
T. cruzi
HGPRT
with low nanomolar affinity. Our results validated the repurposing
of TSAIs to serve as selective inhibitors for orthologous molecular
targets, where primary and secondary structures as well as putatively
common chemical mechanisms are conserved.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.