The applications of binuclear metallohydrolases in medicine: recent advances in the design and development of novel drug leads for purple acid phosphatases, metallo-beta-lactamases and arginases

McGeary, Ross P., Schenk, Gerhard and Guddat, Luke W. (2014) The applications of binuclear metallohydrolases in medicine: recent advances in the design and development of novel drug leads for purple acid phosphatases, metallo-beta-lactamases and arginases. European Journal of Medicinal Chemistry, 76 132-144. doi:10.1016/j.ejmech.2014.02.008


Author McGeary, Ross P.
Schenk, Gerhard
Guddat, Luke W.
Title The applications of binuclear metallohydrolases in medicine: recent advances in the design and development of novel drug leads for purple acid phosphatases, metallo-beta-lactamases and arginases
Formatted title
The applications of binuclear metallohydrolases in medicine: recent advances in the design and development of novel drug leads for purple acid phosphatases, metallo-β-lactamases and arginases
Journal name European Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0223-5234
1768-3254
Publication date 2014-04-09
Year available 2014
Sub-type Article (original research)
DOI 10.1016/j.ejmech.2014.02.008
Open Access Status Not yet assessed
Volume 76
Start page 132
End page 144
Total pages 13
Place of publication Issy les Moulineaux, France
Publisher Elsevier Masson
Language eng
Abstract Binuclear metallohydrolases are a family of proteins that can be targeted for drug discovery. The common feature of these enzymes is the presence of two closely spaced metal ions (i.e. less than 4 angstrom apart) that capture a water molecule that is used as a nucleophile in highly specific hydrolytic reactions. In this mini-review we describe what is known about the biological and catalytic activity, three-dimensional structure and inhibition for three prominent drug targets in this family of enzymes, (i) purple acid phosphatases, (ii) metallo-beta-lactamases and (iii) arginases. These enzymes are targets for the development of chemotherapeutics to treat a range of disorders including osteoporosis, cardiovascular disease and erectile dysfunctions, but also to stem the spread of antibiotic resistance, a major threat to global health care. (C) 2014 Elsevier Masson SAS. All rights reserved.
Formatted abstract
Highlights
• Binuclear metallohydrolases are enzymes involved in various metabolic functions.
• Several binuclear metallohydrolases are current targets for drug development.
• Targeted disorders range from osteoporosis to erectile dysfunctions.
• A major strategy to acquire antibiotic resistance involves enzymes from this group.
• Potent inhibitors with nanomolar inhibition constants have recently been developed.

Binuclear metallohydrolases are a family of proteins that can be targeted for drug discovery. The common feature of these enzymes is the presence of two closely spaced metal ions (i.e. less than 4 Å apart) that capture a water molecule that is used as a nucleophile in highly specific hydrolytic reactions. In this mini-review we describe what is known about the biological and catalytic activity, three-dimensional structure and inhibition for three prominent drug targets in this family of enzymes, (i) purple acid phosphatases, (ii) metallo-β-lactamases and (iii) arginases. These enzymes are targets for the development of chemotherapeutics to treat a range of disorders including osteoporosis, cardiovascular disease and erectile dysfunctions, but also to stem the spread of antibiotic resistance, a major threat to global health care.
Keyword Metalloenzymes
Drug development
Osteoporosis
Antibiotic
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID FT120100694
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
 
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Created: Fri, 07 Mar 2014, 19:55:25 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences