Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTGSVH2)

• DTT Name: Phenylalanine hydroxylase (PAH)
• Synonyms: Phenylalanine4hydroxylase; Phenylalanine-4-hydroxylase; Phe4monooxygenase; Phe-4-monooxygenase
• Gene Name: PAH
• DTT Type: Successful target; [1]
• BioChemical Class: Paired donor oxygen oxidoreductase
• UniProt ID: PH4H_HUMAN
• TTD ID: T76213
• EC Number: EC 1.14.16.1
• 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)
  Metabolic pathways (hsa01100)
  Biosynthesis of amino acids (hsa01230)
• Reactome Pathway:
  Phenylalanine metabolism (R-HSA-8964208)
  Phenylketonuria (R-HSA-2160456)
• BioCyc Pathway: MetaCyc:HS10374-MON

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pegvaliase	DM6NZ2P	Phenylketonuria	5C50.0	Approved	[2]
Sapropterin hydrochloride	DM90TJP	Hyperphenylalaninemia	5C50	Approved	[1]

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
HepaStem	DM8QGPE	Liver failure	DB99.7	Phase 2	[3]
Phenylalanine hydroxylase	DMRP3CV	Autoimmune diabetes	5A10	Phase 2	[4]
BMN-307	DMY0SKM	Phenylketonuria	5C50.0	Phase 1/2	[5]
HMI-102	DM8B85Y	Phenylketonuria	5C50.0	Phase 1/2	[6]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
alpha-methylphenylalanine	DMAUH96	Discovery agent	N.A.	Investigative	[7]
ALTU-236	DMDLN9S	Genetic disease	8E02	Investigative	[3]
BH4	DM4XMZW	Discovery agent	N.A.	Investigative	[8]
BMN-168	DM0VMZ4	Phenylketonuria	5C50.0	Investigative	[3]
fenclonine	DMUBO3E	Discovery agent	N.A.	Investigative	[3]

References

• [1] 2007 FDA drug approvals: a year of flux. Nat Rev Drug Discov. 2008 Feb;7(2):107-9.
• [2] Induction, titration, and maintenance dosing regimen in a phase 2 study of pegvaliase for control of blood phenylalanine in adults with phenylketonuria.Mol Genet Metab. 2018 Nov;125(3):217-227.
• [3] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1240).
• [4] Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial. Lancet. 2014 Jul 5;384(9937):37-44.
• [5] ClinicalTrials.gov (NCT04480567) A Phase 1/2 Open-Label, Dose Escalation Study to Determine the Safety and Efficacy of BMN 307, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Phenylalanine Hydroxylase in Subjects With Phenylketonuria. U.S.National Institutes of Health.
• [6] Clinical pipeline report, company report or official report of Homology Medicines
• [7] Alpha-methylphenylalanine, a new inducer of chronic hyperphenylalaninemia in sucling rats. Science. 1976 Jun 4;192(4243):1007-8.
• [8] Company report of BioMarin