| Structural highlights
Disease
[GCH1_HUMAN] Defects in GCH1 are the cause of GTP cyclohydrolase 1 deficiency (GCH1D) [MIM:233910]; also known as atypical severe phenylketonuria due to GTP cyclohydrolase I deficiency;. GCH1D is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. It is also responsible for defective neurotransmission due to depletion of the neurotransmitters dopamine and serotonin. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing. Some patients may present a phenotype of intermediate severity between severe hyperphenylalaninemia and mild dystonia type 5 (dystonia-parkinsonism with diurnal fluctuation). In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia.[1] [2] Defects in GCH1 are the cause of dystonia type 5 (DYT5) [MIM:128230]; also known as progressive dystonia with diurnal fluctuation, autosomal dominant Segawa syndrome or dystonia-parkinsonism with diurnal fluctuation. DYT5 is a DOPA-responsive dystonia. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT5 typically presents in childhood with walking problems due to dystonia of the lower limbs and worsening of the dystonia towards the evening. It is characterized by postural and motor disturbances showing marked diurnal fluctuation. Torsion of the trunk is unusual. Symptoms are alleviated after sleep and aggravated by fatigue and excercise. There is a favorable response to L-DOPA without side effects.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
Function
[GCH1_HUMAN] Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown.[18] [19] [20] [21] [22]
Publication Abstract from PubMed
Guanosine triphosphate (GTP) cyclohydrolase I (GCH1) catalyzes the conversion of GTP to dihydroneopterin triphosphate (H2NTP), the initiating step in the biosynthesis of tetrahydrobiopterin (BH4). Besides other roles, BH4 functions as cofactor in neurotransmitter biosynthesis. The BH4 biosynthetic pathway and GCH1 have been identified as promising targets to treat pain disorders in patients. The function of mammalian GCH1s is regulated by a metabolic sensing mechanism involving a regulator protein, GCH1 feedback regulatory protein (GFRP). GFRP binds to GCH1 to form inhibited or activated complexes dependent on availability of cofactor ligands, BH4 and phenylalanine, respectively. We determined high-resolution structures of human GCH1-GFRP complexes by cryoelectron microscopy (cryo-EM). Cryo-EM revealed structural flexibility of specific and relevant surface lining loops, which previously was not detected by X-ray crystallography due to crystal packing effects. Further, we studied allosteric regulation of isolated GCH1 by X-ray crystallography. Using the combined structural information, we are able to obtain a comprehensive picture of the mechanism of allosteric regulation. Local rearrangements in the allosteric pocket upon BH4 binding result in drastic changes in the quaternary structure of the enzyme, leading to a more compact, tense form of the inhibited protein, and translocate to the active site, leading to an open, more flexible structure of its surroundings. Inhibition of the enzymatic activity is not a result of hindrance of substrate binding, but rather a consequence of accelerated substrate binding kinetics as shown by saturation transfer difference NMR (STD-NMR) and site-directed mutagenesis. We propose a dissociation rate controlled mechanism of allosteric, noncompetitive inhibition.
A hybrid approach reveals the allosteric regulation of GTP cyclohydrolase I.,Ebenhoch R, Prinz S, Kaltwasser S, Mills DJ, Meinecke R, Rubbelke M, Reinert D, Bauer M, Weixler L, Zeeb M, Vonck J, Nar H Proc Natl Acad Sci U S A. 2020 Nov 23. pii: 2013473117. doi:, 10.1073/pnas.2013473117. PMID:33229582[23]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ichinose H, Ohye T, Segawa M, Nomura Y, Endo K, Tanaka H, Tsuji S, Fujita K, Nagatsu T. GTP cyclohydrolase I gene in hereditary progressive dystonia with marked diurnal fluctuation. Neurosci Lett. 1995 Aug 18;196(1-2):5-8. PMID:7501255
- ↑ Furukawa Y, Kish SJ, Bebin EM, Jacobson RD, Fryburg JS, Wilson WG, Shimadzu M, Hyland K, Trugman JM. Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations. Ann Neurol. 1998 Jul;44(1):10-6. PMID:9667588 doi:10.1002/ana.410440107
- ↑ Ichinose H, Ohye T, Segawa M, Nomura Y, Endo K, Tanaka H, Tsuji S, Fujita K, Nagatsu T. GTP cyclohydrolase I gene in hereditary progressive dystonia with marked diurnal fluctuation. Neurosci Lett. 1995 Aug 18;196(1-2):5-8. PMID:7501255
- ↑ Ichinose H, Ohye T, Takahashi E, Seki N, Hori T, Segawa M, Nomura Y, Endo K, Tanaka H, Tsuji S, et al.. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet. 1994 Nov;8(3):236-42. PMID:7874165 doi:http://dx.doi.org/10.1038/ng1194-236
- ↑ Hirano M, Tamaru Y, Ito H, Matsumoto S, Imai T, Ueno S. Mutant GTP cyclohydrolase I mRNA levels contribute to dopa-responsive dystonia onset. Ann Neurol. 1996 Nov;40(5):796-8. PMID:8957022 doi:10.1002/ana.410400517
- ↑ Bandmann O, Nygaard TG, Surtees R, Marsden CD, Wood NW, Harding AE. Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity. Hum Mol Genet. 1996 Mar;5(3):403-6. PMID:8852666
- ↑ Beyer K, Lao-Villadoniga JI, Vecino-Bilbao B, Cacabelos R, De la Fuente-Fernandez R. A novel point mutation in the GTP cyclohydrolase I gene in a Spanish family with hereditary progressive and dopa responsive dystonia. J Neurol Neurosurg Psychiatry. 1997 Apr;62(4):420-1. PMID:9120469
- ↑ Jarman PR, Bandmann O, Marsden CD, Wood NW. GTP cyclohydrolase I mutations in patients with dystonia responsive to anticholinergic drugs. J Neurol Neurosurg Psychiatry. 1997 Sep;63(3):304-8. PMID:9328244
- ↑ Bandmann O, Valente EM, Holmans P, Surtees RA, Walters JH, Wevers RA, Marsden CD, Wood NW. Dopa-responsive dystonia: a clinical and molecular genetic study. Ann Neurol. 1998 Oct;44(4):649-56. PMID:9778264 doi:10.1002/ana.410440411
- ↑ Hwu WL, Wang PJ, Hsiao KJ, Wang TR, Chiou YW, Lee YM. Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation. Hum Genet. 1999 Sep;105(3):226-30. PMID:10987649
- ↑ Suzuki T, Ohye T, Inagaki H, Nagatsu T, Ichinose H. Characterization of wild-type and mutants of recombinant human GTP cyclohydrolase I: relationship to etiology of dopa-responsive dystonia. J Neurochem. 1999 Dec;73(6):2510-6. PMID:10582612
- ↑ Brique S, Destee A, Lambert JC, Mouroux V, Delacourte A, Amouyel P, Chartier-Harlin MC. A new GTP-cyclohydrolase I mutation in an unusual dopa-responsive dystonia, familial form. Neuroreport. 1999 Feb 25;10(3):487-91. PMID:10208576
- ↑ Hirano M, Komure O, Ueno S. A novel missense mutant inactivates GTP cyclohydrolase I in dopa-responsive dystonia. Neurosci Lett. 1999 Feb 5;260(3):181-4. PMID:10076897
- ↑ Tassin J, Durr A, Bonnet AM, Gil R, Vidailhet M, Lucking CB, Goas JY, Durif F, Abada M, Echenne B, Motte J, Lagueny A, Lacomblez L, Jedynak P, Bartholome B, Agid Y, Brice A. Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations? Brain. 2000 Jun;123 ( Pt 6):1112-21. PMID:10825351
- ↑ Steinberger D, Korinthenberg R, Topka H, Berghauser M, Wedde R, Muller U. Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa. German Dystonia Study Group. Neurology. 2000 Dec 12;55(11):1735-7. PMID:11113234
- ↑ Leuzzi V, Carducci C, Carducci C, Cardona F, Artiola C, Antonozzi I. Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive myoclonus-dystonia syndrome. Neurology. 2002 Oct 22;59(8):1241-3. PMID:12391354
- ↑ Ohta E, Funayama M, Ichinose H, Toyoshima I, Urano F, Matsuo M, Tomoko N, Yukihiko K, Yoshino S, Yokoyama H, Shimazu H, Maeda K, Hasegawa K, Obata F. Novel mutations in the guanosine triphosphate cyclohydrolase 1 gene associated with DYT5 dystonia. Arch Neurol. 2006 Nov;63(11):1605-10. PMID:17101830 doi:10.1001/archneur.63.11.1605
- ↑ Gutlich M, Jaeger E, Rucknagel KP, Werner T, Rodl W, Ziegler I, Bacher A. Human GTP cyclohydrolase I: only one out of three cDNA isoforms gives rise to the active enzyme. Biochem J. 1994 Aug 15;302 ( Pt 1):215-21. PMID:8068008
- ↑ Katusic ZS, Stelter A, Milstien S. Cytokines stimulate GTP cyclohydrolase I gene expression in cultured human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol. 1998 Jan;18(1):27-32. PMID:9445252
- ↑ Cai S, Alp NJ, McDonald D, Smith I, Kay J, Canevari L, Heales S, Channon KM. GTP cyclohydrolase I gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells: effects on nitric oxide synthase activity, protein levels and dimerisation. Cardiovasc Res. 2002 Sep;55(4):838-49. PMID:12176133
- ↑ Duan CL, Su Y, Zhao CL, Lu LL, Xu QY, Yang H. The assays of activities and function of TH, AADC, and GCH1 and their potential use in ex vivo gene therapy of PD. Brain Res Brain Res Protoc. 2005 Dec;16(1-3):37-43. PMID:16338639 doi:S1385-299X(05)00087-5
- ↑ Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, Ehnert C, Nejim J, Marian C, Scholz J, Wu T, Allchorne A, Diatchenko L, Binshtok AM, Goldman D, Adolph J, Sama S, Atlas SJ, Carlezon WA, Parsegian A, Lotsch J, Fillingim RB, Maixner W, Geisslinger G, Max MB, Woolf CJ. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006 Nov;12(11):1269-77. Epub 2006 Oct 22. PMID:17057711 doi:10.1038/nm1490
- ↑ Ebenhoch R, Prinz S, Kaltwasser S, Mills DJ, Meinecke R, Rubbelke M, Reinert D, Bauer M, Weixler L, Zeeb M, Vonck J, Nar H. A hybrid approach reveals the allosteric regulation of GTP cyclohydrolase I. Proc Natl Acad Sci U S A. 2020 Nov 23. pii: 2013473117. doi:, 10.1073/pnas.2013473117. PMID:33229582 doi:http://dx.doi.org/10.1073/pnas.2013473117
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