Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTESDI4D)

• DOT Name: Glutamate--cysteine ligase catalytic subunit (GCLC)
• Synonyms: EC 6.3.2.2; GCS heavy chain; Gamma-ECS; Gamma-glutamylcysteine synthetase
• Gene Name: GCLC
• Related Disease: Gamma-glutamylcysteine synthetase deficiency
• UniProt ID: GSH1_HUMAN
• EC Number: 6.3.2.2
• Pfam ID: PF03074
• Sequence:
  MGLLSQGSPLSWEETKRHADHVRRHGILQFLHIYHAVKDRHKDVLKWGDEVEYMLVSFDH
  ENKKVRLVLSGEKVLETLQEKGERTNPNHPTLWRPEYGSYMIEGTPGQPYGGTMSEFNTV
  EANMRKRRKEATSILEENQALCTITSFPRLGCPGFTLPEVKPNPVEGGASKSLFFPDEAI
  NKHPRFSTLTRNIRHRRGEKVVINVPIFKDKNTPSPFIETFTEDDEASRASKPDHIYMDA
  MGFGMGNCCLQVTFQACSISEARYLYDQLATICPIVMALSAASPFYRGYVSDIDCRWGVI
  SASVDDRTREERGLEPLKNNNYRISKSRYDSIDSYLSKCGEKYNDIDLTIDKEIYEQLLQ
  EGIDHLLAQHVAHLFIRDPLTLFEEKIHLDDANESDHFENIQSTNWQTMRFKPPPPNSDI
  GWRVEFRPMEVQLTDFENSAYVVFVVLLTRVILSYKLDFLIPLSKVDENMKVAQKRDAVL
  QGMFYFRKDICKGGNAVVDGCGKAQNSTELAAEEYTLMSIDTIINGKEGVFPGLIPILNS
  YLENMEVDVDTRCSILNYLKLIKKRASGELMTVARWMREFIANHPDYKQDSVITDEMNYS
  LILKCNQIANELCECPELLGSAFRKVKYSGSKTDSSN
• Function: Catalyzes the ATP-dependent ligation of L-glutamate and L-cysteine and participates in the first and rate-limiting step in glutathione biosynthesis.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Glutathione metabolism (hsa00480)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Ferroptosis (hsa04216)
• Reactome Pathway:
  Defective GCLC causes HAGGSD (R-HSA-5578999)
  NFE2L2 regulating anti-oxidant/detoxification enzymes (R-HSA-9818027)
  Glutathione synthesis and recycling (R-HSA-174403)
• BioCyc Pathway: MetaCyc:ENSG00000001084-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
Gamma-glutamylcysteine synthetase deficiency	DISFREPH	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Glutamate--cysteine ligase catalytic subunit (GCLC) decreases the response to substance of Doxorubicin.	[73]
Gefitinib	DM15F0X	Approved	Glutamate--cysteine ligase catalytic subunit (GCLC) affects the response to substance of Gefitinib.	[74]
Artesunate	DMR27C8	Approved	Glutamate--cysteine ligase catalytic subunit (GCLC) decreases the response to substance of Artesunate.	[75]
Acetylcholine	DMDF79Z	Approved	Glutamate--cysteine ligase catalytic subunit (GCLC) decreases the response to substance of Acetylcholine.	[77]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Glutathione	DMAHMT9	Approved	Glutamate--cysteine ligase catalytic subunit (GCLC) increases the abundance of Glutathione.	[76]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[13]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[14]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[15]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[17]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[18]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[19]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[20]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[21]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[13]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[22]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[23]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[24]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[7]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[7]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[7]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[25]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[23]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[26]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[19]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[27]
Chenodiol	DMQ8JIK	Approved	Chenodiol increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[28]
Ampicillin	DMHWE7P	Approved	Ampicillin decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[29]
Bosentan	DMIOGBU	Approved	Bosentan increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[30]
Methimazole	DM25FL8	Approved	Methimazole increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[31]
Clavulanate	DM2FGRT	Approved	Clavulanate increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[32]
Benzoic acid	DMKB9FI	Approved	Benzoic acid increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[22]
Gamolenic acid	DMQN30Z	Approved	Gamolenic acid increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[33]
Naproxen	DMZ5RGV	Approved	Naproxen increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[23]
Ketoprofen	DMRKXPT	Approved	Ketoprofen increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[23]
Nitrofurantoin	DM7PQIK	Approved	Nitrofurantoin increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[34]
Suprofen	DMKXJZ7	Approved	Suprofen increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[35]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[23]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[36]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[37]
HMPL-004	DM29XGY	Phase 3	HMPL-004 decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[38]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[38]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[39]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[19]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[40]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[41]
PEITC	DMOMN31	Phase 2	PEITC increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[42]
Disulfiram	DMCL2OK	Phase 2 Trial	Disulfiram increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[22]
Impoyz	DMB1N6P	Phase 2	Impoyz decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[43]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[45]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[46]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[22]
T83193	DMHO29Y	Patented	T83193 increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[48]
Tetramethylpyrazine	DMC0WNB	Discontinued in Phase 2	Tetramethylpyrazine increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[49]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[50]
Scriptaid	DM9JZ21	Preclinical	Scriptaid increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[51]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[37]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[52]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[54]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[55]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[56]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[57]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[58]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[59]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[48]
acrolein	DMAMCSR	Investigative	acrolein increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[60]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[61]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[62]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid affects the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[63]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[64]
Kaempferol	DMHEMUB	Investigative	Kaempferol increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[10]
Linalool	DMGZQ5P	Investigative	Linalool increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[52]
Apigenin	DMI3491	Investigative	Apigenin increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[10]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol decreases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[38]
	DM9CEI5		increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[28]
15-deoxy-Delta(12, 14)-prostaglandin J(2)	DM8VUX3	Investigative	15-deoxy-Delta(12, 14)-prostaglandin J(2) increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[65]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[66]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[67]
USNIC ACID	DMGOURX	Investigative	USNIC ACID increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[68]
Icosapentum	DMF1CM7	Investigative	Icosapentum increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[33]
methyl salicylate	DMKCG8H	Investigative	methyl salicylate increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[22]
OXYRESVERATROL	DMN7S4L	Investigative	OXYRESVERATROL increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[69]
2-Propanol, Isopropanol	DML5O0H	Investigative	2-Propanol, Isopropanol increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[22]
All-trans-retinal	DM6CEVB	Investigative	All-trans-retinal increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[70]
Alpha-linolenic acid	DMY64HE	Investigative	Alpha-linolenic acid increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[33]
THIOCTIC ACID	DMNFCXW	Investigative	THIOCTIC ACID increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[71]
2-chloro-5-nitro-N-phenylbenzamide	DMUGQIV	Investigative	2-chloro-5-nitro-N-phenylbenzamide increases the expression of Glutamate--cysteine ligase catalytic subunit (GCLC).	[72]

3 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 Glutamate--cysteine ligase catalytic subunit (GCLC).	[44]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Glutamate--cysteine ligase catalytic subunit (GCLC).	[47]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the methylation of Glutamate--cysteine ligase catalytic subunit (GCLC).	[53]

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