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Pyrroline‐5‐carboxylate synthase and proline biosynthesis: From osmotolerance to rare metabolic disease
Author(s) -
PérezArellano Isabel,
CarmonaÁlvarez Francisco,
Martínez Ana I.,
RodríguezDíaz Jesús,
Cervera Javier
Publication year - 2010
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.340
Subject(s) - proline , phosphofructokinase 2 , biochemistry , ornithine aminotransferase , enzyme , biosynthesis , mutant , citrulline , glycosyltransferase , biology , active site , atp synthase , ornithine , chemistry , amino acid , arginine , gene
Pyrroline‐5‐carboxylate synthase (P5CS) is a bifunctional enzyme that exhibits glutamate kinase (GK) and γ‐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.