title: Pyrroline-5-carboxylate synthase and proline biosynthesis: from osmotolerance to rare metabolic disease.
abstract: Pyrroline-5-carboxylate synthase (P5CS) is a bifunctional enzyme that exhibits glutamate kinase (GK) and gamma-glutamyl phosphate reductase (GPR) activities. The enzyme is highly relevant in humans because it belongs to a combined route for the interconversion of glutamate, ornithine and proline. The deficiency of P5CS activity in humans is associated with a rare, inherited metabolic disease. It is well established that some bacteria and plants accumulate proline in response to osmotic stress. The alignment of P5CSs from different species and analysis of the solved structures of GK and GPR reveal high sequence and structural conservation. The information acquired from different mutant enzymes with increased osmotolerant properties, together with the position of the insertion found in the longer human isoform, permit the delimitation of the regulatory site of GK and P5CS and the proposal of a model of P5CS architecture. Additionally, the GK moiety of the human enzyme has been modeled and the known clinical mutations and polymorphisms have been mapped.
authors.affiliation: Molecular Recognition Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Pérez-Arellano
authors.forename: Francisco
authors.initials: F
authors.lastname: Carmona-Alvarez
authors.forename: Ana I
authors.initials: AI
authors.lastname: Martínez
authors.forename: Jesús
authors.initials: J
authors.lastname: Rodríguez-Díaz
authors.forename: Javier
authors.initials: J
authors.lastname: Cervera
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001419:Bacteria / Q000201:enzymology; D006801:Humans; D008659:Metabolic Diseases / Q000201:enzymology* / Q000235:genetics; D009953:Ornithine-Oxo-Acid Transaminase / Q000235:genetics / Q000378:metabolism*; D009996:Osmotic Fragility; D009997:Osmotic Pressure; D010944:Plants / Q000201:enzymology; D011392:Proline / Q000096:biosynthesis*; D011487:Protein Conformation; D016415:Sequence Alignment
chemical_list: D011392:Proline; D009953:Ornithine-Oxo-Acid Transaminase