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Title: Slow ligand-induced conformational switch increases the catalytic rate in Plasmodium falciparum hypoxanthine guanine xanthine phosphoribosyltransferase
Authors: Roy, Sourav
Karmakar, Tarak
Rao, Vasudeva S. Prahlada
Nagappa, Lakshmeesha K.
Balasubramanian, Sundaram
Balaram, Hemalatha
Keywords: Biochemistry & Molecular Biology
Steady-State Kinetics
2.0 Angstrom Structure
ternary Complex
Flexible Loop
6-Oxopurine Phosphoribosyltransferases
Issue Date: 2015
Publisher: Royal Society of Chemistry
Citation: Molecular Biosystems
Roy, S.; Karmakar, T.; Rao, V. S. P.; Nagappa, L. K.; Balasubramanian, S.; Balaram, H., Slow ligand-induced conformational switch increases the catalytic rate in Plasmodium falciparum hypoxanthine guanine xanthine phosphoribosyltransferase. Molecular Biosystems 2015, 11 (5), 1410-1424.
Abstract: P. falciparum (Pf) hypoxanthine guanine xanthine phosphoribosyltransferase (HGXPRT) exhibits a unique mechanism of activation where the enzyme switches from a low activity (unactivated) to a high activity (activated) state upon pre-incubation with substrate/products. Xanthine phosphoribosylation by unactivated PfHGXPRT exhibits a lag phase, the duration of which reduces with an increase in concentration of the enzyme or substrate, PRPP center dot Mg2+. Activated PfHGXPRT does not display the lag phase and exhibits a ten-fold drop in the Km value for PRPP center dot Mg2+. These observations suggest the involvement of ligand-mediated oligomerization and conformational changes in the process of activation. The dipeptide Leu-Lys in the PPi binding site of human and T. gondii HG(X)PRT that facilitates PRPP center dot Mg2+ binding by isomerization from trans to cis conformation is conserved in PfHGXPRT. Free energy calculations using the well-tempered metadynamics technique show the ligand- free enzyme to be more stable when this dipeptide is in the trans conformation than in the cis conformation. The high rotational energy barrier observed for the conformational change from experimental and computational studies permits delineation of the activation mechanism.
Description: Restricted access
ISSN: 1742-206X
Appears in Collections:Research Articles (Balasubramanian Sundaram)

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