Details of Drug Off-Target (DOT)

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

• DOT Name: Multifunctional protein CAD (CAD)
• Synonyms: Carbamoyl phosphate synthetase 2-aspartate transcarbamylase-dihydroorotase
• Gene Name: CAD
• Related Disease: Developmental and epileptic encephalopathy, 50
• UniProt ID: PYR1_HUMAN
• PDB ID: 4BY3 ; 4C6B ; 4C6C ; 4C6D ; 4C6E ; 4C6F ; 4C6I ; 4C6J ; 4C6K ; 4C6L ; 4C6M ; 4C6N ; 4C6O ; 4C6P ; 4C6Q ; 5G1N ; 5G1O ; 5G1P ; 5YNZ ; 6HFD ; 6HFE ; 6HFF ; 6HFH ; 6HFI ; 6HFJ ; 6HFK ; 6HFL ; 6HFN ; 6HFP ; 6HFQ ; 6HFR ; 6HFS ; 6HFU ; 6HG1 ; 8GVZ ; 8GW0 ; 8PBE ; 8PBG ; 8PBH ; 8PBI ; 8PBJ ; 8PBK ; 8PBM ; 8PBN ; 8PBP ; 8PBQ ; 8PBR ; 8PBS ; 8PBT ; 8PBU
• EC Number: 2.1.3.2; 3.5.1.2; 3.5.2.3; 6.3.4.16; 6.3.5.5
• Pfam ID: PF01979 ; PF02786 ; PF02787 ; PF00988 ; PF00117 ; PF02142 ; PF00185 ; PF02729
• Sequence:
  MAALVLEDGSVLRGQPFGAAVSTAGEVVFQTGMVGYPEALTDPSYKAQILVLTYPLIGNY
  GIPPDEMDEFGLCKWFESSGIHVAALVVGECCPTPSHWSATRTLHEWLQQHGIPGLQGVD
  TRELTKKLREQGSLLGKLVQNGTEPSSLPFLDPNARPLVPEVSIKTPRVFNTGGAPRILA
  LDCGLKYNQIRCLCQRGAEVTVVPWDHALDSQEYEGLFLSNGPGDPASYPSVVSTLSRVL
  SEPNPRPVFGICLGHQLLALAIGAKTYKMRYGNRGHNQPCLLVGSGRCFLTSQNHGFAVE
  TDSLPADWAPLFTNANDGSNEGIVHNSLPFFSVQFHPEHQAGPSDMELLFDIFLETVKEA
  TAGNPGGQTVRERLTERLCPPGIPTPGSGLPPPRKVLILGSGGLSIGQAGEFDYSGSQAI
  KALKEENIQTLLINPNIATVQTSQGLADKVYFLPITPHYVTQVIRNERPDGVLLTFGGQT
  ALNCGVELTKAGVLARYGVRVLGTPVETIELTEDRRAFAARMAEIGEHVAPSEAANSLEQ
  AQAAAERLGYPVLVRAAFALGGLGSGFASNREELSALVAPAFAHTSQVLVDKSLKGWKEI
  EYEVVRDAYGNCVTVCNMENLDPLGIHTGESIVVAPSQTLNDREYQLLRQTAIKVTQHLG
  IVGECNVQYALNPESEQYYIIEVNARLSRSSALASKATGYPLAYVAAKLALGIPLPELRN
  SVTGGTAAFEPSVDYCVVKIPRWDLSKFLRVSTKIGSCMKSVGEVMGIGRSFEEAFQKAL
  RMVDENCVGFDHTVKPVSDMELETPTDKRIFVVAAALWAGYSVDRLYELTRIDRWFLHRM
  KRIIAHAQLLEQHRGQPLPPDLLQQAKCLGFSDKQIALAVLSTELAVRKLRQELGICPAV
  KQIDTVAAEWPAQTNYLYLTYWGTTHDLTFRTPHVLVLGSGVYRIGSSVEFDWCAVGCIQ
  QLRKMGYKTIMVNYNPETVSTDYDMCDRLYFDEISFEVVMDIYELENPEGVILSMGGQLP
  NNMAMALHRQQCRVLGTSPEAIDSAENRFKFSRLLDTIGISQPQWRELSDLESARQFCQT
  VGYPCVVRPSYVLSGAAMNVAYTDGDLERFLSSAAAVSKEHPVVISKFIQEAKEIDVDAV
  ASDGVVAAIAISEHVENAGVHSGDATLVTPPQDITAKTLERIKAIVHAVGQELQVTGPFN
  LQLIAKDDQLKVIECNVRVSRSFPFVSKTLGVDLVALATRVIMGEEVEPVGLMTGSGVVG
  VKVPQFSFSRLAGADVVLGVEMTSTGEVAGFGESRCEAYLKAMLSTGFKIPKKNILLTIG
  SYKNKSELLPTVRLLESLGYSLYASLGTADFYTEHGVKVTAVDWHFEEAVDGECPPQRSI
  LEQLAEKNFELVINLSMRGAGGRRLSSFVTKGYRTRRLAADFSVPLIIDIKCTKLFVEAL
  GQIGPAPPLKVHVDCMTSQKLVRLPGLIDVHVHLREPGGTHKEDFASGTAAALAGGITMV
  CAMPNTRPPIIDAPALALAQKLAEAGARCDFALFLGASSENAGTLGTVAGSAAGLKLYLN
  ETFSELRLDSVVQWMEHFETWPSHLPIVAHAEQQTVAAVLMVAQLTQRSVHICHVARKEE
  ILLIKAAKARGLPVTCEVAPHHLFLSHDDLERLGPGKGEVRPELGSRQDVEALWENMAVI
  DCFASDHAPHTLEEKCGSRPPPGFPGLETMLPLLLTAVSEGRLSLDDLLQRLHHNPRRIF
  HLPPQEDTYVEVDLEHEWTIPSHMPFSKAHWTPFEGQKVKGTVRRVVLRGEVAYIDGQVL
  VPPGYGQDVRKWPQGAVPQLPPSAPATSEMTTTPERPRRGIPGLPDGRFHLPPRIHRASD
  PGLPAEEPKEKSSRKVAEPELMGTPDGTCYPPPPVPRQASPQNLGTPGLLHPQTSPLLHS
  LVGQHILSVQQFTKDQMSHLFNVAHTLRMMVQKERSLDILKGKVMASMFYEVSTRTSSSF
  AAAMARLGGAVLSFSEATSSVQKGESLADSVQTMSCYADVVVLRHPQPGAVELAAKHCRR
  PVINAGDGVGEHPTQALLDIFTIREELGTVNGMTITMVGDLKHGRTVHSLACLLTQYRVS
  LRYVAPPSLRMPPTVRAFVASRGTKQEEFESIEEALPDTDVLYMTRIQKERFGSTQEYEA
  CFGQFILTPHIMTRAKKKMVVMHPMPRVNEISVEVDSDPRAAYFRQAENGMYIRMALLAT
  VLGRF
• Function: Multifunctional protein that encodes the first 3 enzymatic activities of the de novo pyrimidine pathway: carbamoylphosphate synthetase (CPSase; EC 6.3.5.5), aspartate transcarbamylase (ATCase; EC 2.1.3.2) and dihydroorotase (DHOase; EC 3.5.2.3). The CPSase-function is accomplished in 2 steps, by a glutamine-dependent amidotransferase activity (GATase) that binds and cleaves glutamine to produce ammonia, followed by an ammonium-dependent carbamoyl phosphate synthetase, which reacts with the ammonia, hydrogencarbonate and ATP to form carbamoyl phosphate. The endogenously produced carbamoyl phosphate is sequestered and channeled to the ATCase active site. ATCase then catalyzes the formation of carbamoyl-L-aspartate from L-aspartate and carbamoyl phosphate. In the last step, DHOase catalyzes the cyclization of carbamoyl aspartate to dihydroorotate.
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Pyrimidine biosynthesis (R-HSA-500753)
• BioCyc Pathway: MetaCyc:ENSG00000084774-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 50	DISMTMWO	Definitive	Autosomal recessive	[1]

14 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 Multifunctional protein CAD (CAD).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Multifunctional protein CAD (CAD).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Multifunctional protein CAD (CAD).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Multifunctional protein CAD (CAD).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Multifunctional protein CAD (CAD).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Multifunctional protein CAD (CAD).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Multifunctional protein CAD (CAD).	[8]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Multifunctional protein CAD (CAD).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Multifunctional protein CAD (CAD).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Multifunctional protein CAD (CAD).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Multifunctional protein CAD (CAD).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Multifunctional protein CAD (CAD).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Multifunctional protein CAD (CAD).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Multifunctional protein CAD (CAD).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Multifunctional protein CAD (CAD).	[14]

References

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• [11] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
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