TISIDB

Summary
Symbol	GCH1
Name	GTP cyclohydrolase 1
Aliases	GTPCH1; DYT5a; dopa-responsive dystonia; GCH; DYT5; GTP-CH-1; HPABH4B; GTP-CH-I; guanosine 5'-triphosphate c ......
Chromosomal Location	14q22.1-q22.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cytoplasm Nucleus
Domain	PF01227 GTP cyclohydrolase I
Function	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.

> Gene Ontology [ TOP ]
Biological Process	GO:0000302 response to reactive oxygen species GO:0000303 response to superoxide GO:0000305 response to oxygen radical GO:0002237 response to molecule of bacterial origin GO:0003013 circulatory system process GO:0003018 vascular process in circulatory system GO:0006575 cellular modified amino acid metabolic process GO:0006584 catecholamine metabolic process GO:0006729 tetrahydrobiopterin biosynthetic process GO:0006732 coenzyme metabolic process GO:0006760 folic acid-containing compound metabolic process GO:0006801 superoxide metabolic process GO:0006809 nitric oxide biosynthetic process GO:0006979 response to oxidative stress GO:0008015 blood circulation GO:0008217 regulation of blood pressure GO:0009108 coenzyme biosynthetic process GO:0009396 folic acid-containing compound biosynthetic process GO:0009636 response to toxic substance GO:0009712 catechol-containing compound metabolic process GO:0009713 catechol-containing compound biosynthetic process GO:0010035 response to inorganic substance GO:0014916 regulation of lung blood pressure GO:0018958 phenol-containing compound metabolic process GO:0019430 removal of superoxide radicals GO:0032496 response to lipopolysaccharide GO:0032768 regulation of monooxygenase activity GO:0032770 positive regulation of monooxygenase activity GO:0033555 multicellular organismal response to stress GO:0034341 response to interferon-gamma GO:0034599 cellular response to oxidative stress GO:0034612 response to tumor necrosis factor GO:0034614 cellular response to reactive oxygen species GO:0035150 regulation of tube size GO:0035998 7,8-dihydroneopterin 3'-triphosphate biosynthetic process GO:0042311 vasodilation GO:0042398 cellular modified amino acid biosynthetic process GO:0042416 dopamine biosynthetic process GO:0042417 dopamine metabolic process GO:0042423 catecholamine biosynthetic process GO:0042558 pteridine-containing compound metabolic process GO:0042559 pteridine-containing compound biosynthetic process GO:0045776 negative regulation of blood pressure GO:0046146 tetrahydrobiopterin metabolic process GO:0046189 phenol-containing compound biosynthetic process GO:0046209 nitric oxide metabolic process GO:0046653 tetrahydrofolate metabolic process GO:0046654 tetrahydrofolate biosynthetic process GO:0048265 response to pain GO:0050880 regulation of blood vessel size GO:0050884 neuromuscular process controlling posture GO:0050905 neuromuscular process GO:0050999 regulation of nitric-oxide synthase activity GO:0051000 positive regulation of nitric-oxide synthase activity GO:0051066 dihydrobiopterin metabolic process GO:0051186 cofactor metabolic process GO:0051188 cofactor biosynthetic process GO:0051259 protein oligomerization GO:0051260 protein homooligomerization GO:0051291 protein heterooligomerization GO:0051341 regulation of oxidoreductase activity GO:0051353 positive regulation of oxidoreductase activity GO:0071450 cellular response to oxygen radical GO:0071451 cellular response to superoxide GO:0072593 reactive oxygen species metabolic process GO:0090066 regulation of anatomical structure size GO:0090322 regulation of superoxide metabolic process GO:0098754 detoxification GO:0098869 cellular oxidant detoxification GO:1900407 regulation of cellular response to oxidative stress GO:1901031 regulation of response to reactive oxygen species GO:1901615 organic hydroxy compound metabolic process GO:1901617 organic hydroxy compound biosynthetic process GO:1902882 regulation of response to oxidative stress GO:1903409 reactive oxygen species biosynthetic process GO:1990748 cellular detoxification GO:2000121 regulation of removal of superoxide radicals GO:2000377 regulation of reactive oxygen species metabolic process GO:2001057 reactive nitrogen species metabolic process
Molecular Function	GO:0003933 GTP cyclohydrolase activity GO:0003934 GTP cyclohydrolase I activity GO:0005525 GTP binding GO:0016810 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds GO:0016814 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amidines GO:0019001 guanyl nucleotide binding GO:0019238 cyclohydrolase activity GO:0030742 GTP-dependent protein binding GO:0031369 translation initiation factor binding GO:0032561 guanyl ribonucleotide binding GO:0048037 cofactor binding GO:0050662 coenzyme binding
Cellular Component	GO:0005635 nuclear envelope GO:0031965 nuclear membrane

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa00790 Folate biosynthesis hsa01100 Metabolic pathways
Reactome	R-HSA-1430728: Metabolism R-HSA-202131: Metabolism of nitric oxide R-HSA-1474151: Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation R-HSA-203765: eNOS activation and regulation

Summary
Symbol	GCH1
Name	GTP cyclohydrolase 1
Aliases	GTPCH1; DYT5a; dopa-responsive dystonia; GCH; DYT5; GTP-CH-1; HPABH4B; GTP-CH-I; guanosine 5'-triphosphate c ......
Chromosomal Location	14q22.1-q22.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between GCH1 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between GCH1 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
22753274	Colon Carcinoma	Inhibit immunity	We found that inhibition or silencing of GCH1 reduced tumor cell proliferation and survival and the tube formation of human umbilical vein endothelial cells, which upon hypoxia increased GCH1 and endothelial NOS expression, the latter prevented by inhibition of GCH1. The treatment with the GCH1 inhibitor shifted the phenotype of tumor associated macrophages from the proangiogenic M2 towards M1, accompanied with a shift of plasma chemokine profiles towards tumor-attacking chemokines including CXCL10 and RANTES. GCH1 expression was increased in mouse AOM/DSS-induced colon tumors and in high grade human colon and skin cancer and oppositely, the growth of GCH1-deficient HT29-Luc tumor cells in mice was strongly reduced. The data suggest that GCH1 inhibition reduces tumor growth by (i) direct killing of tumor cells, (ii) by inhibiting angiogenesis, and (iii) by enhancing the antitumoral immune response.

Summary
Symbol	GCH1
Name	GTP cyclohydrolase 1
Aliases	GTPCH1; DYT5a; dopa-responsive dystonia; GCH; DYT5; GTP-CH-1; HPABH4B; GTP-CH-I; guanosine 5'-triphosphate c ......
Chromosomal Location	14q22.1-q22.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of GCH1 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	GCH1
Name	GTP cyclohydrolase 1
Aliases	GTPCH1; DYT5a; dopa-responsive dystonia; GCH; DYT5; GTP-CH-1; HPABH4B; GTP-CH-I; guanosine 5'-triphosphate c ......
Chromosomal Location	14q22.1-q22.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of GCH1 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0.448	0.284
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.496	0.717
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.42	0.659
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.574	0.169
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.092	0.945
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	1.425	0.438
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.451	0.282
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.737	0.514
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.127	0.92
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.302	0.711
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.362	0.78
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.026	0.79

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of GCH1 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	1.4	-1.4	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	1.7	-1.7	1
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	0	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	1

Summary
Symbol	GCH1
Name	GTP cyclohydrolase 1
Aliases	GTPCH1; DYT5a; dopa-responsive dystonia; GCH; DYT5; GTP-CH-1; HPABH4B; GTP-CH-I; guanosine 5'-triphosphate c ......
Chromosomal Location	14q22.1-q22.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of GCH1. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	GCH1
Name	GTP cyclohydrolase 1
Aliases	GTPCH1; DYT5a; dopa-responsive dystonia; GCH; DYT5; GTP-CH-1; HPABH4B; GTP-CH-I; guanosine 5'-triphosphate c ......
Chromosomal Location	14q22.1-q22.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of GCH1. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by GCH1. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	GCH1
Name	GTP cyclohydrolase 1
Aliases	GTPCH1; DYT5a; dopa-responsive dystonia; GCH; DYT5; GTP-CH-1; HPABH4B; GTP-CH-I; guanosine 5'-triphosphate c ......
Chromosomal Location	14q22.1-q22.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of GCH1. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	GCH1
Name	GTP cyclohydrolase 1
Aliases	GTPCH1; DYT5a; dopa-responsive dystonia; GCH; DYT5; GTP-CH-1; HPABH4B; GTP-CH-I; guanosine 5'-triphosphate c ......
Chromosomal Location	14q22.1-q22.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of GCH1 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	GCH1
Name	GTP cyclohydrolase 1
Aliases	GTPCH1; DYT5a; dopa-responsive dystonia; GCH; DYT5; GTP-CH-1; HPABH4B; GTP-CH-I; guanosine 5'-triphosphate c ......
Chromosomal Location	14q22.1-q22.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between GCH1 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	GCH1
Name	GTP cyclohydrolase 1
Aliases	GTPCH1; DYT5a; dopa-responsive dystonia; GCH; DYT5; GTP-CH-1; HPABH4B; GTP-CH-I; guanosine 5'-triphosphate c ......
Chromosomal Location	14q22.1-q22.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting GCH1 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting GCH1.

ID	Name	Drug Type	Targets	#Targets
DB02325	Isopropyl Alcohol	Small Molecule	ACP5, ADI1, AHCY, CHIT1, DCXR, DDX39B, GCH1, GDF5, GM2A, PLA2G2A, ......	15
DB02377	Guanine	Small Molecule	GCH1, PNP	2

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