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Title: Rational Design Synthesis and Evaluation of First Generation Inhibitors of the Giardia Lamblia Fructose-1 6-biphosphate Aldolase

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 Zn{sup 2+} 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{sub i} = 14 {micro}M) that is comparable to that of FBP (K{sub m} = 2 {micro}M) or its inert analog TBP (K{sub i} = 1 {micro}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 Zn{sup 2+}. The observed distances and orientation of the pyridone ring O=C-C-OH relative to Zn{sup 2+} are not consistent with a strong interaction. To determine if Zn{sup 2+} coordination occurs in the GlFBPA-inhibitor 8 complex in solution, EXAFS spectra were measured. A four coordinate geometry comprised of the three enzymemore » histidine ligands and an oxygen atom from the pyridone ring O=C-C-OH was indicated. Analysis of the Zn{sup 2+} coordination geometries in recently reported structures of class II FBPAs suggests that strong Zn{sup 2+} coordination is reserved for the enediolate-like transition state, accounting for minimal contribution of Zn{sup 2+} coordination to binding of 8 to GlFBPA.« less

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE SC OFFICE OF SCIENCE (SC)
OSTI Identifier:
1042010
Report Number(s):
BNL-97688-2012-JA
Journal ID: ISSN 0162-0134; JIBIDJ; TRN: US201212%%421
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Journal of Inorganic Biochemistry
Additional Journal Information:
Journal Volume: 105; Journal Issue: 4; Journal ID: ISSN 0162-0134
Country of Publication:
United States
Language:
English
Subject:
08 HYDROGEN; AFFINITY; ALDOLASES; ATOMS; DESIGN; ENZYMES; EVALUATION; FRUCTOSE; GEOMETRY; HISTIDINE; HYDROGEN; ORIENTATION; OXYGEN; PHOSPHATES; RESIDUES; SPECTRA; STRONG INTERACTIONS; SUBSTRATES; SYNTHESIS

Citation Formats

Li, Z, Liu, Z, Cho, D, Zou, J, Gong, M, Breece, R, Galkin, A, Li, L, Zhao, H, and et al. Rational Design Synthesis and Evaluation of First Generation Inhibitors of the Giardia Lamblia Fructose-1 6-biphosphate Aldolase. United States: N. p., 2011. Web. doi:10.1016/j.jinorgbio.2010.12.012.
Li, Z, Liu, Z, Cho, D, Zou, J, Gong, M, Breece, R, Galkin, A, Li, L, Zhao, H, & et al. Rational Design Synthesis and Evaluation of First Generation Inhibitors of the Giardia Lamblia Fructose-1 6-biphosphate Aldolase. United States. https://doi.org/10.1016/j.jinorgbio.2010.12.012
Li, Z, Liu, Z, Cho, D, Zou, J, Gong, M, Breece, R, Galkin, A, Li, L, Zhao, H, and et al. Sat . "Rational Design Synthesis and Evaluation of First Generation Inhibitors of the Giardia Lamblia Fructose-1 6-biphosphate Aldolase". United States. https://doi.org/10.1016/j.jinorgbio.2010.12.012.
@article{osti_1042010,
title = {Rational Design Synthesis and Evaluation of First Generation Inhibitors of the Giardia Lamblia Fructose-1 6-biphosphate Aldolase},
author = {Li, Z and Liu, Z and Cho, D and Zou, J and Gong, M and Breece, R and Galkin, A and Li, L and Zhao, H and et al.},
abstractNote = {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 Zn{sup 2+} 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{sub i} = 14 {micro}M) that is comparable to that of FBP (K{sub m} = 2 {micro}M) or its inert analog TBP (K{sub i} = 1 {micro}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 Zn{sup 2+}. The observed distances and orientation of the pyridone ring O=C-C-OH relative to Zn{sup 2+} are not consistent with a strong interaction. To determine if Zn{sup 2+} coordination occurs in the GlFBPA-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 Zn{sup 2+} coordination geometries in recently reported structures of class II FBPAs suggests that strong Zn{sup 2+} coordination is reserved for the enediolate-like transition state, accounting for minimal contribution of Zn{sup 2+} coordination to binding of 8 to GlFBPA.},
doi = {10.1016/j.jinorgbio.2010.12.012},
url = {https://www.osti.gov/biblio/1042010}, journal = {Journal of Inorganic Biochemistry},
issn = {0162-0134},
number = 4,
volume = 105,
place = {United States},
year = {2011},
month = {12}
}