Rational design, synthesis and evaluation of first generation inhibitors of the Giardia lamblia fructose-1,6-biphosphate aldolase

Title
Rational design, synthesis and evaluation of first generation inhibitors of the Giardia lamblia fructose-1,6-biphosphate aldolase
Author(s)
조대원Zhimin Li[Zhimin Li]Zhengang Liu[Zhengang Liu]Jiwen Zou[Jiwen Zou]Maozhen Gong[Maozhen Gong]Robert M. Breece[Robert M. Breece]Andrey Galkin[Andrey Galkin]Ling Li[Ling Li]Hong Zhao[Hong Zhao]Gabriel D. Maestas[Gabriel D. Maestas]David L. Tierney[David L. Tierney]Osnat Herzberg[Osnat Herzberg]Debra Dunaway-Mariano[Debra Dunaway-Mariano]Patrick S. Mariano[Patrick S. Mariano]
Keywords
MATRIX-METALLOPROTEINASE INHIBITORS; ZINC-BINDING GROUPS; FRUCTOSE-1,6-BISPHOSPHATE ALDOLASE; ENERGY-METABOLISM; YEAST ALDOLASE; SITE; CATALYSIS; PROTOZOA
Issue Date
201104
Publisher
ELSEVIER SCIENCE INC
Citation
JOURNAL OF INORGANIC BIOCHEMISTRY, v.105, no.4, pp.509 - 517
Abstract
Inhibitors of the Giardia lamblia fructose 1,6-bisphosphate aldolase (GlFBPA), which transforms fructose 1,6-bisphosphate (FBP) to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, were designed based on 3-hydroxy-2-pyridone and 1,2-dihydroxypyridine scaffolds that position two negatively charged tetrahedral groups for interaction with substrate phosphate binding residues, a hydrogen bond donor to the catalytic Asp83, and a Zn2+ binding group. The inhibition activities for the GlFBPA catalyzed reaction of FBP of the prepared alkyl phosphonate/phosphate substituted 3-hydroxy-2-pyridinones and a dihydroxypyridine were determined. The 3-hydroxy-2-pyridone inhibitor 8 was found to bind to GlFBPA with an affinity (K-i = 14 mu M) that is comparable to that of FBP (K-m = 2 mu m) or its inert analog TBP (K-i = 1 mu M). The X-ray structure of the GlFBPA-inhibitor 8 complex (2.3 angstrom) shows that 8 binds to the active site in the manner predicted by in silico docking with the exception of coordination with Zn2+. The observed distances and orientation of the pyridone ring O=C-C-OH relative to Zn2+ are not consistent with a strong interaction. To determine if Zn2+ coordination occurs in the GIFBPA-inhibitor 8 complex in solution, EXAFS spectra were measured. A four coordinate geometry comprised of the three enzyme histidine ligands and an oxygen atom from the pyridone ring O=C-C-OH was indicated. Analysis of the Zn2+ coordination geometries in recently reported structures of class II FBPAs suggests that strong Zn2+ coordination is reserved for the enediolate-like transition state, accounting for minimal contribution of Zn2+ coordination to binding of 8 to GlFBPA. (C) 2010 Elsevier Inc. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/25388http://dx.doi.org/10.1016/j.jinorgbio.2010.12.012
ISSN
0162-0134
Appears in Collections:
이과대학 > 화학생화학부 > Articles
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE