Theoretical Analysis of the Catalytic Mechanism of Helicobacter pylori Glutamate Racemase

2012 ◽  
Vol 116 (41) ◽  
pp. 12406-12414 ◽  
Author(s):  
Edgar Mixcoha ◽  
Mireia Garcia-Viloca ◽  
José M. Lluch ◽  
Àngels González-Lafont
Keyword(s):  
Helicobacter Pylori ◽  
Theoretical Analysis ◽  
Catalytic Mechanism ◽  
Glutamate Racemase

scholarly journals Pyridodiazepine Amines Are Selective Therapeutic Agents for Helicobacter pylori by Suppressing Growth through Inhibition of Glutamate Racemase but Are Predicted To Require Continuous Elevated Levels in Plasma To Achieve Clinical Efficacy

2015 ◽  
Vol 59 (4) ◽  
pp. 2337-2342 ◽  
Author(s):  
Boudewijn L. M. de Jonge ◽  
Amy Kutschke ◽  
Joseph V. Newman ◽  
Michael T. Rooney ◽  
Wei Yang ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Therapeutic Agents ◽  
Infection Model ◽  
Content Type ◽  
Peptidoglycan Biosynthesis ◽  
Glutamate Racemase ◽  
Mouse Infection Model ◽  
Exposure Levels ◽  
H Pylori ◽  
Extended Exposure

ABSTRACTA pyridodiazepine amine inhibitor ofHelicobacter pyloriglutamate racemase (MurI) was characterized. The compound was selectively active againstH. pylori, and growth suppression was shown to be mediated through the inhibition of MurI by several methods. In killing kinetics experiments, the compound showed concentration-independent activity, with about a 2-log loss of viability in 24 h. A demonstration of efficacy in a mouse infection model was attempted but not achieved, and this was attributed to the failure to attain extended exposure levels above the MIC for >95% of the time. This index and magnitude were derived from pharmacokinetic-pharmacodynamic (PK-PD) studies with amoxicillin, another inhibitor of peptidoglycan biosynthesis that showed slow killing kinetics similar to those of the pyridodiazepine amines. These studies indicate that MurI and other enzymes involved in peptidoglycan biosynthesis may be less desirable targets for monotherapy directed againstH. pyloriif once-a-day dosing is required.

scholarly journals Pyrazolopyrimidinediones Are Selective Agents for Helicobacter pylori That Suppress Growth through Inhibition of Glutamate Racemase (MurI)

2009 ◽  
Vol 53 (8) ◽  
pp. 3331-3336 ◽  
Author(s):  
B. L. M. de Jonge ◽  
A. Kutschke ◽  
M. Uria-Nickelsen ◽  
H. D. Kamp ◽  
S. D. Mills
Keyword(s):  
Helicobacter Pylori ◽  
Peptidoglycan Biosynthesis ◽  
Glutamate Racemase ◽  
Selective Agents ◽  
Essential Enzyme ◽  
H Pylori ◽  
Selective Therapy ◽  
High Degree

ABSTRACT Pyrazolopyrimidinediones are a novel series of compounds that inhibit growth of Helicobacter pylori specifically. Using a variety of methods, advanced analogues were shown to suppress the growth of H. pylori through the inhibition of glutamate racemase, an essential enzyme in peptidoglycan biosynthesis. The high degree of selectivity of the series for H. pylori makes these compounds attractive candidates for novel H. pylori-selective therapy.

On the 3D structure and catalytic mechanism study of AmiF formamidase of Helicobacter pylori

Polymer ◽  
2007 ◽  
Vol 48 (13) ◽  
pp. 3726-3731 ◽  
Author(s):  
Wei-Wei Han ◽  
Yi-Han Zhou ◽  
Quan Luo ◽  
Yuan Yao ◽  
Ze-Sheng Li
Keyword(s):  
Helicobacter Pylori ◽  
Catalytic Mechanism ◽  
3D Structure ◽  
Mechanism Study

Potent and selective inhibitors of Helicobacter pylori glutamate racemase (MurI): Pyridodiazepine amines

2009 ◽  
Vol 19 (3) ◽  
pp. 930-936 ◽  
Author(s):  
Bolin Geng ◽  
Gregory Basarab ◽  
Janelle Comita-Prevoir ◽  
Madhusudhan Gowravaram ◽  
Pamela Hill ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Selective Inhibitors ◽  
Glutamate Racemase

scholarly journals Flavodoxin:Quinone Reductase (FqrB): a Redox Partner of Pyruvate:Ferredoxin Oxidoreductase That Reversibly Couples Pyruvate Oxidation to NADPH Production in Helicobacter pylori and Campylobacter jejuni

2007 ◽  
Vol 189 (13) ◽  
pp. 4764-4773 ◽  
Author(s):  
Martin St. Maurice ◽  
Nunilo Cremades ◽  
Matthew A. Croxen ◽  
Gary Sisson ◽  
Javier Sancho ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Campylobacter Jejuni ◽  
Catalytic Mechanism ◽  
Reductase Activity ◽  
Specific Inhibitor ◽  
Quinone Reductase ◽  
Dependent Manner ◽  
Quinone Reduction ◽  
Cell Extracts ◽  
Pyruvate:Ferredoxin Oxidoreductase

ABSTRACT Pyruvate-dependent reduction of NADP has been demonstrated in cell extracts of the human gastric pathogen Helicobacter pylori. However, NADP is not a substrate of purified pyruvate:ferredoxin oxidoreductase (PFOR), suggesting that other redox active enzymes mediate this reaction. Here we show that fqrB (HP1164), which is essential and highly conserved among the epsilonproteobacteria, exhibits NADPH oxidoreductase activity. FqrB was purified by nickel interaction chromatography following overexpression in Escherichia coli. The protein contained flavin adenine dinucleotide and exhibited NADPH quinone reductase activity with menadione or benzoquinone and weak activity with cytochrome c, molecular oxygen, and 5,5′-dithio-bis-2-nitrobenzoic acid (DTNB). FqrB exhibited a ping-pong catalytic mechanism, a k cat of 122 s−1, and an apparent Km of 14 μM for menadione and 26 μM for NADPH. FqrB also reduced flavodoxin (FldA), the electron carrier of PFOR. In coupled enzyme assays with purified PFOR and FldA, FqrB reduced NADP in a pyruvate- and reduced coenzyme A (CoA)-dependent manner. Moreover, in the presence of NADPH, CO2, and acetyl-CoA, the PFOR:FldA:FqrB complex generated pyruvate via CO2 fixation. PFOR was the rate-limiting enzyme in the complex, and nitazoxanide, a specific inhibitor of PFOR of H. pylori and Campylobacter jejuni, also inhibited NADP reduction in cell-free lysates. These capnophilic (CO2-requiring) organisms contain gaps in pathways of central metabolism that would benefit substantially from pyruvate formation via CO2 fixation. Thus, FqrB provides a novel function in pyruvate metabolism and, together with production of superoxide anions via quinone reduction under high oxygen tensions, contributes to the unique microaerobic lifestyle that defines the epsilonproteobacterial group.

Microdiffraction Patterns of Small Metallic Particles II; Theoretical Analysis

1982 ◽  
Vol 40 ◽  
pp. 668-669
Author(s):  
A. Gómez ◽  
P. Schabes-Retchkiman ◽  
M. José-Yacamán ◽  
T. Ocaña
Keyword(s):  
Experimental Data ◽  
Electron Diffraction ◽  
Theoretical Analysis ◽  
Size Range ◽  
Dynamical Theory ◽  
Metallic Particles ◽  
Splitting Effect

The splitting effect that is observed in microdiffraction pat-terns of small metallic particles in the size range 50-500 Å can be understood using the dynamical theory of electron diffraction for the case of a crystal containing a finite wedge. For the experimental data we refer to part I of this work in these proceedings.

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