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Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
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discounted EARLY registration ends Dec 31, 2014
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MetaCyc Enzyme: δ-1-pyrroline-5-carboxylate synthase

Gene: ALDH18A1 Accession Number: HS00730 (MetaCyc)

Synonyms: GSAS, P5CS, PYCS, aldehyde dehydrogenase family 18 member A1, gamma-glutamyl kinase, GK, glutamate-5-semialdehyde dehydrogenase, glutamyl-gamma-semialdehyde dehydrogenase, GPR

Species: Homo sapiens

Summary:
Bifunctional δ-1-pyrroline-5-carboxylate synthase possesses both γ-glutamyl kinase and γ-glutamyl phosphate reductase activities [Aral96]. It is a mitochondrial inner membrane protein [Hu99]. The enzyme catalyzes the ATP-dependent reduction of L-glutamate to γ-L-glutamyl 5-phosphate and the NADPH-dependent conversion of γ-L-glutamyl 5-phosphate toL-glutamate-5-semialdehyde. Both are critical steps in the de novo biosynthesis of proline, arginine and ornithine.

There are two isoforms of the enzyme, long and short, expressed in tissue. The isoforms arise from "exon sliding", a form of alternate splicing. The short form demonstrates sensitivity to inhibition by ornithine, while the long form does not [Hu99].

Deficiencies in δ-1-pyrroline-5-carboxylate synthase are caused by autosomal recessive neurocutaneous syndrome [Bicknell08]. Phenotypic characteristics include joint hyperlaxity, skin hyperelasticity, cataract and mental retardation with hyperammonemia and low plasma levels of proline, citrulline and ornithine [Aral96, Baumgartner05].

Locations: mitochondrion

Map Position: [96,599,353 <- 96,650,033]

Molecular Weight of Polypeptide: 87.302 kD (from nucleotide sequence)

Unification Links: Ensembl:ENSG00000059573 , Entrez-gene:5832 , Entrez-Nucleotide:U68758 , Entrez-Nucleotide:U76542 , Entrez-Nucleotide:X94453 , Entrez:AAD00169 , Entrez:AAD17454 , Entrez:CAA64224 , GeneCards:PYCS , Mint:MINT-3020614 , ModBase:P54886 , MOPED:P54886 , OMIM:138250 , PhosphoSite:P54886 , Pride:P54886 , Protein Model Portal:P54886 , RefSeq:NM_002860 , RefSeq:NP_002851 , SMR:P54886 , Swiss-Model:P54886 , UCSC Human Genome:NM_002860 , UniGene:114366 , UniProt:P54886

Relationship Links: InterPro:IN-FAMILY:IPR000965 , InterPro:IN-FAMILY:IPR001048 , InterPro:IN-FAMILY:IPR001057 , InterPro:IN-FAMILY:IPR005766 , InterPro:IN-FAMILY:IPR015590 , InterPro:IN-FAMILY:IPR016161 , InterPro:IN-FAMILY:IPR016162 , InterPro:IN-FAMILY:IPR016163 , InterPro:IN-FAMILY:IPR019797 , InterPro:IN-FAMILY:IPR020593 , PDB:Structure:2H5G , Pfam:IN-FAMILY:PF00171 , Pfam:IN-FAMILY:PF00696 , Prints:IN-FAMILY:PR00474 , Prosite:IN-FAMILY:PS00902 , Prosite:IN-FAMILY:PS01223

Gene-Reaction Schematic: ?

GO Terms:

Molecular Function: GO:0003942 - N-acetyl-gamma-glutamyl-phosphate reductase activity
GO:0004349 - glutamate 5-kinase activity
GO:0004350 - glutamate-5-semialdehyde dehydrogenase activity
Cellular Component: GO:0005739 - mitochondrion
GO:0019866 - organelle inner membrane


Enzymatic reaction of: γ-glutamyl phosphate reductase (δ-1-pyrroline-5-carboxylate synthase)

EC Number: 1.2.1.41

L-glutamate-5-semialdehyde + NADP+ + phosphate <=> γ-L-glutamyl 5-phosphate + NADPH + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the opposite direction.

In Pathways: superpathway of citrulline metabolism , citrulline biosynthesis , ornithine de novo biosynthesis , proline biosynthesis I


Enzymatic reaction of: γ-glutamyl kinase (δ-1-pyrroline-5-carboxylate synthase)

EC Number: 2.7.2.11

L-glutamate + ATP <=> γ-L-glutamyl 5-phosphate + ADP

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: superpathway of citrulline metabolism , citrulline biosynthesis , ornithine de novo biosynthesis , proline biosynthesis I


References

Aral96: Aral B, Schlenzig JS, Liu G, Kamoun P (1996). "Database cloning human delta 1-pyrroline-5-carboxylate synthetase (P5CS) cDNA: a bifunctional enzyme catalyzing the first 2 steps in proline biosynthesis." C R Acad Sci III 319(3);171-8. PMID: 8761662

Baumgartner00: Baumgartner MR, Hu CA, Almashanu S, Steel G, Obie C, Aral B, Rabier D, Kamoun P, Saudubray JM, Valle D (2000). "Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase." Hum Mol Genet 9(19);2853-8. PMID: 11092761

Baumgartner05: Baumgartner MR, Rabier D, Nassogne MC, Dufier JL, Padovani JP, Kamoun P, Valle D, Saudubray JM (2005). "Delta1-pyrroline-5-carboxylate synthase deficiency: neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonaemia and reduced ornithine, citrulline, arginine and proline." Eur J Pediatr 164(1);31-6. PMID: 15517380

Bicknell08: Bicknell LS, Pitt J, Aftimos S, Ramadas R, Maw MA, Robertson SP (2008). "A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome." Eur J Hum Genet 16(10);1176-86. PMID: 18478038

Hu99: Hu CA, Lin WW, Obie C, Valle D (1999). "Molecular enzymology of mammalian Delta1-pyrroline-5-carboxylate synthase. Alternative splice donor utilization generates isoforms with different sensitivity to ornithine inhibition." J Biol Chem 274(10);6754-62. PMID: 10037775


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Sun Dec 21, 2014, biocyc13.