Different mechanistic and stereochemical courses for the reactions catalysed by type I and type II dehydroquinases

Harris, J. H.; Kleanthous, Colin; Coggins, John R.; Hawkins, Alastair R.; Abell, Chris

doi:10.1039/c39930001080

Cited by 66 publications

(53 citation statements)

References 7 publications

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“…Little is known about the structure and mechanism of the type II dehydroquinases which are clearly mechanistically and structurally different from the better characterised type I enzymes [5,6]. The type I enzymes are exclusively biosynthetic [5], have a conserved active site lysine residue [7], and catalyse a cis elimination via an imine intermediate [4,8] with the participation of a conserved histidine residue as the general base [9]. In contrast the fungal type II enzymes have an exclusively catabolic role [2,10] while the bacterial type II enzymes may be exclusively biosynthetic [11,12] or be involved in both biosynthesis and catabolism [13].…”

Section: Introductionmentioning

confidence: 99%

“…This reaction, which occurs on both the biosynthetic shikimate pathway and the catabolic quinate pathway [1][2][3], involves the trans elimination of water [4]. Little is known about the structure and mechanism of the type II dehydroquinases which are clearly mechanistically and structurally different from the better characterised type I enzymes [5,6].…”

Section: Introductionmentioning

confidence: 99%

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The use of electrospray mass spectrometry to identify an essential arginine residue in type II dehydroquinases

1995

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The arginine-specific reagent phenylglyoxal has been used to identify a hyper-reactive arginine residue which is essential for activity in the type II dehydroquinases of Streptomyces coelicolor and Aspergillus nidulans. Electrospray mass spectrometry was used both to characterise the phenylglyoxal modified protein, and to identify the phenylglyoxal modified peptides following enzymatic digestion. The advantages of using electrospray mass spectrometry for monitoring arginine medication aimed at identifying functional residues in proteins are discussed.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The use of electrospray mass spectrometry to identify an essential arginine residue in type II dehydroquinases

1995

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“…The mechanism of catalysis by these enzymes is known to involve a Schiff base intermediate formed at the invariant residue Lys-170 [21], as well as a general acid\base catalysis involving His-143 [22,23]. Type II enzymes have subunit molecular masses of 16-18 kDa, oligomerize into dodecamers of " 200 kDa, are heat stable (in contrast to the type I enzymes) and catalyse the elimination reaction with trans stereochemistry [24]. Little is known of the mechanism of this class of enzyme.…”

Section: Introductionmentioning

confidence: 99%

Cloning, sequencing, expression, purification and preliminary characterization of a type II dehydroquinase from Helicobacter pylori

Bottomley

Clayton²,

Chalk³

et al. 1996

Biochemical Journal

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A heat-stable dehydroquinase was purified to near homogeneity from a plate-grown suspension of the Gram-negative stomach pathogen Helicobacter pylori, and shown from both its subunit and native molecular masses to be a member of the type II family of dehydroquinases. This was confirmed by N-terminal amino acid sequence data. The gene encoding this activity was isolated following initial identification, by random sequencing of the H. pylori genome, of a 96 bp fragment, the translated sequence of which showed strong identity to a C-terminal region of other type II enzymes. Southern blot analysis of a cosmid library identified several potential clones, one of which complemented an Escherichia coliaroD point mutant strain deficient in host dehydroquinase. The gene encoding the H. pylori type II dehydroquinase (designated aroQ) was sequenced. The translated sequence was identical to the N-terminal sequence obtained directly from the purified protein, and showed strong identity to other members of the type II family of dehydroquinases. The enzyme was readily expressed in E. coli from a plasmid construct from which several milligrams of protein could be isolated, and the molecular mass of the protein was confirmed by electrospray MS. The aroQ gene in H. pylori may function in the central biosynthetic shikimate pathway of this bacterium, thus opening the way for the construction of attenuated strains as potential vaccines as well as offering a new target for selective enzyme inhibition.

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“…The fact that two enzymes have evolved to catalyze the same reaction by entirely different mechanisms and stereochemical courses [38] has been used for the design of compounds that specifically inhibit either DHQ1 or DHQ2 enzymes. Of the two, particular attention has been paid to the inhibition of the DHQ2 enzyme as a potential target for the development of anti-tubercular drugs as well as for the treatment of infectious diseases caused by H. pylori.…”

Section: Targeting Dehydroquinasementioning

confidence: 99%

Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies

González‐Bello

2015

CTMC

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Abstract:The loss of effectiveness of current antibiotics caused by the development of drug resistance has become a severe threat to public health. Current widely used antibiotics are surprisingly targeted at a few bacterial functions -cell wall, DNA, RNA, and protein biosynthesis -and resistance to them is widespread and well identified. There is therefore great interest in the discovery of novel drugs and therapies to tackle antimicrobial resistance, in particular drugs that target other essential processes for bacterial survival. In the past few years a great deal of effort has been focused on the discovery of new inhibitors of the enzymes involved in the biosynthesis of aromatic amino acids, also known as the shikimic acid pathway, in which chorismic acid is synthesized. The latter compound is the synthetic precursor of L-Phe, L-Tyr, L-Phe, and other important aromatic metabolites. These enzymes are recognized as attractive targets for the development of new antibacterial agents because they are essential in important pathogenic bacteria, such as Mycobacterium tuberculosis and Helicobacter pylori, but do not have any counterpart in human cells. This review is focused on two key enzymes of this pathway, shikimate kinase and type II dehydroquinase. An overview of the use of structure-based design and computational studies for the discovery of selective inhibitors of these enzymes will be provided. A detailed view of the structural changes caused by these inhibitors in the catalytic arrangement of these enzymes, which are responsible for the inhibition of their activity, is described.

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Different mechanistic and stereochemical courses for the reactions catalysed by type I and type II dehydroquinases

Cited by 66 publications

References 7 publications

The use of electrospray mass spectrometry to identify an essential arginine residue in type II dehydroquinases

The use of electrospray mass spectrometry to identify an essential arginine residue in type II dehydroquinases

Cloning, sequencing, expression, purification and preliminary characterization of a type II dehydroquinase from Helicobacter pylori

Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies

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