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@ARTICLE{Prakash:642752,
author = {Prakash, Ohm and Führing, Jana and Baruch, Petra and
Fedorov, Roman and Routier, Françoise H.},
title = {{T}he post-reactive structures of {L}eishmania major
{UDP}-sugar pyrophosphorylase provide insights into the
product release mechanism},
journal = {Microbiology spectrum},
volume = {13},
number = {11},
issn = {2165-0497},
address = {Birmingham, Ala.},
publisher = {ASM},
reportid = {PUBDB-2025-05601},
pages = {e00911-25},
year = {2025},
abstract = {Biosynthesis of the nucleotide sugars UDP-glucose (UDP-Glc)
and UDP-galactose (UDP-Gal) is intimately connected and
essential for the viability of trypanosomatid parasites. In
the genus Leishmania, it is controlled by the UDP-glucose
pyrophosphorylase (UGP) and UDP-sugar pyrophosphorylase
(USP). In contrast to UGP, USP has a broad substrate
specificity and may generate several UDP-sugars in vitro,
including UDP-Glc and UDP-Gal. This enzyme, present in
protozoan parasites (including Leishmania species and
Trypanosoma cruzi) and in plants, most likely plays a role
in salvaging monosaccharides. In order to gain a detailed
mechanistic understanding of USPs, we determined
high-resolution X-ray structures of Leishmania major USP
(LmUSP) in post-reactive states. Several positions of the
byproduct pyrophosphate (PPi) were identified and revealed a
product release channel in the forward reaction, as well as
the geometries of post-reactive Michaelis product complexes.
The conformational changes of functional loops (hinge
loop-1, hinge loop-2, and the nucleotide-binding loop)
showed dynamic effects accompanying the product release
process. Structural information about the post-reactive
states of LmUSP also includes the metastable binding
position of a magnesium (Mg2+) ion in the active site. The
proposed product release mechanism was substantiated by
molecular dynamics simulations and can serve as a model for
other UDP-sugar pyrophosphorylases.},
cin = {EMBL-User},
ddc = {570},
cid = {I:(DE-H253)EMBL-User-20120814},
pnm = {6G3 - PETRA III (DESY) (POF4-6G3) / DFG project
G:(GEPRIS)390874280 - EXC 2155: RESIST - Resolving Infection
Susceptibility (390874280)},
pid = {G:(DE-HGF)POF4-6G3 / G:(GEPRIS)390874280},
experiment = {EXP:(DE-H253)P-P13-20150101},
typ = {PUB:(DE-HGF)16},
doi = {10.1128/spectrum.00911-25},
url = {https://bib-pubdb1.desy.de/record/642752},
}