Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTN451K)

• DTT Name: Aromatic-L-amino-acid decarboxylase (DDC)
• Synonyms: DOPA decarboxylase; AADC
• Gene Name: DDC
• DTT Type: Successful target; [1]
• BioChemical Class: Carbon-carbon lyase
• UniProt ID: DDC_HUMAN
• TTD ID: T62193
• EC Number: EC 4.1.1.28
• Sequence:
  MNASEFRRRGKEMVDYMANYMEGIEGRQVYPDVEPGYLRPLIPAAAPQEPDTFEDIINDV
  EKIIMPGVTHWHSPYFFAYFPTASSYPAMLADMLCGAIGCIGFSWAASPACTELETVMMD
  WLGKMLELPKAFLNEKAGEGGGVIQGSASEATLVALLAARTKVIHRLQAASPELTQAAIM
  EKLVAYSSDQAHSSVERAGLIGGVKLKAIPSDGNFAMRASALQEALERDKAAGLIPFFMV
  ATLGTTTCCSFDNLLEVGPICNKEDIWLHVDAAYAGSAFICPEFRHLLNGVEFADSFNFN
  PHKWLLVNFDCSAMWVKKRTDLTGAFRLDPTYLKHSHQDSGLITDYRHWQIPLGRRFRSL
  KMWFVFRMYGVKGLQAYIRKHVQLSHEFESLVRQDPRFEICVEVILGLVCFRLKGSNKVN
  EALLQRINSAKKIHLVPCHLRDKFVLRFAICSRTVESAHVQRAWEHIKELAADVLRAERE
• Function: Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine.
• KEGG Pathway:
  Histidine metabolism (hsa00340)
  Tyrosine metabolism (hsa00350)
  Phenylalanine metabolism (hsa00360)
  Tryptophan metabolism (hsa00380)
  Metabolic pathways (hsa01100)
  Serotonergic synapse (hsa04726)
  Dopaminergic synapse (hsa04728)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
• Reactome Pathway:
  Serotonin and melatonin biosynthesis (R-HSA-209931)
  Catecholamine biosynthesis (R-HSA-209905)
• BioCyc Pathway: MetaCyc:HS05635-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
Carbidopa	DMHRG8Q	Parkinson disease	8A00.0	Approved	[2]
Vitamin B6	DMDBZMV	Vitamin B6 deficiency	5B5D	Approved	[1]

9 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Benserazide	DMLU8NX	N. A.	N. A.	Phase 3	[2]
Patrome	DM3H2U4	Parkinson disease	8A00.0	Phase 3	[3]
AV-201	DMDL9WU	Parkinson disease	8A00.0	Phase 2	[4]
GT-AADC	DM8N3OQ	Aromatic L-amino acid decarboxylase deficiency	5C59.00	Phase 2	[5]
PTC-AADC	DM9ZHE3	Aromatic L-amino acid decarboxylase deficiency	5C59.00	Phase 2	[6]
VY-AADC	DMPSBTL	Parkinson disease	8A00.0	Phase 2	[7]
OXB-102	DMXF9DM	Parkinson disease	8A00.0	Phase 1/2	[8]
ProSavin	DMJ42E6	Parkinson disease	8A00.0	Phase 1/2	[9]
VY-AADC01	DM0N71R	Parkinson disease	8A00.0	Phase 1	[10]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3-hydroxybenzylhydrazine	DMNUM4K	Discovery agent	N.A.	Investigative	[11]
Noradrenalone (arterenone)	DMFNB40	Discovery agent	N.A.	Investigative	[12]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Parkinson's disease	8A00.0	Substantia nigra tissue	7.84E-03	-1.49	-1.01

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: DOPA decarboxylase (DDC) DME Info
• Gene Name: DDC

3 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Droxidopa	DM5YF4M	Chronic fatigue syndrome	8E49	Approved	[13]
L-Tryptophan	DMIBH7M	Depression	6A70-6A7Z	Approved	[14]
Levodopa	DMN3E57	Parkinson disease	8A00.0	Approved	[15]

References

• [1] Functional COMT variant predicts response to high dose pyridoxine in Parkinson's disease. Am J Med Genet B Neuropsychiatr Genet. 2005 Aug 5;137B(1):1-4.
• [2] Catechol-O-methyltransferase inhibitors in the management of Parkinson's disease. Semin Neurol. 2001;21(1):15-22.
• [3] The aromatic-L-amino acid decarboxylase inhibitor carbidopa is selectively cytotoxic to human pulmonary carcinoid and small cell lung carcinoma cells. Clin Cancer Res. 2000 Nov;6(11):4365-72.
• [4] UCSF report
• [5] Clinical pipeline report, company report or official report of PTC Therapeutics.
• [6] ClinicalTrials.gov (NCT04903288) An Open-Label Trial to Address the Safety of the SmartFlow MR-Compatible Ventricular Cannula for Administering Eladocagene Exuparvovec to Pediatric Subjects. U.S.National Institutes of Health.
• [7] Clinical pipeline report, company report or official report of Voyager Therapeutics.
• [8] Clinical pipeline report, company report or official report of Oxford BioMedica.
• [9] Clinical pipeline report, company report or official report of Oxford BioMedica.
• [10] Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial. Neurology. 2022 Jan 4;98(1):e40-e50.
• [11] 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: 1271).
• [12] Activation of an adrenergic pro-drug through sequential stereoselective action of tandem target enzymes. Biochem Biophys Res Commun. 1992 Nov 30;189(1):33-9.
• [13] L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug. Cardiovasc Drug Rev. 2006 Fall-Winter;24(3-4):189-203.
• [14] Origin and metabolism of serotonin. J Cardiovasc Pharmacol. 1990;16 Suppl 3:S1-7.
• [15] Complexity of dopamine metabolism. Cell Commun Signal. 2013 May 17;11(1):34.