ID   GCH1_RAT                Reviewed;         241 AA.
AC   P22288;
DT   01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1991, sequence version 1.
DT   27-MAR-2024, entry version 185.
DE   RecName: Full=GTP cyclohydrolase 1;
DE            EC=3.5.4.16 {ECO:0000269|PubMed:2557335};
DE   AltName: Full=GTP cyclohydrolase I;
DE            Short=GTP-CH-I;
DE   Flags: Precursor;
GN   Name=Gch1; Synonyms=Gch;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RC   STRAIN=Wistar; TISSUE=Liver;
RX   PubMed=1985963; DOI=10.1016/s0021-9258(17)35238-9;
RA   Hatakeyama K., Inoue Y., Harada T., Kagamiyama H.;
RT   "Cloning and sequencing of cDNA encoding rat GTP cyclohydrolase I. The
RT   first enzyme of the tetrahydrobiopterin biosynthetic pathway.";
RL   J. Biol. Chem. 266:765-769(1991).
RN   [2]
RP   PROTEIN SEQUENCE OF 37-46 AND 99-116.
RX   PubMed=7802677; DOI=10.1006/bbrc.1994.2822;
RA   Imazumi K., Sasaki T., Takahashi K., Takai Y.;
RT   "Identification of a rabphilin-3A-interacting protein as GTP cyclohydrolase
RT   I in PC12 cells.";
RL   Biochem. Biophys. Res. Commun. 205:1409-1416(1994).
RN   [3]
RP   PARTIAL PROTEIN SEQUENCE, CATALYTIC ACTIVITY, PATHWAY, BIOPHYSICOCHEMICAL
RP   PROPERTIES, AND ACTIVITY REGULATION.
RX   PubMed=2557335; DOI=10.1016/s0021-9258(20)88236-2;
RA   Hatakeyama K., Harada T., Suzuki S., Watanabe Y., Kagamiyama H.;
RT   "Purification and characterization of rat liver GTP cyclohydrolase I.
RT   Cooperative binding of GTP to the enzyme.";
RL   J. Biol. Chem. 264:21660-21664(1989).
RN   [4]
RP   FUNCTION.
RX   PubMed=17057711; DOI=10.1038/nm1490;
RA   Tegeder I., Costigan M., Griffin R.S., Abele A., Belfer I., Schmidt H.,
RA   Ehnert C., Nejim J., Marian C., Scholz J., Wu T., Allchorne A.,
RA   Diatchenko L., Binshtok A.M., Goldman D., Adolph J., Sama S., Atlas S.J.,
RA   Carlezon W.A., Parsegian A., Loetsch J., Fillingim R.B., Maixner W.,
RA   Geisslinger G., Max M.B., Woolf C.J.;
RT   "GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and
RT   persistence.";
RL   Nat. Med. 12:1269-1277(2006).
RN   [5]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-51, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22673903; DOI=10.1038/ncomms1871;
RA   Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA   Olsen J.V.;
RT   "Quantitative maps of protein phosphorylation sites across 14 different rat
RT   organs and tissues.";
RL   Nat. Commun. 3:876-876(2012).
RN   [6]
RP   X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 12-241 IN COMPLEX WITH GCHFR, AND
RP   SUBUNIT.
RX   PubMed=11818540; DOI=10.1073/pnas.022646999;
RA   Maita N., Okada K., Hatakeyama K., Hakoshima T.;
RT   "Crystal structure of the stimulatory complex of GTP cyclohydrolase I and
RT   its feedback regulatory protein GFRP.";
RL   Proc. Natl. Acad. Sci. U.S.A. 99:1212-1217(2002).
CC   -!- FUNCTION: May positively regulate nitric oxide synthesis in endothelial
CC       cells. May be involved in dopamine synthesis (By similarity). May
CC       modify pain sensitivity and persistence. {ECO:0000250|UniProtKB:P30793,
CC       ECO:0000269|PubMed:17057711}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=GTP + H2O = 7,8-dihydroneopterin 3'-triphosphate + formate +
CC         H(+); Xref=Rhea:RHEA:17473, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:15740, ChEBI:CHEBI:37565, ChEBI:CHEBI:58462; EC=3.5.4.16;
CC         Evidence={ECO:0000269|PubMed:2557335};
CC   -!- ACTIVITY REGULATION: GTP shows a positive allosteric effect, and
CC       tetrahydrobiopterin inhibits the enzyme activity. Zinc is required for
CC       catalytic activity. Inhibited by Mg(2+). {ECO:0000269|PubMed:2557335}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         Vmax=2.7 umol/h/mg enzyme (at pH 7.5 and 37 degrees Celsius)
CC         {ECO:0000269|PubMed:2557335};
CC   -!- PATHWAY: Cofactor biosynthesis; 7,8-dihydroneopterin triphosphate
CC       biosynthesis; 7,8-dihydroneopterin triphosphate from GTP: step 1/1.
CC       {ECO:0000305|PubMed:2557335}.
CC   -!- SUBUNIT: Toroid-shaped homodecamer, composed of two pentamers of five
CC       dimers. Interacts with AHSA1 and GCHFR/GFRP.
CC       {ECO:0000269|PubMed:11818540}.
CC   -!- INTERACTION:
CC       P22288; P70552: Gchfr; NbExp=3; IntAct=EBI-1032708, EBI-1032715;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P30793}. Nucleus
CC       {ECO:0000250|UniProtKB:P30793}.
CC   -!- INDUCTION: By cytokines such as insulin, interferon-gamma, and
CC       phytohemagglutinin in adrenal gland, macrophages, and T-cell
CC       respectively.
CC   -!- PTM: Phosphorylated. {ECO:0000250|UniProtKB:P30793}.
CC   -!- SIMILARITY: Belongs to the GTP cyclohydrolase I family. {ECO:0000305}.
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DR   EMBL; M58364; AAA41299.1; -; mRNA.
DR   PIR; A39080; A39080.
DR   RefSeq; NP_077332.1; NM_024356.1.
DR   PDB; 1IS7; X-ray; 2.80 A; A/B/C/D/E/F/G/H/I/J=12-241.
DR   PDB; 1IS8; X-ray; 2.70 A; A/B/C/D/E/F/G/H/I/J=12-241.
DR   PDB; 1WPL; X-ray; 2.80 A; A/B/C/D/E/F/G/H/I/J=12-241.
DR   PDBsum; 1IS7; -.
DR   PDBsum; 1IS8; -.
DR   PDBsum; 1WPL; -.
DR   AlphaFoldDB; P22288; -.
DR   SMR; P22288; -.
DR   BioGRID; 247920; 2.
DR   CORUM; P22288; -.
DR   IntAct; P22288; 1.
DR   STRING; 10116.ENSRNOP00000014821; -.
DR   iPTMnet; P22288; -.
DR   PhosphoSitePlus; P22288; -.
DR   jPOST; P22288; -.
DR   PaxDb; 10116-ENSRNOP00000014821; -.
DR   Ensembl; ENSRNOT00000014821.8; ENSRNOP00000014821.5; ENSRNOG00000011039.8.
DR   Ensembl; ENSRNOT00055047412; ENSRNOP00055038992; ENSRNOG00055027391.
DR   Ensembl; ENSRNOT00060041347; ENSRNOP00060034254; ENSRNOG00060023866.
DR   Ensembl; ENSRNOT00065056961; ENSRNOP00065046901; ENSRNOG00065033111.
DR   GeneID; 29244; -.
DR   KEGG; rno:29244; -.
DR   UCSC; RGD:61992; rat.
DR   AGR; RGD:61992; -.
DR   CTD; 2643; -.
DR   RGD; 61992; Gch1.
DR   eggNOG; KOG2698; Eukaryota.
DR   GeneTree; ENSGT00390000013481; -.
DR   HOGENOM; CLU_049768_1_3_1; -.
DR   InParanoid; P22288; -.
DR   OMA; CEHMCMS; -.
DR   OrthoDB; 1009at2759; -.
DR   PhylomeDB; P22288; -.
DR   BRENDA; 3.5.4.16; 5301.
DR   Reactome; R-RNO-1474151; Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation.
DR   SABIO-RK; P22288; -.
DR   UniPathway; UPA00848; UER00151.
DR   EvolutionaryTrace; P22288; -.
DR   PRO; PR:P22288; -.
DR   Proteomes; UP000002494; Chromosome 15.
DR   Bgee; ENSRNOG00000011039; Expressed in duodenum and 17 other cell types or tissues.
DR   GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR   GO; GO:0031410; C:cytoplasmic vesicle; ISO:RGD.
DR   GO; GO:0005829; C:cytosol; ISO:RGD.
DR   GO; GO:0005739; C:mitochondrion; IDA:RGD.
DR   GO; GO:0031965; C:nuclear membrane; IEA:Ensembl.
DR   GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR   GO; GO:0005634; C:nucleus; IDA:RGD.
DR   GO; GO:0032991; C:protein-containing complex; IDA:RGD.
DR   GO; GO:0005509; F:calcium ion binding; IDA:RGD.
DR   GO; GO:0005525; F:GTP binding; IDA:RGD.
DR   GO; GO:0003934; F:GTP cyclohydrolase I activity; IDA:RGD.
DR   GO; GO:0030742; F:GTP-dependent protein binding; IPI:RGD.
DR   GO; GO:0003924; F:GTPase activity; ISO:RGD.
DR   GO; GO:0042802; F:identical protein binding; IDA:RGD.
DR   GO; GO:0051019; F:mitogen-activated protein kinase binding; ISO:RGD.
DR   GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR   GO; GO:0044877; F:protein-containing complex binding; IDA:RGD.
DR   GO; GO:0008270; F:zinc ion binding; IDA:RGD.
DR   GO; GO:0035998; P:7,8-dihydroneopterin 3'-triphosphate biosynthetic process; IEA:UniProtKB-UniPathway.
DR   GO; GO:0051066; P:dihydrobiopterin metabolic process; IDA:RGD.
DR   GO; GO:0042416; P:dopamine biosynthetic process; ISO:RGD.
DR   GO; GO:0045776; P:negative regulation of blood pressure; IMP:RGD.
DR   GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IMP:RGD.
DR   GO; GO:2000773; P:negative regulation of cellular senescence; IMP:RGD.
DR   GO; GO:0050884; P:neuromuscular process controlling posture; ISO:RGD.
DR   GO; GO:0010460; P:positive regulation of heart rate; ISO:RGD.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:RGD.
DR   GO; GO:0032212; P:positive regulation of telomere maintenance via telomerase; IMP:RGD.
DR   GO; GO:0065003; P:protein-containing complex assembly; IDA:RGD.
DR   GO; GO:0042559; P:pteridine-containing compound biosynthetic process; ISO:RGD.
DR   GO; GO:0008217; P:regulation of blood pressure; ISO:RGD.
DR   GO; GO:0014916; P:regulation of lung blood pressure; ISO:RGD.
DR   GO; GO:2000121; P:regulation of removal of superoxide radicals; ISO:RGD.
DR   GO; GO:0032496; P:response to lipopolysaccharide; ISO:RGD.
DR   GO; GO:0048265; P:response to pain; IDA:UniProtKB.
DR   GO; GO:0034612; P:response to tumor necrosis factor; ISO:RGD.
DR   GO; GO:0034341; P:response to type II interferon; ISO:RGD.
DR   GO; GO:0006729; P:tetrahydrobiopterin biosynthetic process; ISO:RGD.
DR   GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IEA:InterPro.
DR   GO; GO:0042311; P:vasodilation; IMP:RGD.
DR   CDD; cd00642; GTP_cyclohydro1; 1.
DR   Gene3D; 1.10.286.10; -; 1.
DR   Gene3D; 3.30.1130.10; -; 1.
DR   HAMAP; MF_00223; FolE; 1.
DR   InterPro; IPR043133; GTP-CH-I_C/QueF.
DR   InterPro; IPR043134; GTP-CH-I_N.
DR   InterPro; IPR001474; GTP_CycHdrlase_I.
DR   InterPro; IPR018234; GTP_CycHdrlase_I_CS.
DR   InterPro; IPR020602; GTP_CycHdrlase_I_dom.
DR   NCBIfam; TIGR00063; folE; 1.
DR   PANTHER; PTHR11109:SF11; GTP CYCLOHYDROLASE 1; 1.
DR   PANTHER; PTHR11109; GTP CYCLOHYDROLASE I; 1.
DR   Pfam; PF01227; GTP_cyclohydroI; 1.
DR   SUPFAM; SSF55620; Tetrahydrobiopterin biosynthesis enzymes-like; 1.
DR   PROSITE; PS00859; GTP_CYCLOHYDROL_1_1; 1.
DR   PROSITE; PS00860; GTP_CYCLOHYDROL_1_2; 1.
DR   Genevisible; P22288; RN.
PE   1: Evidence at protein level;
KW   3D-structure; Allosteric enzyme; Cytoplasm; Direct protein sequencing;
KW   GTP-binding; Hydrolase; Metal-binding; Nucleotide-binding; Nucleus;
KW   Phosphoprotein; Reference proteome; Tetrahydrobiopterin biosynthesis; Zinc.
FT   PROPEP          1..11
FT                   /id="PRO_0000010720"
FT   CHAIN           12..241
FT                   /note="GTP cyclohydrolase 1"
FT                   /id="PRO_0000010721"
FT   REGION          1..58
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         132
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P30793"
FT   BINDING         135
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P30793"
FT   BINDING         203
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P30793"
FT   SITE            87
FT                   /note="Involved in pterin ring binding"
FT                   /evidence="ECO:0000250"
FT   SITE            96
FT                   /note="Involved in pterin ring binding"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         51
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:22673903"
FT   MOD_RES         72
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P30793"
FT   HELIX           52..73
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   TURN            80..84
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   HELIX           85..96
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   HELIX           98..101
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   HELIX           105..108
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   STRAND          109..111
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   STRAND          112..117
FT                   /evidence="ECO:0007829|PDB:1IS7"
FT   STRAND          121..132
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   TURN            133..135
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   STRAND          138..148
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   STRAND          150..154
FT                   /evidence="ECO:0007829|PDB:1IS7"
FT   HELIX           156..167
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   STRAND          168..171
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   HELIX           173..188
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   STRAND          191..201
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   HELIX           202..205
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   STRAND          207..210
FT                   /evidence="ECO:0007829|PDB:1IS7"
FT   STRAND          215..223
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   HELIX           224..227
FT                   /evidence="ECO:0007829|PDB:1IS8"
FT   HELIX           229..239
FT                   /evidence="ECO:0007829|PDB:1IS8"
SQ   SEQUENCE   241 AA;  27057 MW;  8226E3319816325B CRC64;
     MEKPRGVRCT NGFPERELPR PGASRPAEKS RPPEAKGAQP ADAWKAGRPR SEEDNELNLP
     NLAAAYSSIL RSLGEDPQRQ GLLKTPWRAA TAMQFFTKGY QETISDVLND AIFDEDHDEM
     VIVKDIDMFS MCEHHLVPFV GRVHIGYLPN KQVLGLSKLA RIVEIYSRRL QVQERLTKQI
     AVAITEALQP AGVGVVIEAT HMCMVMRGVQ KMNSKTVTST MLGVFREDPK TREEFLTLIR
     S
//