mutLBSgeneDB

mutLBSgeneDB
mutated Ligand Binding Site gene DataBase

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Gene Summary

Ligand Binding Site Mutation Information

Protein Structure Related Information

Gene Expression and Gene-Gene Network

Phenotype Information

Pharmacological Information

Conservation Information for LBS

Gene summary for PAH
Gene summary
Basic gene Info.Gene symbolPAH
Gene namephenylalanine hydroxylase
SynonymsPH|PKU|PKU1
CytomapUCSC genome browser: 12q22-q24.2
Type of geneprotein-coding
RefGenesNM_000277.1,
Descriptionphe-4-monooxygenasephenylalanine 4-monooxygenasephenylalanine-4-hydroxylase
Modification date20141219
dbXrefs MIM : 612349
HGNC : HGNC
Ensembl : ENSG00000171759
HPRD : 08943
Vega : OTTHUMG00000169966
ProteinUniProt: P00439
go to UniProt's Cross Reference DB Table
ExpressionCleanEX: HS_PAH
BioGPS: 5053
PathwayNCI Pathway Interaction Database: PAH
KEGG: PAH
REACTOME: PAH
Pathway Commons: PAH
ContextiHOP: PAH
ligand binding site mutation search in PubMed: PAH
UCL Cancer Institute: PAH
Assigned class in mutLBSgeneDBA: This gene has a literature evidence and it belongs to targetable_mutLBSgenes.
References showing study about ligand binding site mutation for PAH.1. Patel, D., Kopec, J., Fitzpatrick, F., McCorvie, T. J., & Yue, W. W. (2016). Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain. Scientific reports, 6. 27049649

Gene ontology having evidence of Inferred from Direct Assay (IDA) from Entrez
GO IDGO TermPubMed ID


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Ligand binding site mutations for PAH

Cancer type specific mutLBS sorted by frequency
LBSAAchange of nsSNVCancer type# samples
E280E280KGBM1
R270G272RHNSC1
H290H290YHNSC1
S251S251PKIRC1
E330V329LLUAD1
A322T323KLUAD1
G247G247SLUSC1
H290G289RSKCM1
E286E286KSKCM1
A322A322DSTAD1
cf) Cancer type abbreviation. BLCA: Bladder urothelial carcinoma, BRCA: Breast invasive carcinoma, CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma, COAD: Colon adenocarcinoma, GBM: Glioblastoma multiforme, LGG: Brain lower grade glioma, HNSC: Head and neck squamous cell carcinoma, KICH: Kidney chromophobe, KIRC: Kidney renal clear cell carcinoma, KIRP: Kidney renal papillary cell carcinoma, LAML: Acute myeloid leukemia, LUAD: Lung adenocarcinoma, LUSC: Lung squamous cell carcinoma, OV: Ovarian serous cystadenocarcinoma, PAAD: Pancreatic adenocarcinoma, PRAD: Prostate adenocarcinoma, SKCM: Skin cutaneous melanoma, STAD: Stomach adenocarcinoma, THCA: Thyroid carcinoma, UCEC: Uterine corpus endometrial carcinoma.


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Protein structure related information for PAH
Relative protein structure stability change (ΔΔE) using Mupro 1.1
Mupro score denotes assessment of the effect of mutations on thermodynamic stability.
  (ΔΔE<0: mutation decreases stability, ΔΔE>0: mutation increases stability)
: nsSNV at non-LBS: nsSNV at LBS

nsSNVs sorted by the relative stability change of protein structure by each mutation
Blue: mutations of positive stability change. and red : the most recurrent mutation for this gene.
LBSAAchange of nsSNVRelative stability change
E330V329L0.12446426
A322T323K-1.2523615
E280E280K-1.2071619
A322A322D-1.0361385
H290G289R-0.88010982
H290H290Y-0.63449628
G247G247S-0.60806823
S251S251P-0.56206614
R270G272R-0.40770711
E286E286K-0.24268502
(MuPro1.1: Jianlin Cheng et al., Prediction of Protein Stability Changes for Single-Site Mutations Using Support Vector Machines, PROTEINS: Structure, Function, and Bioinformatics. 2006, 62:1125-1132)

Structure image for PAH from PDB

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Differential gene expression and gene-gene network for PAH
Differential gene expression between mutated and non-mutated LBS samples in all 16 major cancer types

Differential co-expressed gene network based on protein-protein interaction data (CePIN)
* Left PPI network was created from samples with mutations in the LBS of PAH and the right PPI network was created from samples without mutations in the LBS of PAH. Only genes with p-value < 0.05 are shown.
Red circle: input gene. Orange circle: LBSgene. Blue circle: other gene.


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Phenotype information for PAH
Gene level disease information (DisGeNet)
Disease IDDisease name# PubMedAssociation type
umls:C0031485Phenylketonurias263Biomarker, GeneticVariation
umls:C0751434Classical phenylketonuria251Biomarker, GeneticVariation
umls:C0751435Hyperphenylalaninemia102Biomarker, GeneticVariation

Mutation level pathogenic information (ClinVar annotation)
Allele IDAA changeClinical significanceOriginPhenotype IDs
15619E280KPathogenicGermlineGeneReviews:NBK1504
MedGen:C0031485
OMIM:261600
Orphanet:ORPHA716
SNOMED CT:154735006
MedGen:CN221809
108551G247Snot providedNot providedMedGen:CN221809
108616E286Knot providedNot providedMedGen:CN221809
108618G289Rnot providedNot providedMedGen:CN221809

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Pharmacological information for PAH
Gene expression profile of anticancer drug treated cell-lines (CCLE)
Heatmap showing the correlation between gene expression and drug response across all the cell-lines. We chose the top 20 among 138 drugs.We used Pearson's correlation coefficient.

Gene-centered drug-gene interaction network
Drug information targeting mutLBSgene (Approved drugs only)
Drug statusDrugBank IDNameTypeDrug structure
Approved|nutraceuticalDB00120L-PhenylalanineSmall molecule
Approved|investigationalDB00360SapropterinSmall molecule
ApprovedDB00368NorepinephrineSmall molecule
Approved|vet_approvedDB00668EpinephrineSmall molecule
ExperimentalDB02562Quinonoid 7,8-TetrahydrobiopterinSmall molecule
ExperimentalDB02692(6r,1'r,2's)-5,6,7,8 TetrahydrobiopterinSmall molecule
ExperimentalDB03673Beta(2-Thienyl)AlanineSmall molecule
ExperimentalDB044007,8-DihydrobiopterinSmall molecule
ExperimentalDB04419NorleucineSmall molecule
Approved|investigationalDB06262DroxidopaSmall molecule

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of PAH go to BioLip
Ligand IDLigand short nameLigand long namePDB IDPDB namemutLBS
FEIRON(3+)2pahAE286 H290 E330
FEIRON(3+)2pahBE286 H290 E330
HBI7,8-DIHYDROBIOPTERIN1lrmAG247 S251
HBI7,8-DIHYDROBIOPTERIN1dmwAG247 S251 A322
H4B5,6,7,8-TETRAHYDROBIOPTERIN1j8uAG247 S251 A322
H2BQUINONOID 7,8-TETRAHYDROBIOPTERIN1tg2AG247 S251 A322
H4B5,6,7,8-TETRAHYDROBIOPTERIN1kw0AG247 S251 E286 E330
H4B5,6,7,8-TETRAHYDROBIOPTERIN1mmtAG247 S251 E286 E330
H4B5,6,7,8-TETRAHYDROBIOPTERIN1mmkAG247 S251 E286 H290 E330
FEIRON(3+)1dmwAH290 E330
FE2IRON(2+)1j8tAH290 E330
FE2IRON(2+)1j8uAH290 E330
FE2IRON(2+)1kw0AH290 E330
FEIRON(3+)1lrmAH290 E330
FE2IRON(2+)1mmkAH290 E330
FE2IRON(2+)1mmtAH290 E330
FEIRON(3+)1pahAH290 E330
FEIRON(3+)1tdwAH290 E330
FEIRON(3+)1tg2AH290 E330
FEIRON(3+)3pahAH290 E330
ALEADRENALINE3pahAH290 E330
FEIRON(3+)4anpAH290 E330
FEIRON(3+)4pahAH290 E330
LNR(R)-NORADRENALINE4pahAH290 E330
FEIRON(3+)5pahAH290 E330
LDPDOPAMINIUM(1+)5pahAH290 E330
FEIRON(3+)6pahAH290 E330
DAHL-DOPA6pahAH290 E330
NLEL-NORLEUCINE1mmtAR270
TIH3-(2-THIENYL)-L-ALANINE1kw0AR270 E280 E330
TIH3-(2-THIENYL)-L-ALANINE1mmkAR270 E280 E330
3QI5,6-DIMETHYL-3-(4-METHYL-2-PYRIDINYL)-2-THIOXO-2,3-DIHYDROTHIENO[2,3- D]PYRIMIDIN-4(1H)-ONE4anpAS251 E330


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Conservation information for LBS of PAH
Multiple alignments for P00439 in multiple species
LBSAA sequence# speciesSpecies
A322YIEKLATIYWF3Homo sapiens, Mus musculus, Bos taurus
A322VIEKLATLYWF1Caenorhabditis elegans
A322YIEKLSTIFWF1Drosophila melanogaster
E280PMYTPEPDICH3Homo sapiens, Mus musculus, Bos taurus
E280PKYTPEPDICH1Caenorhabditis elegans
E280PMYTPEPDVCH1Drosophila melanogaster
E286PDICHELLGHV4Homo sapiens, Caenorhabditis elegans, Mus musculus, Bos taurus
E286PDVCHELMGHV1Drosophila melanogaster
E330YWFTVEFGLCK3Homo sapiens, Mus musculus, Bos taurus
E330YWFTIEFGICQ1Caenorhabditis elegans
E330FWFTVEYGVCR1Drosophila melanogaster
F254LSSRDFLGGLA3Homo sapiens, Mus musculus, Bos taurus
F254LSSRDFLAGLA2Caenorhabditis elegans, Drosophila melanogaster
F331WFTVEFGLCKQ2Homo sapiens, Bos taurus
F331WFTIEFGICQQ1Caenorhabditis elegans
F331WFTVEYGVCRQ1Drosophila melanogaster
F331WFTVEFGLCKE1Mus musculus
G247LRPVAGLLSSR4Homo sapiens, Drosophila melanogaster, Mus musculus, Bos taurus
G247IRPVAGLLSSR1Caenorhabditis elegans
H264AFRVFHCTQYI3Homo sapiens, Mus musculus, Bos taurus
H264AFRVFHSTQYI2Caenorhabditis elegans, Drosophila melanogaster
H285EPDICHELLGH4Homo sapiens, Caenorhabditis elegans, Mus musculus, Bos taurus
H285EPDVCHELMGH1Drosophila melanogaster
H290HELLGHVPLFS3Homo sapiens, Mus musculus, Bos taurus
H290HELLGHVPLFA1Caenorhabditis elegans
H290HELMGHVPLFA1Drosophila melanogaster
L248RPVAGLLSSRD5Homo sapiens, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus, Bos taurus
L249PVAGLLSSRDF5Homo sapiens, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus, Bos taurus
L255SSRDFLGGLAF3Homo sapiens, Mus musculus, Bos taurus
L255SSRDFLAGLAF2Caenorhabditis elegans, Drosophila melanogaster
P279KPMYTPEPDIC3Homo sapiens, Mus musculus, Bos taurus
P279APKYTPEPDIC1Caenorhabditis elegans
P279KPMYTPEPDVC1Drosophila melanogaster
P281MYTPEPDICHE3Homo sapiens, Mus musculus, Bos taurus
P281KYTPEPDICHE1Caenorhabditis elegans
P281MYTPEPDVCHE1Drosophila melanogaster
R270CTQYIRHGSKP3Homo sapiens, Mus musculus, Bos taurus
R270STQYIRHHSAP1Caenorhabditis elegans
R270STQYIRHPSKP1Drosophila melanogaster
S251AGLLSSRDFLG3Homo sapiens, Mus musculus, Bos taurus
S251AGLLSSRDFLA2Caenorhabditis elegans, Drosophila melanogaster
S349GAGLLSSFGEL4Homo sapiens, Caenorhabditis elegans, Mus musculus, Bos taurus
S349GAGLLSSYGEL1Drosophila melanogaster
S350AGLLSSFGELQ4Homo sapiens, Caenorhabditis elegans, Mus musculus, Bos taurus
S350AGLLSSYGELE1Drosophila melanogaster
T278SKPMYTPEPDI3Homo sapiens, Mus musculus, Bos taurus
T278SAPKYTPEPDI1Caenorhabditis elegans
T278SKPMYTPEPDV1Drosophila melanogaster
V245FRLRPVAGLLS3Homo sapiens, Mus musculus, Bos taurus
V245YTIRPVAGLLS1Caenorhabditis elegans
V245FTLRPVAGLLS1Drosophila melanogaster
W326LATIYWFTVEF3Homo sapiens, Mus musculus, Bos taurus
W326LATLYWFTIEF1Caenorhabditis elegans
W326LSTIFWFTVEY1Drosophila melanogaster
Y277GSKPMYTPEPD3Homo sapiens, Mus musculus, Bos taurus
Y277HSAPKYTPEPD1Caenorhabditis elegans
Y277PSKPMYTPEPD1Drosophila melanogaster
Y325KLATIYWFTVE3Homo sapiens, Mus musculus, Bos taurus
Y325KLATLYWFTIE1Caenorhabditis elegans
Y325KLSTIFWFTVE1Drosophila melanogaster


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