Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6GT2K8)

• DOT Name: Phenylalanine-4-hydroxylase (PAH)
• Synonyms: PAH; EC 1.14.16.1; Phe-4-monooxygenase
• Gene Name: PAH
• Related Disease:
  Phenylketonuria
  Classic phenylketonuria
  Maternal phenylketonuria
  Mild hyperphenylalaninemia
  Mild phenylketonuria
  Tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria
• UniProt ID: PH4H_HUMAN
• PDB ID: 1DMW; 1J8T; 1J8U; 1KW0; 1LRM; 1MMK; 1MMT; 1PAH; 1TDW; 1TG2; 2PAH; 3PAH; 4ANP; 4PAH; 5FII; 5PAH; 6HPO; 6HYC; 6N1K; 6PAH
• EC Number: 1.14.16.1
• Pfam ID: PF01842 ; PF00351
• Sequence:
  MSTAVLENPGLGRKLSDFGQETSYIEDNCNQNGAISLIFSLKEEVGALAKVLRLFEENDV
  NLTHIESRPSRLKKDEYEFFTHLDKRSLPALTNIIKILRHDIGATVHELSRDKKKDTVPW
  FPRTIQELDRFANQILSYGAELDADHPGFKDPVYRARRKQFADIAYNYRHGQPIPRVEYM
  EEEKKTWGTVFKTLKSLYKTHACYEYNHIFPLLEKYCGFHEDNIPQLEDVSQFLQTCTGF
  RLRPVAGLLSSRDFLGGLAFRVFHCTQYIRHGSKPMYTPEPDICHELLGHVPLFSDRSFA
  QFSQEIGLASLGAPDEYIEKLATIYWFTVEFGLCKQGDSIKAYGAGLLSSFGELQYCLSE
  KPKLLPLELEKTAIQNYTVTEFQPLYYVAESFNDAKEKVRNFAATIPRPFSVRYDPYTQR
  IEVLDNTQQLKILADSINSEIGILCSALQKIK
• Function: Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.
• KEGG Pathway:
  Phenylalanine metabolism (hsa00360)
  Phenylalanine, tyrosine and tryptophan biosynthesis (hsa00400)
  Folate biosynthesis (hsa00790)
  Metabolic pathways (hsa01100)
  Biosynthesis of amino acids (hsa01230)
• Reactome Pathway:
  Phenylalanine metabolism (R-HSA-8964208)
  Phenylketonuria (R-HSA-2160456)
• BioCyc Pathway: MetaCyc:HS10374-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Phenylketonuria	DISCU56J	Definitive	Autosomal recessive	[1]
Classic phenylketonuria	DISLU64N	Supportive	Autosomal recessive	[2]
Maternal phenylketonuria	DISAVNUV	Supportive	Autosomal recessive	[3]
Mild hyperphenylalaninemia	DIS9NTZ6	Supportive	Autosomal recessive	[2]
Mild phenylketonuria	DISS326Y	Supportive	Autosomal recessive	[2]
Tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria	DISHK5Y6	Supportive	Autosomal recessive	[4]

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Phenylalanine-4-hydroxylase (PAH).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phenylalanine-4-hydroxylase (PAH).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phenylalanine-4-hydroxylase (PAH).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phenylalanine-4-hydroxylase (PAH).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phenylalanine-4-hydroxylase (PAH).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Phenylalanine-4-hydroxylase (PAH).	[9]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Phenylalanine-4-hydroxylase (PAH).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Phenylalanine-4-hydroxylase (PAH).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phenylalanine-4-hydroxylase (PAH).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Phenylalanine-4-hydroxylase (PAH).	[15]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Phenylalanine-4-hydroxylase (PAH).	[16]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Phenylalanine-4-hydroxylase (PAH).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Phenylalanine-4-hydroxylase (PAH).	[14]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [updated 2017 Jan 5]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Maternal phenylketonuria syndrome in cousins caused by mild, unrecognized phenylketonuria in their mothers homozygous for the phenylalanine hydroxylase Arg-261-Gln mutation. Eur J Pediatr. 1991 May;150(7):493-7. doi: 10.1007/BF01958431.
• [4] Two novel genetic lesions and a common BH4-responsive mutation of the PAH gene in Italian patients with hyperphenylalaninemia. Mol Genet Metab. 2002 Nov;77(3):260-6. doi: 10.1016/s1096-7192(02)00166-x.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [16] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.