Dataset Information

Metallo-beta-lactamase fold within nucleic acids processing enzymes: the beta-CASP family.

ABSTRACT: A separate family of enzymes within the metallo-beta-lactamase fold comprises several important proteins acting on nucleic acid substrates, involved in DNA repair (Artemis, SNM1 and PSO2) and RNA processing [cleavage and polyadenylation specificity factor (CPSF) subunit]. Proteins of this family, named beta-CASP after the names of its representative members, possess specific features relative to those of other metallo-beta-lactamases, that are concentrated in the C-terminal part of the domain. In this study, using sensitive methods of sequence analysis, we identified highly conserved amino acids specific to the beta-CASP family, some of which were unidentified to date, that are predicted to play critical roles in the enzymatic function. The identification and characterisation of all the extant, detectable beta-CASP members within sequence databases and genome data also allowed us to unravel particular sequence features which are likely to be involved in substrate specificity, as well as to describe new but as yet uncharacterised members which may play critical roles in DNA and RNA metabolism.

SUBMITTER: Callebaut I

PROVIDER: S-EPMC134238 | biostudies-literature | 2002 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Metallo-beta-lactamase fold within nucleic acids processing enzymes: the beta-CASP family.

Callebaut Isabelle I Moshous Despina D Mornon Jean-Paul JP de Villartay Jean-Pierre JP

Nucleic acids research 20020801 16

A separate family of enzymes within the metallo-beta-lactamase fold comprises several important proteins acting on nucleic acid substrates, involved in DNA repair (Artemis, SNM1 and PSO2) and RNA processing [cleavage and polyadenylation specificity factor (CPSF) subunit]. Proteins of this family, named beta-CASP after the names of its representative members, possess specific features relative to those of other metallo-beta-lactamases, that are concentrated in the C-terminal part of the domain. I ...[more]

PMID: 12177301

Similar Datasets

Project description:Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance in Enterobacteriaceae Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistant Enterobacteriaceae (CRE). We report here that sulfamoyl heteroarylcarboxylic acids (SHCs) can competitively inhibit the globally spreading and clinically relevant MBLs (i.e., IMP-, NDM-, and VIM-type MBLs) at nanomolar to micromolar orders of magnitude. Addition of SHCs restored meropenem efficacy against 17/19 IMP-type and 7/14 NDM-type MBL-producing Enterobacteriaceae to satisfactory clinical levels. SHCs were also effective against IMP-type MBL-producing Acinetobacter spp. and engineered Escherichia coli strains overproducing individual minor MBLs (i.e., TMB-2, SPM-1, DIM-1, SIM-1, and KHM-1). However, SHCs were less effective against MBL-producing Pseudomonas aeruginosa Combination therapy with meropenem and SHCs successfully cured mice infected with IMP-1-producing E. coli and dually NDM-1/VIM-1-producing Klebsiella pneumoniae clinical isolates. X-ray crystallographic analyses revealed the inhibition mode of SHCs against MBLs; the sulfamoyl group of SHCs coordinated to two zinc ions, and the carboxylate group coordinated to one zinc ion and bound to positively charged amino acids Lys224/Arg228 conserved in MBLs. Preclinical testing revealed that the SHCs showed low toxicity in cell lines and mice and high stability in human liver microsomes. Our results indicate that SHCs are promising lead compounds for inhibitors of MBLs to combat MBL-producing CRE.IMPORTANCE Carbapenem antibiotics are the last resort for control of severe infectious diseases, bloodstream infections, and pneumonia caused by Gram-negative bacteria, including Enterobacteriaceae However, carbapenem-resistant Enterobacteriaceae (CRE) strains have spread globally and are a critical concern in clinical settings because CRE infections are recognized as a leading cause of increased mortality among hospitalized patients. Most CRE produce certain kinds of serine carbapenemases (e.g., KPC- and GES-type β-lactamases) or metallo-β-lactamases (MBLs), which can hydrolyze carbapenems. Although effective MBL inhibitors are expected to restore carbapenem efficacy against MBL-producing CRE, no MBL inhibitor is currently clinically available. Here, we synthesized 2,5-diethyl-1-methyl-4-sulfamoylpyrrole-3-carboxylic acid (SPC), which is a potent inhibitor of MBLs. SPC is a remarkable lead compound for clinically useful MBL inhibitors and can potentially provide a considerable benefit to patients receiving treatment for lethal infectious diseases caused by MBL-producing CRE.

Dataset Information

Metallo-beta-lactamase fold within nucleic acids processing enzymes: the beta-CASP family.

Publications

Metallo-beta-lactamase fold within nucleic acids processing enzymes: the beta-CASP family.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets