View source for Aldehyde dehydrogenase 18 family, member A1

{{Infobox_gene}}
'''Delta-1-pyrroline-5-carboxylate synthetase''' ('''P5CS''') is an [[enzyme]] that in humans is encoded by the ''ALDH18A1'' [[gene]].<ref name="pmid8921385">{{cite journal | vauthors = Liu G, Maunoury C, Kamoun P, Aral B | title = Assignment of the human gene encoding the delta 1-pyrroline-5-carboxylate synthetase (P5CS) to 10q24.3 by in situ hybridization | journal = Genomics | volume = 37 | issue = 1 | pages = 145–6 | date = Oct 1996 | pmid = 8921385 | pmc =  | doi = 10.1006/geno.1996.0535 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ALDH18A1 aldehyde dehydrogenase 18 family, member A1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5832| accessdate = }}</ref>
This gene is a member of the [[aldehyde dehydrogenase]] family and encodes a bifunctional [[Adenosine triphosphate|ATP]]- and [[NADPH]]-dependent [[mitochondrial|mitochondrial enzyme]] with both gamma-glutamyl [[kinase]] and gamma-glutamyl [[phosphate]] [[reductase]] activities. The encoded protein [[catalyzes]] the reduction of [[glutamate]] to delta1-pyrroline-5-carboxylate, a critical step in the [[de novo synthesis|de novo biosynthesis]] of [[proline]], [[ornithine]] and [[arginine]]. [[Mutations]] in this gene lead to [[hyperammonemia]], hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and may be associated with [[neurodegeneration]], [[cataracts]] and [[connective tissue diseases]]. Alternatively spliced [[Transcription (genetics)|transcript]] variants, encoding different [[isoforms]], have been described for this gene.<ref name="entrez"/>

== Structure ==

P5CS consists of two domains: gamma-glutamyl kinase and gamma-glutamyl phosphate reductase, each of which are used to complete the two steps to create ornithine and proline. The gamma-glutamyl kinase domain employs a 367-[[Amino acid|residue]] chain that folds into an [[N-terminal]] amino acid kinase domain, responsible for [[catalysis]] and proline inhibition, and a [[C-terminal]] PUA [[RNA]] binding domain. This enzyme is also a [[tetramer]] formed by two [[Protein dimer|dimers]], and the [[monomers]] and dimers are assembled in a manner that allows the amino acid kinase active pockets to be alternatively oriented in the tetramer.<ref name="pmid20970428">{{cite journal | vauthors = Pérez-Arellano I, Carmona-Álvarez F, Gallego J, Cervera J | title = Molecular mechanisms modulating glutamate kinase activity. Identification of the proline feedback inhibitor binding site | journal = Journal of Molecular Biology | volume = 404 | issue = 5 | pages = 890–901 | date = Dec 2010 | pmid = 20970428 | doi = 10.1016/j.jmb.2010.10.019 }}</ref> The short version (P5CS.short) and the long version (P5CS.long) of PC5S are two isoforms of this enzyme which differs by the addition of two amino acids in the long form and with an extra 6-bp insert following bp+711. This slight difference creates a dramatic difference in how they are affected by the [[Reaction inhibitor|inhibition]] of ornithine.<ref name="pmid10037775">{{cite journal | vauthors = Hu CA, Lin WW, Obie C, Valle D | title = Molecular enzymology of mammalian Delta1-pyrroline-5-carboxylate synthase. Alternative splice donor utilization generates isoforms with different sensitivity to ornithine inhibition | journal = The Journal of Biological Chemistry | volume = 274 | issue = 10 | pages = 6754–62 | date = Mar 1999 | pmid = 10037775 | doi=10.1074/jbc.274.10.6754}}</ref> The ''ALDH18A1'' gene spans 15 [[Base pairs|kb]], is mapped on 10q24.3, and has an [[exon]] count of 18.<ref name="entrez"/><ref name="pmid18401542">{{cite journal | vauthors = Hu CA, Khalil S, Zhaorigetu S, Liu Z, Tyler M, Wan G, Valle D | title = Human Delta1-pyrroline-5-carboxylate synthase: function and regulation | journal = Amino Acids | volume = 35 | issue = 4 | pages = 665–72 | date = Nov 2008 | pmid = 18401542 | doi = 10.1007/s00726-008-0075-0 | pmc=2707934}}</ref>

== Function ==

P5CS catalyzes the [[phosphorylation]]- and [[Reduction reaction|reduction]]-conversion of glutamate to Delta-1-pyrroline-5-carboxylate (P5C). This occurs through a process in which glutamate is converted into gamma-glutamyl phosphate in the gamma-glutamyl kinase domain and then the gamma-glutamyl phosphate is  the made into gamma-glutamic semi-aldehyde in the gamma-glutamyl phosphate reductase domain. The gamma-glutamic semi-aldehyde is in [[tautomeric]] [[Equilibrium reaction|equilibrium]] with P5C and it is the obligatory [[Chemical Intermediate|intermediate]] in the interconversions of proline, ornithine, and glutamate.<ref name="pmid18401542"/> The two isoforms (PC5S.short and PC5S.long) are both involved in different activities as well. The short version has high activity in the gut and is a main participant in the [[biosynthesis]] of arginine. The long version of PC5S is expressed in various tissues and is significant for its ability to synthesize proline from glutamate. Also, the short version is inhibited by ornithine, whereas the long version is insensitive to the amino acid.<ref name="pmid11092761">{{cite journal | vauthors = Baumgartner MR, Hu CA, Almashanu S, Steel G, Obie C, Aral B, Rabier D, Kamoun P, Saudubray JM, Valle D | title = 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 | journal = Human Molecular Genetics | volume = 9 | issue = 19 | pages = 2853–8 | date = Nov 2000 | pmid = 11092761 | doi=10.1093/hmg/9.19.2853}}</ref>

== Clinical significance ==

Ornithine and/or arginine are key intermediates for the synthesis of [[urea]], [[creatine]], [[nitric oxide]], [[polyamines]], and [[protein]]; while proline is a major component of the connective tissue
proteins, [[collagen]] and [[elastin]]. Because all three of these amino acids are a part of very significant processes, the presence of P5CS becomes an important regulator which makes sure that none of these three become deficient.<ref name="pmid22170564">{{cite journal | vauthors = Martinelli D, Häberle J, Rubio V, Giunta C, Hausser I, Carrozzo R, Gougeard N, Marco-Marín C, Goffredo BM, Meschini MC, Bevivino E, Boenzi S, Colafati GS, Brancati F, Baumgartner MR, Dionisi-Vici C | title = Understanding pyrroline-5-carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structure-based analysis, and novel therapy with arginine | journal = Journal of Inherited Metabolic Disease | volume = 35 | issue = 5 | pages = 761–76 | date = Sep 2012 | pmid = 22170564 | doi = 10.1007/s10545-011-9411-8 }}</ref> Therefore, a lack of P5CS, due to mutations in the ''ALDH18A1'' gene, often leads to neurodegeneration, [[Laxity of ligament|joint laxity]], skin [[hyperelasticity]], bilateral sub capsular cataracts, and a plethora of other complications associated with impaired proline and ornithine synthesis.<ref name="pmid11092761"/>

== Interactions ==

P5CS has been seen to interact with:
* [[glutamate]]
* [[glutamyl|gamma-glutamyl phosphate]]
* [[ornithine]]

== References ==
{{reflist}}

==External links==
* {{UCSC gene info|ALDH18A1}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = Jan 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Aral B, Schlenzig JS, Liu G, Kamoun P | title = Database cloning human delta 1-pyrroline-5-carboxylate synthetase (P5CS) cDNA: a bifunctional enzyme catalyzing the first 2 steps in proline biosynthesis | journal = Comptes Rendus De L'Académie Des Sciences. Série III, Sciences De La Vie | volume = 319 | issue = 3 | pages = 171–8 | date = Mar 1996 | pmid = 8761662 | doi =  }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = Oct 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
* {{cite journal | vauthors = Hu CA, Lin WW, Obie C, Valle D | title = Molecular enzymology of mammalian Delta1-pyrroline-5-carboxylate synthase. Alternative splice donor utilization generates isoforms with different sensitivity to ornithine inhibition | journal = The Journal of Biological Chemistry | volume = 274 | issue = 10 | pages = 6754–62 | date = Mar 1999 | pmid = 10037775 | doi = 10.1074/jbc.274.10.6754 }}
* {{cite journal | vauthors = Baumgartner MR, Hu CA, Almashanu S, Steel G, Obie C, Aral B, Rabier D, Kamoun P, Saudubray JM, Valle D | title = 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 | journal = Human Molecular Genetics | volume = 9 | issue = 19 | pages = 2853–8 | date = Nov 2000 | pmid = 11092761 | doi = 10.1093/hmg/9.19.2853 }}
* {{cite journal | vauthors = Baumgartner MR, Rabier D, Nassogne MC, Dufier JL, Padovani JP, Kamoun P, Valle D, Saudubray JM | title = Delta1-pyrroline-5-carboxylate synthase deficiency: neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonaemia and reduced ornithine, citrulline, arginine and proline | journal = European Journal of Pediatrics | volume = 164 | issue = 1 | pages = 31–6 | date = Jan 2005 | pmid = 15517380 | doi = 10.1007/s00431-004-1545-3 }}
{{refend}}

{{PDB Gallery|geneid=5832}}
{{Aldehyde dehydrogenases}}

[[Category:Genes mutated in mice]]