Abstract
Cytidine deaminase (CDA), is one of the enzymes involved in the pyrimidine salvage pathways, which catalyzes the formation of uridine and deoxyuridine by the hydrolytic deamination of cytidine and deoxycytidine, respectively. Human CDA is a tetrameric enzyme of identical 15 kDa subunits, each containing an essential zinc atom in the active site. The substrate binds to each active site independently and the cooperativity between subunits has not been reported. CDA is able to recognize as substrates some antitumor and antiviral cytidine analogs rendering them pharmacologically inactive. In light of the role played by this enzyme, a deep knowledge of CDA active site and mechanism of catalysis is required. Site-directed mutagenesis, associated with molecular modeling studies, may be an important tool to discover the active site structure of an enzyme and consequently its mechanism of action. In this review are summarized the site-directed mutagenesis experiments performed on human CDA: through these studies it was possible to understand the role exerted by specific amino acid residues in CDA active site and in the contacts between subunits. The obtained results may open a way for designing new cytidine based drugs or more potent CDA inhibitors.
Keywords: Active site, cytidine deaminase, mechanism of catalysis, site-directed mutagenesis
Protein & Peptide Letters
Title:Site Directed Mutagenesis as a Tool to Understand the Catalytic Mechanism of Human Cytidine Deaminase
Volume: 20 Issue: 5
Author(s): Silvia Vincenzetti, Stefania Pucciarelli, Francesco M. Carpi, Daniela Micozzi, Valeria Polzonetti, Paolo Natalini, Ivano Santarelli, Paolo Polidori and Alberto Vita
Affiliation:
Keywords: Active site, cytidine deaminase, mechanism of catalysis, site-directed mutagenesis
Abstract: Cytidine deaminase (CDA), is one of the enzymes involved in the pyrimidine salvage pathways, which catalyzes the formation of uridine and deoxyuridine by the hydrolytic deamination of cytidine and deoxycytidine, respectively. Human CDA is a tetrameric enzyme of identical 15 kDa subunits, each containing an essential zinc atom in the active site. The substrate binds to each active site independently and the cooperativity between subunits has not been reported. CDA is able to recognize as substrates some antitumor and antiviral cytidine analogs rendering them pharmacologically inactive. In light of the role played by this enzyme, a deep knowledge of CDA active site and mechanism of catalysis is required. Site-directed mutagenesis, associated with molecular modeling studies, may be an important tool to discover the active site structure of an enzyme and consequently its mechanism of action. In this review are summarized the site-directed mutagenesis experiments performed on human CDA: through these studies it was possible to understand the role exerted by specific amino acid residues in CDA active site and in the contacts between subunits. The obtained results may open a way for designing new cytidine based drugs or more potent CDA inhibitors.
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Vincenzetti Silvia, Pucciarelli Stefania, M. Carpi Francesco, Micozzi Daniela, Polzonetti Valeria, Natalini Paolo, Santarelli Ivano, Polidori Paolo and Vita Alberto, Site Directed Mutagenesis as a Tool to Understand the Catalytic Mechanism of Human Cytidine Deaminase, Protein & Peptide Letters 2013; 20 (5) . https://dx.doi.org/10.2174/0929866511320050007
DOI https://dx.doi.org/10.2174/0929866511320050007 |
Print ISSN 0929-8665 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5305 |
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