TISIDB

Summary
Symbol	PAH
Name	phenylalanine hydroxylase
Aliases	PH; phenylalanine 4-monooxygenase; PKU; PKU1; phe-4-monooxygenase; Phenylalanine-4-hydroxylase
Chromosomal Location	12q22-q24.2
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	-
Domain	PF01842 ACT domain PF00351 Biopterin-dependent aromatic amino acid hydroxylase
Function	-

> Gene Ontology [ TOP ]
Biological Process	GO:0001505 regulation of neurotransmitter levels GO:0006520 cellular amino acid metabolic process GO:0006558 L-phenylalanine metabolic process GO:0006559 L-phenylalanine catabolic process GO:0006584 catecholamine metabolic process GO:0008652 cellular amino acid biosynthetic process GO:0009063 cellular amino acid catabolic process GO:0009072 aromatic amino acid family metabolic process GO:0009712 catechol-containing compound metabolic process GO:0009713 catechol-containing compound biosynthetic process GO:0016053 organic acid biosynthetic process GO:0016054 organic acid catabolic process GO:0018958 phenol-containing compound metabolic process GO:0042133 neurotransmitter metabolic process GO:0042136 neurotransmitter biosynthetic process GO:0042423 catecholamine biosynthetic process GO:0044282 small molecule catabolic process GO:0044283 small molecule biosynthetic process GO:0046189 phenol-containing compound biosynthetic process GO:0046394 carboxylic acid biosynthetic process GO:0046395 carboxylic acid catabolic process GO:1901565 organonitrogen compound catabolic process GO:1901615 organic hydroxy compound metabolic process GO:1901617 organic hydroxy compound biosynthetic process
Molecular Function	GO:0004497 monooxygenase activity GO:0004505 phenylalanine 4-monooxygenase activity GO:0005506 iron ion binding GO:0016597 amino acid binding GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen GO:0016714 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced pteridine as one donor, and incorporation of one atom of oxygen GO:0031406 carboxylic acid binding GO:0043168 anion binding
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa00360 Phenylalanine metabolism hsa00400 Phenylalanine, tyrosine and tryptophan biosynthesis hsa01100 Metabolic pathways hsa01230 Biosynthesis of amino acids
Reactome	R-HSA-6788656: Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism R-HSA-1430728: Metabolism R-HSA-71291: Metabolism of amino acids and derivatives R-HSA-71182: Phenylalanine and tyrosine catabolism

Summary
Symbol	PAH
Name	phenylalanine hydroxylase
Aliases	PH; phenylalanine 4-monooxygenase; PKU; PKU1; phe-4-monooxygenase; Phenylalanine-4-hydroxylase
Chromosomal Location	12q22-q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between PAH 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 [ TOP ]
There is no record.

Summary
Symbol	PAH
Name	phenylalanine hydroxylase
Aliases	PH; phenylalanine 4-monooxygenase; PKU; PKU1; phe-4-monooxygenase; Phenylalanine-4-hydroxylase
Chromosomal Location	12q22-q24.2
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 PAH 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	PAH
Name	phenylalanine hydroxylase
Aliases	PH; phenylalanine 4-monooxygenase; PKU; PKU1; phe-4-monooxygenase; Phenylalanine-4-hydroxylase
Chromosomal Location	12q22-q24.2
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 PAH 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	0.817	0.168
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.134	0.889
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	1.33	0.117
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	1.717	0.0447
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	1.368	0.32
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	2.161	0.182
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.256	0.809
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.204	0.908
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.61	0.731
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	1.573	0.35
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	2.984	0.173
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.114	0.803

> Mutation difference between responders and non-responders

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

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	7.4	4.1	3.3	0.61
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	7.4	5.1	2.3	0.647
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	19	0	19	0.113
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	12.5	0	12.5	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	23.1	0	23.1	0.223
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	6.2	-6.2	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	14.3	-14.3	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	5.3	3.7	1.6	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	7.7	-3.2	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	6.2	0	6.2	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	PAH
Name	phenylalanine hydroxylase
Aliases	PH; phenylalanine 4-monooxygenase; PKU; PKU1; phe-4-monooxygenase; Phenylalanine-4-hydroxylase
Chromosomal Location	12q22-q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of PAH. 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	PAH
Name	phenylalanine hydroxylase
Aliases	PH; phenylalanine 4-monooxygenase; PKU; PKU1; phe-4-monooxygenase; Phenylalanine-4-hydroxylase
Chromosomal Location	12q22-q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of PAH. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by PAH. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	PAH
Name	phenylalanine hydroxylase
Aliases	PH; phenylalanine 4-monooxygenase; PKU; PKU1; phe-4-monooxygenase; Phenylalanine-4-hydroxylase
Chromosomal Location	12q22-q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of PAH. 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	PAH
Name	phenylalanine hydroxylase
Aliases	PH; phenylalanine 4-monooxygenase; PKU; PKU1; phe-4-monooxygenase; Phenylalanine-4-hydroxylase
Chromosomal Location	12q22-q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of PAH expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	PAH
Name	phenylalanine hydroxylase
Aliases	PH; phenylalanine 4-monooxygenase; PKU; PKU1; phe-4-monooxygenase; Phenylalanine-4-hydroxylase
Chromosomal Location	12q22-q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between PAH and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	PAH
Name	phenylalanine hydroxylase
Aliases	PH; phenylalanine 4-monooxygenase; PKU; PKU1; phe-4-monooxygenase; Phenylalanine-4-hydroxylase
Chromosomal Location	12q22-q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting PAH collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting PAH.

ID	Name	Drug Type	Targets	#Targets
DB00120	L-Phenylalanine	Small Molecule	FARS2, FARSA, FARSB, PAH, SLC7A8, TAT, TH	7
DB00360	Sapropterin	Small Molecule	NOS3, PAH, TH, TPH1	4
DB00368	Norepinephrine	Small Molecule	ADRA1A, ADRA1B, ADRA1D, ADRA2A, ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB ......	12
DB00668	Epinephrine	Small Molecule	ADRA1A, ADRA1B, ADRA1D, ADRA2A, ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB ......	12
DB02562	Quinonoid 7,8-Tetrahydrobiopterin	Small Molecule	PAH	1
DB03673	Beta(2-Thienyl)Alanine	Small Molecule	PAH	1
DB04400	L-erythro-7,8-dihydrobiopterin	Small Molecule	NOS2, PAH, PCBD1, TH	4
DB04419	D-norleucine	Small Molecule	HNF1A, PAH, PTH	3
DB06262	Droxidopa	Small Molecule	ADRA1A, ADRA1B, ADRA1D, ADRA2A, ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB ......	10

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