title: Chemogenomics of pyridoxal 5'-phosphate dependent enzymes.
abstract: Pyridoxal 5'-phosphate (PLP) dependent enzymes comprise a large family that plays key roles in amino acid metabolism and are acquiring an increasing interest as drug targets. For the identification of compounds inhibiting PLP-dependent enzymes, a chemogenomics-based approach has been adopted in this work. Chemogenomics exploits the information coded in sequences and three-dimensional structures to define pharmacophore models. The analysis was carried out on a dataset of 65 high-resolution PLP-dependent enzyme structures, including representative members of four-fold types. Evolutionarily conserved residues relevant to coenzyme or substrate binding were identified on the basis of sequence-structure comparisons. A dataset was obtained containing the information on conserved residues at substrate and coenzyme binding site for each representative PLP-dependent enzyme. By linking coenzyme and substrate pharmacophores, bifunctional pharmacophores were generated that will constitute the basis for future development of small inhibitors targeting specific PLP-dependent enzymes.
authors.affiliation: Department of Biochemistry and Molecular Biology and Laboratory of Molecular Modelling, University of Parma, Parma, Italy.
authors.forename: Ratna
authors.initials: R
authors.lastname: Singh
authors.forename: Francesca
authors.initials: F
authors.lastname: Spyrakis
authors.forename: Pietro
authors.initials: P
authors.lastname: Cozzini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Paiardini
authors.forename: Stefano
authors.initials: S
authors.lastname: Pascarella
authors.forename: Andrea
authors.initials: A
authors.lastname: Mozzarelli
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002262:Carboxy-Lyases / Q000737:chemistry / Q000378:metabolism; D017124:Conserved Sequence; D030562:Databases, Protein; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism*; D019143:Evolution, Molecular; D008190:Lyases / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D011732:Pyridoxal Phosphate / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D000637:Transaminases / Q000737:chemistry / Q000378:metabolism
chemical_list: D004798:Enzymes; D011732:Pyridoxal Phosphate; D000637:Transaminases; D008190:Lyases; D002262:Carboxy-Lyases