Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTZPS91)

• DTT Name: Dihydrothymine dehydrogenase (DPYD)
• Synonyms: Dihydrouracil dehydrogenase; Dihydropyrimidine dehydrogenase [NADP(+)]; Dihydropyrimidine dehydrogenase; DPD; DHPDHase
• Gene Name: DPYD
• DTT Type: Successful target; [1]
• BioChemical Class: CH/CH donor oxidoreductase
• UniProt ID: DPYD_HUMAN
• TTD ID: T75890
• EC Number: EC 1.3.1.2
• Sequence:
  MAPVLSKDSADIESILALNPRTQTHATLCSTSAKKLDKKHWKRNPDKNCFNCEKLENNFD
  DIKHTTLGERGALREAMRCLKCADAPCQKSCPTNLDIKSFITSIANKNYYGAAKMIFSDN
  PLGLTCGMVCPTSDLCVGGCNLYATEEGPINIGGLQQFATEVFKAMSIPQIRNPSLPPPE
  KMSEAYSAKIALFGAGPASISCASFLARLGYSDITIFEKQEYVGGLSTSEIPQFRLPYDV
  VNFEIELMKDLGVKIICGKSLSVNEMTLSTLKEKGYKAAFIGIGLPEPNKDAIFQGLTQD
  QGFYTSKDFLPLVAKGSKAGMCACHSPLPSIRGVVIVLGAGDTAFDCATSALRCGARRVF
  IVFRKGFVNIRAVPEEMELAKEEKCEFLPFLSPRKVIVKGGRIVAMQFVRTEQDETGKWN
  EDEDQMVHLKADVVISAFGSVLSDPKVKEALSPIKFNRWGLPEVDPETMQTSEAWVFAGG
  DVVGLANTTVESVNDGKQASWYIHKYVQSQYGASVSAKPELPLFYTPIDLVDISVEMAGL
  KFINPFGLASATPATSTSMIRRAFEAGWGFALTKTFSLDKDIVTNVSPRIIRGTTSGPMY
  GPGQSSFLNIELISEKTAAYWCQSVTELKADFPDNIVIASIMCSYNKNDWTELAKKSEDS
  GADALELNLSCPHGMGERGMGLACGQDPELVRNICRWVRQAVQIPFFAKLTPNVTDIVSI
  ARAAKEGGANGVTATNTVSGLMGLKSDGTPWPAVGIAKRTTYGGVSGTAIRPIALRAVTS
  IARALPGFPILATGGIDSAESGLQFLHSGASVLQVCSAIQNQDFTVIEDYCTGLKALLYL
  KSIEELQDWDGQSPATVSHQKGKPVPRIAELMDKKLPSFGPYLEQRKKIIAENKIRLKEQ
  NVAFSPLKRNCFIPKRPIPTIKDVIGKALQYLGTFGELSNVEQVVAMIDEEMCINCGKCY
  MTCNDSGYQAIQFDPETHLPTITDTCTGCTLCLSVCPIVDCIKMVSRTTPYEPKRGVPLS
  VNPVC
• Function: Catalyzes the reduction of uracil and thymine. Also involved the degradation of the chemotherapeutic drug 5-fluorouracil. Involved in pyrimidine base degradation.
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  beta-Alanine metabolism (hsa00410)
  Pantothenate and CoA biosynthesis (hsa00770)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Pyrimidine catabolism (R-HSA-73621)
• BioCyc Pathway: MetaCyc:HS06975-MON

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fluorouracil	DMUM7HZ	Adenocarcinoma	2D40	Approved	[1]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Eniluracil	DM96NCR	Hyperlipidaemia	5C80	Phase 2	[2]
RO-09-4889	DMQ65YW	Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
FL-386	DMUQN83	Hyperlipidaemia	5C80	Discontinued in Phase 2	[4]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(5s)-5-Iododihydro-2,4(1h,3h)-Pyrimidinedione	DMA5DO2	Discovery agent	N.A.	Investigative	[5]
5-Iodouracil	DM4O6I5	Discovery agent	N.A.	Investigative	[5]
6-Carboxymethyluracil	DM9MPDK	Discovery agent	N.A.	Investigative	[5]
Flavin-Adenine Dinucleotide	DM5S4GK	Discovery agent	N.A.	Investigative	[5]
Uracil	DMNPO9Q	Discovery agent	N.A.	Investigative	[6]

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

• DTT DME Name: Dihydrothymine dehydrogenase (DPYD) DME Info
• Gene Name: DPYD

1 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fluorouracil	DMUM7HZ	Adenocarcinoma	2D40	Approved	[7]

References

• [1] Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2,4-dihydroxypyridine (CDHP) in human tumour cells. Eur J Cancer. 2002 Jun;38(9):1271-7.
• [2] Eniluracil: an irreversible inhibitor of dihydropyrimidine dehydrogenase. Expert Opin Investig Drugs. 2000 Jul;9(7):1635-49.
• [3] Single ascending dose tolerability, pharmacokinetic-pharmacodynamic study of dihydropyrimidine dehydrogenase inhibitor Ro 09-4889. Clin Cancer Res. 2004 Apr 1;10(7):2327-35.
• [4] Effects of FL-386 on faecal lipid excretion in humans. J Int Med Res. 1993 Sep-Oct;21(5):225-33.
• [5] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [6] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [7] 5-Fluorouracil toxicity-attributable IVS14 + 1G > A mutation of the dihydropyrimidine dehydrogenase gene in Polish colorectal cancer patients. Pharmacol Rep. 2008 Mar-Apr;60(2):238-42.