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Deciphering the mechanism by which 1-pyrrolin-5-carboxylate synthetase defects associate with dominant and recessive human pathologies

AutorEscamilla Honrubia, Juan Manuel; Marco-Marín, Clara ; Gougeard, Nadine; Rubio, Vicente
Fecha de publicación7-sep-2015
CitaciónXXXVIII Congreso de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM). (2015)
ResumenΔ1-Pyrrolin-5-carboxylate synthetase (P5CS) is a bifunctional enzyme that catalyzesthe first two steps of ornithine/proline biosynthesis in plants and animals. It is composed of an N-terminal glutamate-5-kinase (G5K) domain that uses ATP to phosphorylate the γ-carboxylate of glutamate, and of a C-terminal L-glutamyl-5-phosphate reductase (G5PR) domain that reductively dephosphorylates L-glutamyl-5-phosphate to L-glutamate-5-semialdehyde. This compound spontaneously cyclizes to Δ1-pyrrolin-5-carboxylate, thus being a precursor of both ornithine and proline. Human P5CS deficiency was associated with a fasting hyperammonemia syndrome with cataracts and vomiting. Then the syndrome was expanded to include a cutis laxa phenotype and more recently it has been associated with spastic paraplegia of dominant or recessive inheritance. Using our baculovirus/insect cell system for producing pure recombinant human P5CS, we introduced dominant and recessive mutations in the enzyme by site-directed mutagenesis, assaying enzyme activity. All the mutations, irrespectively of the type of inheritance they gave, inactivated the catalytic domain of P5CS where they mapped. Gel filtration and modelling evidence strongly suggests that the mutations giving dominant inheritance appear to cause their effects by a negative dominant mechanism. In particular, they are located on the surface of the two domains, in places that in E. coli G5K (a monofuntional tetrameric enzyme) are used in interactions with adjacent domains. Therefore, these dominant mutations may disturb the hexameric enzyme architecture, preventing potential "in vivo" channelling of L-glutamyl-5-phosphate from the G5K domain to a G5PR domain from an adjacent subunit.
DescripciónPóster original presentado al XXXVIII Congreso de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM), celebrado en Valencia, 7-10 de septiembre de 2015
URIhttp://hdl.handle.net/10261/123116
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