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Shikimic Acid Pathway (shikimic + acid_pathway)

Distribution by Scientific Domains
Chemistry100%

Selected Abstracts

Progress in type II dehydroquinase inhibitors: From concept to practice

MEDICINAL RESEARCH REVIEWS, Issue 2 2007
Concepción González-Bello
Abstract Scientists are concerned by an ever-increasing rise in bacterial resistance to antibiotics, particularly in diseases such as malaria, toxoplasmosis, tuberculosis, and pneumonia, where the currently used therapies become progressively less efficient. It is therefore necessary to develop new, safe, and more efficient antibiotics. Recently, the existence of the shikimic acid pathway has been demonstrated in certain parasites such as the malaria parasite. These types of parasites cause more than a million casualties per year, and their effects are particularly strong in people with a compromised immune system such as HIV patients. In such cases it is possible that inhibitors of this pathway could be active against a large variety of microorganisms responsible for the more opportunistic infections in HIV patients. Interest in this pathway has resulted in the development of a wide variety of inhibitors for the enzymes involved. This review covers recent progress made in the development of inhibitors of the third enzyme of this pathway, i.e., the type II dehydroquinase. The X-ray crystal structures of several dehydroquinases (Streptomyces coelicolor, Mycobacterium tuberculosis, etc.) with an inhibitor bound in the active site have recently been solved. These complexes identified a number of key interactions involved in inhibitor binding and have shed light on several aspects of the catalytic mechanism. These crystal structures have also proven to be a useful tool for the design of potent and selective enzyme inhibitors, a feature that will also be discussed. © 2006 Wiley Periodicals, Inc. Med Res Rev [source]

Glyphosate applied at low doses can stimulate plant growth

PEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 4 2008
Edivaldo D Velini
Abstract BACKGROUND:Glyphosate blocks the shikimic acid pathway, inhibiting the production of aromatic amino acids and several secondary compounds derived from these amino acids. Non-target plants can be exposed to low doses of glyphosate by herbicide drift of spray droplets and contact with treated weeds. Previous studies have reported that low doses of glyphosate stimulate growth, although these data are very limited. The objective of this study was to determine the effects of low glyphosate doses on growth of a range of plant species. RESULTS:Growth of maize, conventional soybean, Eucalyptus grandis Hill ex Maiden, Pinus caribea L. and Commelia benghalensis L. was enhanced by 1.8,36 g glyphosate ha,1. Growth of glyphosate-resistant soybean was unaffected by any glyphosate dose from 1.8 to 720 g AE ha,1. The optimum doses for growth stimulation were distinct for plant species and tissue evaluated. The greatest stimulation of growth was observed for C. benghalensis and P. caribea. Shikimic acid levels in tissues of glyphosate-treated soybean and maize were measured and found to be elevated at growth-stimulating doses. CONCLUSION:Subtoxic doses of glyphosate stimulate the growth of a range of plant species, as measured in several plant organs. This hormesis effect is likely to be related to the molecular target of glyphosate, since the effect was not seen in glyphosate-resistant plants, and shikimate levels were enhanced in plants with stimulated growth. Copyright © 2008 Society of Chemical Industry [source]

Understanding the Key Factors that Control the Inhibition of Type,II Dehydroquinase by (2R)-2-Benzyl-3-dehydroquinic Acids

CHEMMEDCHEM, Issue 10 2010
Antonio Peón
Abstract The binding mode of several substrate analogues, (2R)-2-benzyl-3-dehydroquinic acids 4, which are potent reversible competitive inhibitors of type,II dehydroquinase (DHQ2), the third enzyme of the shikimic acid pathway, has been investigated by structural and computational studies. The crystal structures of Mycobacterium tuberculosis and Helicobacter pylori DHQ2 in complex with one of the most potent inhibitor, p -methoxybenzyl derivative 4,a, have been solved at 2.40,Å and 2.75,Å, respectively. This has allowed the resolution of the M.,tuberculosis DHQ2 loop containing residues 20,25 for the first time. These structures show the key interactions of the aromatic ring in the active site of both enzymes and additionally reveal an important change in the conformation and flexibility of the loop that closes over substrate binding. The loop conformation and the binding mode of compounds 4,b,d has been also studied by molecular dynamics simulations, which suggest that the benzyl group of inhibitors 4 prevent appropriate orientation of the catalytic tyrosine of the loop for proton abstraction and disrupts its basicity. [source]

Nanomolar Competitive Inhibitors of Mycobacterium tuberculosis and Streptomyces coelicolor Type,II Dehydroquinase

CHEMMEDCHEM, Issue 2 2007
Verónica F.
Abstract Isomeric nitrophenyl and heterocyclic analogues of the known inhibitor (1S,3R,4R)-1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid have been synthesized and tested as inhibitors of M.,tuberculosis and S.,coelicolor type,II dehydroquinase, the third enzyme of the shikimic acid pathway. The target compounds were synthesized by a combination of Suzuki and Sonogashira cross-coupling and copper(I)-catalyzed 2,3-dipolar cycloaddition reactions from a common vinyl triflate intermediate. These studies showed that a para -nitrophenyl derivative is almost 20-fold more potent as a competitive inhibitor against the S.,coelicolor enzyme than that of M.,tuberculosis. The opposite results were obtained with the meta isomer. Five of the bicyclic analogues reported herein proved to be potent competitive inhibitors of S.,coelicolor dehydroquinase, with inhibition constants in the low nanomolar range (4,30,nM). These derivatives are also competitive inhibitors of the M.,tuberculosis enzyme, but with lower affinities. The most potent inhibitor against the S.,coelicolor enzyme, a 6-benzothiophenyl derivative, has a Ki value of 4,nM,over 2000-fold more potent than the best previously known inhibitor, (1R,4R,5R)-1,5-dihydroxy-4-(2-nitrophenyl)cyclohex-2-en-1-carboxylic acid (8,,M), making it the most potent known inhibitor against any dehydroquinase. The binding modes of the analogues in the active site of the S.,coelicolor enzyme (GOLD,3.0.1), suggest a key , -stacking interaction between the aromatic rings and Tyr,28, a residue that has been identified as essential for enzyme activity. [source]