Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCPI0E8)

• DOT Name: Arginase-2, mitochondrial (ARG2)
• Synonyms: EC 3.5.3.1; Arginase II; Kidney-type arginase; Non-hepatic arginase; Type II arginase
• Gene Name: ARG2
• UniProt ID: ARGI2_HUMAN
• PDB ID: 1PQ3; 4HZE; 4I06; 4IE2; 4IE3; 4IXU; 4IXV; 6Q37; 6Q39; 6SS2; 6SS4; 6SS6
• EC Number: 3.5.3.1
• Pfam ID: PF00491
• Sequence:
  MSLRGSLSRLLQTRVHSILKKSVHSVAVIGAPFSQGQKRKGVEHGPAAIREAGLMKRLSS
  LGCHLKDFGDLSFTPVPKDDLYNNLIVNPRSVGLANQELAEVVSRAVSDGYSCVTLGGDH
  SLAIGTISGHARHCPDLCVVWVDAHADINTPLTTSSGNLHGQPVSFLLRELQDKVPQLPG
  FSWIKPCISSASIVYIGLRDVDPPEHFILKNYDIQYFSMRDIDRLGIQKVMERTFDLLIG
  KRQRPIHLSFDIDAFDPTLAPATGTPVVGGLTYREGMYIAEEIHNTGLLSALDLVEVNPQ
  LATSEEEAKTTANLAVDVIASSFGQTREGGHIVYDQLPTPSSPDESENQARVRI
• Function: May play a role in the regulation of extra-urea cycle arginine metabolism and also in down-regulation of nitric oxide synthesis. Extrahepatic arginase functions to regulate L-arginine bioavailability to nitric oxid synthase (NOS). Arginine metabolism is a critical regulator of innate and adaptive immune responses. Seems to be involved in negative regulation of the survival capacity of activated CD4(+) and CD8(+) T cells. May suppress inflammation-related signaling in asthmatic airway epithelium. May contribute to the immune evasion of H.pylori by restricting M1 macrophage activation and polyamine metabolism. In fetal dendritic cells may play a role in promoting immune suppression and T cell TNF-alpha production during gestation. Regulates RPS6KB1 signaling, which promotes endothelial cell senescence and inflammation and implicates NOS3/eNOS dysfunction. Can inhibit endothelial autophagy independently of its enzymatic activity implicating mTORC2 signaling. Involved in vascular smooth muscle cell senescence and apoptosis independently of its enzymatic activity. Since NOS is found in the penile corpus cavernosum smooth muscle, the clitoral corpus cavernosum and the vagina, arginase-2 plays a role in both male and female sexual arousal.
• Tissue Specificity: Expressed most strongly in kidney and prostate, much less strongly in the brain, skeletal muscle, placenta, lung, mammary gland, macrophage, uterus, testis and gut, but apparently not in the liver, heart and pancreas. Expressed in activated T cells .
• KEGG Pathway:
  Arginine biosynthesis (hsa00220)
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
  Biosynthesis of amino acids (hsa01230)
  Efferocytosis (hsa04148)
  Amoebiasis (hsa05146)
• Reactome Pathway: Urea cycle (R-HSA-70635)
• BioCyc Pathway: MetaCyc:HS01388-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Urea	DMUK75B	Approved	Arginase-2, mitochondrial (ARG2) increases the chemical synthesis of Urea.	[31]

33 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 Arginase-2, mitochondrial (ARG2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Arginase-2, mitochondrial (ARG2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Arginase-2, mitochondrial (ARG2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Arginase-2, mitochondrial (ARG2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Arginase-2, mitochondrial (ARG2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Arginase-2, mitochondrial (ARG2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Arginase-2, mitochondrial (ARG2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Arginase-2, mitochondrial (ARG2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Arginase-2, mitochondrial (ARG2).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Arginase-2, mitochondrial (ARG2).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Arginase-2, mitochondrial (ARG2).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Arginase-2, mitochondrial (ARG2).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Arginase-2, mitochondrial (ARG2).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Arginase-2, mitochondrial (ARG2).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Arginase-2, mitochondrial (ARG2).	[14]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Arginase-2, mitochondrial (ARG2).	[15]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Arginase-2, mitochondrial (ARG2).	[16]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Arginase-2, mitochondrial (ARG2).	[17]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Arginase-2, mitochondrial (ARG2).	[18]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Arginase-2, mitochondrial (ARG2).	[19]
Isoflavone	DM7U58J	Phase 4	Isoflavone decreases the expression of Arginase-2, mitochondrial (ARG2).	[20]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Arginase-2, mitochondrial (ARG2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Arginase-2, mitochondrial (ARG2).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Arginase-2, mitochondrial (ARG2).	[22]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Arginase-2, mitochondrial (ARG2).	[23]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Arginase-2, mitochondrial (ARG2).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Arginase-2, mitochondrial (ARG2).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Arginase-2, mitochondrial (ARG2).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Arginase-2, mitochondrial (ARG2).	[27]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Arginase-2, mitochondrial (ARG2).	[28]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Arginase-2, mitochondrial (ARG2).	[29]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Arginase-2, mitochondrial (ARG2).	[19]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Arginase-2, mitochondrial (ARG2).	[8]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
S-(2-boronoethyl)-L-cysteine	DMMZQB5	Investigative	S-(2-boronoethyl)-L-cysteine affects the binding of Arginase-2, mitochondrial (ARG2).	[30]

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