6-Pyruvoyltetrahydropterin synthase

This enzyme belongs to the family of lyases, to be specific, those carbon-oxygen lyases acting on phosphates. The systematic name of this enzyme class is 6-[(1S,2R)-1,2-dihydroxy-3′-triphosphooxypropyl]-7,8-dihydropterin triphosphate-lyase (6-pyruvoyl-5,6,7,8-tetrahydropterin-forming). Other names in common use include 2-amino-4-oxo-6-[(1S,2R)-1,2-dihydroxy-3-triphosphooxypropyl]-7,8-, and dihydroxypteridine triphosphate lyase.

6-pyruvoyltetrahydropterin synthase (PTPS) is a hexamer with D3 symmetry, and dimensions 60 × 60 × 60 A ̊.{{cite book | title = Encyclopedia of Inorganic and Bioinorganic Chemistry | last = Nar | first = Herbert | name-list-style = vanc | date = 2011 | publisher = John Wiley & Sons, Ltd | isbn = 978-1-119-95143-8 | doi = 10.1002/9781119951438.eibc0475 }} It is composed of identical subunits formed from a dimer of trimers. A 12-stranded antiparallel b-barrel is formed by the trimer of dimers and creates a pore within PTPS, with a 6 to 12 A ̊ diameter.{{cite journal | vauthors = Ploom T, Thöny B, Yim J, Lee S, Nar H, Leimbacher W, Richardson J, Huber R, Auerbach G | title = Crystallographic and kinetic investigations on the mechanism of 6-pyruvoyl tetrahydropterin synthase | journal = Journal of Molecular Biology | volume = 286 | issue = 3 | pages = 851–60 | date = February 1999 | pmid = 10024455 | doi = 10.1006/jmbi.1998.2511 }} The trimers are connected by contact between the β-sheets of monomers, which are perpendicular to each other, separated by less than 4 Angstroms, and connected in three locations residues 20–24, 48–51, and 89–91.

One enzymatic active site is located where the three monomers come together in each subunit of the hexamer. Three histidine residues: His23, His48 and His50 create a transition metal binding site where Zn(II) binds and is the cause of enzymatic{{cite journal | first1 = Nenad | last1 = Blaui | first2 = Beat | last2 = Thony | first3= Claus W. | last3 = Heizmanni | first4 = Jean-Louis | last4 = Dhondt | name-list-style = vanc | url = http://doc.rero.ch/record/297208/files/pteridines | title = Tetrahydrobiopterin Deficiency: From Phenotype to Genotype | journal = Pteridines | volume = 4 | date = 1993 | pages = 1–10 | doi = 10.1515/pteridines.1993.4.1.1 | s2cid = 53485331 | doi-access = free }} activity in the center of the pore.{{cite journal | vauthors = Nar H, Huber R, Heizmann CW, Thöny B, Bürgisser D | title = Three-dimensional structure of 6-pyruvoyl tetrahydropterin synthase, an enzyme involved in tetrahydrobiopterin biosynthesis | journal = The EMBO Journal | volume = 13 | issue = 6 | pages = 1255–62 | date = March 1994 | pmid = 8137809 | pmc = 394939 | doi = 10.1002/j.1460-2075.1994.tb06377.x }} Above the Zn(II) ion are GluA133 and CysA42, which are catalytically important because they are close to the metal but do not bind to it. The lack of binding implies that the substrate binds to the Zn(II) inside the pore during catalysis.

This enzyme 6-pyruvoyltetrahydropterin synthase is encoded by the PTS gene. A mutation in the 6-PTS gene may be the cause of a hereditary dystonic disorder.{{Cite web|url=https://ghr.nlm.nih.gov/condition/tetrahydrobiopterin-deficiency|title=Tetrahydrobiopterin deficiency|last=Reference|first=Genetics Home|website=Genetics Home Reference|language=en|access-date=2018-03-09}} There have been four mutations of the 6-PTS gene found. The mutations include two homozygous mutations, R25Q and I114V, and two compound heterozygous mutations, R16C and K120stop.{{cite journal | vauthors = Thöny B, Blau N | title = Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes | journal = Human Mutation | volume = 10 | issue = 1 | pages = 11–20 | date = 1997 | pmid = 9222755 | doi = 10.1002/(SICI)1098-1004(1997)10:1<11::AID-HUMU2>3.0.CO;2-P | s2cid = 9085242 }} The deficiency is only associated with the recessive gene being passed on from parent to child.

6-Pyruvoyltetrahydropterin synthase deficiency is the most common cause of a deficiency of tetrahydrobiopterin. Tetrahydrobiopterin deficiency leads to hyperphenylalaninemia and the inability to make neurotransmitters such as dopamine and serotonin.{{cite journal | vauthors = Hanihara T, Inoue K, Kawanishi C, Sugiyama N, Miyakawa T, Onishi H, Yamada Y, Osaka H, Kosaka K, Iwabuchi K, Owada M | title = 6-Pyruvoyl-tetrahydropterin synthase deficiency with generalized dystonia and diurnal fluctuation of symptoms: a clinical and molecular study | journal = Movement Disorders | volume = 12 | issue = 3 | pages = 408–11 | date = May 1997 | pmid = 9159737 | doi = 10.1002/mds.870120321 | s2cid = 43917747 }} PTPS deficiency has been shown to lead to severe mental retardation, delayed motor development, and seizures. Low levels of tetrahydrobiopterin production, opposed to near complete lack of tetrahydrobiopterin may cause fluctuations in the symptoms experienced throughout the day.

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• {{cite journal | vauthors = Milstien S, Kaufman S | title = The biosynthesis of tetrahydrobiopterin in rat brain. Purification and characterization of 6-pyruvoyl tetrahydropterin (2'-oxo)reductase | journal = The Journal of Biological Chemistry | volume = 264 | issue = 14 | pages = 8066–73 | date = May 1989 | doi = 10.1016/S0021-9258(18)83151-9 | pmid = 2656673 | doi-access = free }}
• {{cite journal | vauthors = Thöny B, Leimbacher W, Bürgisser D, Heizmann CW | title = Human 6-pyruvoyltetrahydropterin synthase: cDNA cloning and heterologous expression of the recombinant enzyme | journal = Biochemical and Biophysical Research Communications | volume = 189 | issue = 3 | pages = 1437–43 | date = December 1992 | pmid = 1282802 | doi = 10.1016/0006-291X(92)90235-D }}

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{{Metabolism of vitamins, coenzymes, and cofactors}}

{{Carbon-oxygen lyases}}

{{Enzymes}}

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Category:EC 4.2.3

Category:Enzymes of known structure