Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGOZG2M)

• DOT Name: Glutaminase kidney isoform, mitochondrial (GLS)
• Synonyms: GLS; EC 3.5.1.2; K-glutaminase; L-glutamine amidohydrolase
• Gene Name: GLS
• Related Disease:
  Glutaminase deficiency
  Global developmental delay, progressive ataxia, and elevated glutamine
  Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development
  Developmental and epileptic encephalopathy, 71
• UniProt ID: GLSK_HUMAN
• PDB ID: 3CZD ; 3UNW ; 3UO9 ; 3VOY ; 3VOZ ; 3VP0 ; 3VP1 ; 3VP2 ; 3VP3 ; 3VP4 ; 4O7D ; 5D3O ; 5FI2 ; 5FI6 ; 5FI7 ; 5HL1 ; 5I94 ; 5JYO ; 5JYP ; 5U0I ; 5U0J ; 5UQE ; 5WJ6 ; 6LOX ; 6UJG ; 6UJM ; 6UK6 ; 6UKB ; 6UL9 ; 6ULA ; 6ULJ ; 6UMC ; 6UMD ; 6UME ; 6UMF ; 7REN ; 7RGG ; 7SBM ; 7SBN ; 8BSK ; 8BSL ; 8BSM ; 8BSN ; 8GWR ; 8JUB ; 8JUE
• EC Number: 3.5.1.2
• Pfam ID: PF12796 ; PF17959 ; PF04960
• Sequence:
  MMRLRGSGMLRDLLLRSPAGVSATLRRAQPLVTLCRRPRGGGRPAAGPAAAARLHPWWGG
  GGWPAEPLARGLSSSPSEILQELGKGSTHPQPGVSPPAAPAAPGPKDGPGETDAFGNSEG
  KELVASGENKIKQGLLPSLEDLLFYTIAEGQEKIPVHKFITALKSTGLRTSDPRLKECMD
  MLRLTLQTTSDGVMLDKDLFKKCVQSNIVLLTQAFRRKFVIPDFMSFTSHIDELYESAKK
  QSGGKVADYIPQLAKFSPDLWGVSVCTVDGQRHSTGDTKVPFCLQSCVKPLKYAIAVNDL
  GTEYVHRYVGKEPSGLRFNKLFLNEDDKPHNPMVNAGAIVVTSLIKQGVNNAEKFDYVMQ
  FLNKMAGNEYVGFSNATFQSERESGDRNFAIGYYLKEKKCFPEGTDMVGILDFYFQLCSI
  EVTCESASVMAATLANGGFCPITGERVLSPEAVRNTLSLMHSCGMYDFSGQFAFHVGLPA
  KSGVAGGILLVVPNVMGMMCWSPPLDKMGNSVKGIHFCHDLVSLCNFHNYDNLRHFAKKL
  DPRREGGDQRVKSVINLLFAAYTGDVSALRRFALSAMDMEQRDYDSRTALHVAAAEGHVE
  VVKFLLEACKVNPFPKDRWNNTPMDEALHFGHHDVFKILQEYQVQYTPQGDSDNGKENQT
  VHKNLDGLL
• Function: Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate, the main excitatory neurotransmitter in the brain ; [Isoform 2]: Lacks catalytic activity.
• Tissue Specificity: Isoform 1 and isoform 3 are detected in brain cortex. Isoform 3 is highly expressed in astrocytoma, ganglioglioma and ependymoma. Isoform 1 is highly expressed in brain and kidney, but not detected in liver. Isoform 3 is highly expressed in heart and pancreas, detected at lower levels in placenta, lung, pancreas and kidney, but is not detected in liver. Isoform 2 is expressed in cardiac and skeletal muscle.
• KEGG Pathway:
  Arginine biosynthesis (hsa00220)
  Alanine, aspartate and glutamate metabolism (hsa00250)
  D-Amino acid metabolism (hsa00470)
  Metabolic pathways (hsa01100)
  Glutamatergic sy.pse (hsa04724)
  GABAergic sy.pse (hsa04727)
  Proximal tubule bicarbo.te reclamation (hsa04964)
  MicroR.s in cancer (hsa05206)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Glutamate and glutamine metabolism (R-HSA-8964539)
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glutaminase deficiency	DISZQNR0	Definitive	Autosomal recessive	[1]
Global developmental delay, progressive ataxia, and elevated glutamine	DIS59XM6	Strong	Autosomal recessive	[2]
Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development	DIS420W8	Moderate	Autosomal dominant	[3]
Developmental and epileptic encephalopathy, 71	DISB74OL	Limited	Autosomal recessive	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Glutaminase kidney isoform, mitochondrial (GLS) decreases the response to substance of Hydrogen peroxide.	[42]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hexadecanoic acid	DMWUXDZ	Investigative	Glutaminase kidney isoform, mitochondrial (GLS) decreases the oxidation of Hexadecanoic acid.	[31]

41 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 Glutaminase kidney isoform, mitochondrial (GLS).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the activity of Glutaminase kidney isoform, mitochondrial (GLS).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[20]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[21]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[22]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[23]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[24]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[25]
Palbociclib	DMD7L94	Approved	Palbociclib increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[26]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[27]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[27]
LY2835219	DM93VBZ	Approved	LY2835219 increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[28]
3,4-Dihydroxycinnamic Acid	DMVZL26	Phase 4	3,4-Dihydroxycinnamic Acid increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[29]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[30]
CB-839	DM094UH	Phase 2	CB-839 decreases the activity of Glutaminase kidney isoform, mitochondrial (GLS).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[32]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[34]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[35]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[38]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[39]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[40]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Glutaminase kidney isoform, mitochondrial (GLS).	[41]
Phenylarsonic acid	DMFRA1Y	Investigative	Phenylarsonic acid decreases the activity of Glutaminase kidney isoform, mitochondrial (GLS).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Glutaminase kidney isoform, mitochondrial (GLS).	[37]

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