FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2056418905> ?p ?o ?g. }

• W2056418905 endingPage "617" @default.
• W2056418905 startingPage "616" @default.
• W2056418905 abstract "Helicobacter pylori is a spiral-shaped, Gram-negative bacterium that lives in the stomach and duodenum. H. pylori infection is associated with peptic ulcer disease, chronic gastritis, mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma. The enzyme 3-dehydroquinate dehydratase or 3-dehydroquinase (DHQase; EC 4.2.1.10), which catalyzes the interconversion of 3-dehydroquinate and 3-dehydroshikimate, is an attractive target for developing antibacterial compounds specific for H. pylori. DHQases fall into two groups: type I and type II. They have different biochemical and biophysical properties, and no sequence similarity exists between them.1 Type I enzymes are generally found in the biosynthetic shikimate pathway and use a Schiff base intermediate formed at the conserved lysine residue, and catalyze the elimination of water with syn stereochemistry.2, 3 They have subunit molecular masses of ∼25 kDa, form dimers in the case of monofuntional enzymes such as Escherichia coli type I DHQase, and are thermally labile.3 Type II enzymes serve either the biosynthetic shikimate pathway or catabolic quinate pathway,1 or both.4 They have smaller subunit molecular masses than type I enzymes (16–18 kDa), oligomerize into dodecamers of ∼200 kDa, and are heat stable. H. pylori has only the type II enzyme (167 residues, 18,483 Da), in contrast with gut organisms such as E. coli, which have type I enzymes only. Crystal structures of type II DHQases from Mycobacterium tuberculosis5 and Streptomyces coelicolor,6 as well as type I DHQase from Salmonella typhi,5 have been reported. The type II DHQases from M. tuberculosis (147 residues) and S. coelicolor (157 residues) show 34.7% and 37.7% sequence identity, respectively, to that from H. pylori over the entire polypeptide chain. There are subtle differences among the type II DHQases, as indicated by the discrimination between different type II enzymes by rationally designed inhibitors7 and different interactions of type II DHQases from M. tuberculosis and S. coelicolor with phosphate and sulfate.8 Therefore, structural information on DHQase from H. pylori will be valuable for structure-based design of selective inhibitors against H. pylori. Here, we present its crystal structure, which reveals an electron density for a ligand bound in the active site. Overexpression of H. pylori type II DHQase in the intact form, its crystallization, and X-ray data collection have been reported elsewhere.9 The structure was solved by the molecular replacement method with the use of the structure of M. tuberculosis DHQase [Protein Data Bank (PDB) code 2DHQ] as a search model. The refined model (PDB code 1J2Y) consists of 1,221 nonhydrogen atoms from 158 amino acid residues (residues 1–158) in a monomer, 19 water molecules, and one 3-dehydroquinate molecule in the asymmetric unit. The crystallographic R/Rfree values are 21.8%/27.2% for reflections with I > 2σ in the resolution range 20.0–2.6 Å. Refinement statistics are shown in Table I. Of 136 nonglycine and nonproline residues, 86.0% are in the most favored regions of the Ramachandran plot, 12.5% in additionally allowed regions, and 1.5% in generously allowed regions. Compared with most other type II DHQases, H. pylori DHQase is longer at its C-terminus by ∼13–21 residues. Part of this C-terminal extension (residues 159–167) does not have an electron density, presumably because it is disordered in the crystal. A truncated form (residues 1–147) of H. pylori type II DHQase has also been overexpressed and crystallized, with the hope that it would result in better diffracting crystals. However, the crystals diffracted to ∼3.4 Å resolution only, and the reflection spots were split. Thus, the truncated form was not pursued further. H. pylori DHQase forms a dodecamer of 23 symmetry, with each of the four trimers occupying the face of a tetrahedron [Fig. 1(A)]. Each subunit has a flavodoxin-like fold, comprised of a central five-stranded parallel β-sheet, which is flanked by two α-helices (α1 and α5) on one side and three α-helices (α2, α3, and α4) on the other side [Fig. 1(B)]. This is the same fold as that seen in M. tuberculosis and S. coelicolor enzymes. The root-mean-square difference between M. tuberculosis (PDB code 2DHQ) and H. pylori enzymes is 1.21 Å for 126 Cα atom pairs, and that between S. coelicolor (PDB code 1GU1; A chain) and H. pylori enzymes is 1.84 Å for 129 Cα atom pairs, respectively. Structure of H. pyloritype II DHQase. A: Dodecameric architecture. B: Monomer fold. C: Stereo view of the active site with a molecule of dehydroquinate (in red). The Cα backbone of one subunit is colored green, whereas that of the neighboring subunit is pink. Sidechains of 10 key residues are colored blue or cyan. In the structure of H. pylori DHQase, the active-site lid domain (residues 16–23) is in the closed conformation, similar to the 2,3-anhydro-quinic acid complex or the phosphate complex of S. coelicolor DHQase. In the apo structure of S. coelicolor DHQase, the lid domain is more open. The lid domain of H. pylori DHQase contains two key residues, Arg17 and Tyr22. Corresponding residues of M. tuberculosis DHQase have been found to be essential for enzyme activity.10 However, in M. tuberculosis DHQase, only a weak electron density defines poorly the flexible loop consisting of residues Arg19–Tyr24. An extra electron density was identified in the active site of H. pylori DHQase, although we did not include any ligand in the crystallization medium. The electron density was modeled as the substrate dehydroquinate in the absence of information about its identity. Ten key residues in the active site are shown in Figure 1(C). The orientation of the substrate and the arrangement of the key residues in the active site are highly similar to the 2,3-anhydro-quinic acid complex of S. coelicolor DHQase.6 Thus, it is possible to assign likely roles of key residues by analogy. Tyr22(Tyr28) abstracts a proton by acting as a base, and its pKa value is modulated by the charged sidechains of Arg17(Arg23) and Arg109(Arg113). The corresponding residues of S. coelicolor DHQase are given in parentheses. Asp89*(Asp92*) and Arg113(Arg117) form an ion pair, and their effects on Tyr22(Tyr28) may be canceled out. An asterisk after the residue number denotes that the residue comes from a neighboring subunit. Arg23 in the 2,3-anhydro-quinic acid complex of S. coelicolor DHQase is displaced away from the sidechain of Tyr 28 by the bound molecules of glycerol and tartrate. His82(His85) is close to the C5 hydroxyl group of the substrate. His102(His106) acts as a general acid for donating a proton to the C1 hydroxyl group, which is held in the proper position by interacting with Asn76(Asn79). The residue corresponding to Thr104 in H. pylori DHQase is Ser in all other type II DHQases. We thank Professor N. Sakabe and his staff for assistance during data collection at beamline BL-18B of Photon Factory, Japan." @default.
• W2056418905 created "2016-06-24" @default.
• W2056418905 creator A5029633820 @default.
• W2056418905 creator A5054547100 @default.
• W2056418905 creator A5060047552 @default.
• W2056418905 date "2003-05-05" @default.
• W2056418905 modified "2023-09-27" @default.
• W2056418905 title "Crystal structure of the type II 3-dehydroquinase from Helicobacter pylori" @default.
• W2056418905 cites W117267310 @default.
• W2056418905 cites W1604294821 @default.
• W2056418905 cites W1980987453 @default.
• W2056418905 cites W2019412059 @default.
• W2056418905 cites W2027788995 @default.
• W2056418905 cites W2088568869 @default.
• W2056418905 cites W2108020804 @default.
• W2056418905 cites W2141565472 @default.
• W2056418905 cites W2148430693 @default.
• W2056418905 cites W2196549155 @default.
• W2056418905 doi "https://doi.org/10.1002/prot.10415" @default.
• W2056418905 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/12784220" @default.
• W2056418905 hasPublicationYear "2003" @default.
• W2056418905 type Work @default.
• W2056418905 sameAs 2056418905 @default.
• W2056418905 citedByCount "14" @default.
• W2056418905 countsByYear W20564189052013 @default.
• W2056418905 countsByYear W20564189052014 @default.
• W2056418905 countsByYear W20564189052015 @default.
• W2056418905 countsByYear W20564189052017 @default.
• W2056418905 countsByYear W20564189052019 @default.
• W2056418905 countsByYear W20564189052020 @default.
• W2056418905 crossrefType "journal-article" @default.
• W2056418905 hasAuthorship W2056418905A5029633820 @default.
• W2056418905 hasAuthorship W2056418905A5054547100 @default.
• W2056418905 hasAuthorship W2056418905A5060047552 @default.
• W2056418905 hasConcept C115624301 @default.
• W2056418905 hasConcept C185592680 @default.
• W2056418905 hasConcept C18903297 @default.
• W2056418905 hasConcept C2776409635 @default.
• W2056418905 hasConcept C2777299769 @default.
• W2056418905 hasConcept C54355233 @default.
• W2056418905 hasConcept C8010536 @default.
• W2056418905 hasConcept C86803240 @default.
• W2056418905 hasConceptScore W2056418905C115624301 @default.
• W2056418905 hasConceptScore W2056418905C185592680 @default.
• W2056418905 hasConceptScore W2056418905C18903297 @default.
• W2056418905 hasConceptScore W2056418905C2776409635 @default.
• W2056418905 hasConceptScore W2056418905C2777299769 @default.
• W2056418905 hasConceptScore W2056418905C54355233 @default.
• W2056418905 hasConceptScore W2056418905C8010536 @default.
• W2056418905 hasConceptScore W2056418905C86803240 @default.
• W2056418905 hasIssue "4" @default.
• W2056418905 hasLocation W20564189051 @default.
• W2056418905 hasLocation W20564189052 @default.
• W2056418905 hasOpenAccess W2056418905 @default.
• W2056418905 hasPrimaryLocation W20564189051 @default.
• W2056418905 hasRelatedWork W1969215021 @default.
• W2056418905 hasRelatedWork W1969352129 @default.
• W2056418905 hasRelatedWork W2011272194 @default.
• W2056418905 hasRelatedWork W2045757565 @default.
• W2056418905 hasRelatedWork W2083548216 @default.
• W2056418905 hasRelatedWork W2117209888 @default.
• W2056418905 hasRelatedWork W2315457165 @default.
• W2056418905 hasRelatedWork W2711806730 @default.
• W2056418905 hasRelatedWork W2950083354 @default.
• W2056418905 hasRelatedWork W2560944600 @default.
• W2056418905 hasVolume "51" @default.
• W2056418905 isParatext "false" @default.
• W2056418905 isRetracted "false" @default.
• W2056418905 magId "2056418905" @default.
• W2056418905 workType "article" @default.