Details of Drug Off-Target (DOT)

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

• DOT Name: Arginase-1 (ARG1)
• Synonyms: EC 3.5.3.1; Liver-type arginase; Type I arginase
• Gene Name: ARG1
• Related Disease: Arginase 1 deficiency
• UniProt ID: ARGI1_HUMAN
• PDB ID: 1WVA ; 1WVB ; 2AEB ; 2PHA ; 2PHO ; 2PLL ; 2ZAV ; 3DJ8 ; 3E6K ; 3E6V ; 3F80 ; 3GMZ ; 3GN0 ; 3KV2 ; 3LP4 ; 3LP7 ; 3MFV ; 3MFW ; 3MJL ; 3SJT ; 3SKK ; 3TF3 ; 3TH7 ; 3THE ; 3THH ; 3THJ ; 4FCI ; 4FCK ; 4GSM ; 4GSV ; 4GSZ ; 4GWC ; 4GWD ; 4HWW ; 4HXQ ; 4IE1 ; 6Q92 ; 6Q9P ; 6QAF ; 6V7C ; 6V7D ; 6V7E ; 6V7F ; 7K4G ; 7K4H ; 7K4I ; 7K4J ; 7K4K ; 7KLK ; 7KLL ; 7KLM ; 7LEX ; 7LEY ; 7LEZ ; 7LF0 ; 7LF1 ; 7LF2 ; 8AUP ; 8E5M ; 8E5N
• EC Number: 3.5.3.1
• Pfam ID: PF00491
• Sequence:
  MSAKSRTIGIIGAPFSKGQPRGGVEEGPTVLRKAGLLEKLKEQECDVKDYGDLPFADIPN
  DSPFQIVKNPRSVGKASEQLAGKVAEVKKNGRISLVLGGDHSLAIGSISGHARVHPDLGV
  IWVDAHTDINTPLTTTSGNLHGQPVSFLLKELKGKIPDVPGFSWVTPCISAKDIVYIGLR
  DVDPGEHYILKTLGIKYFSMTEVDRLGIGKVMEETLSYLLGRKKRPIHLSFDVDGLDPSF
  TPATGTPVVGGLTYREGLYITEEIYKTGLLSGLDIMEVNPSLGKTPEEVTRTVNTAVAIT
  LACFGLAREGNHKPIDYLNPPK
• Function: Key element of the urea cycle converting L-arginine to urea and L-ornithine, which is further metabolized into metabolites proline and polyamides that drive collagen synthesis and bioenergetic pathways critical for cell proliferation, respectively; the urea cycle takes place primarily in the liver and, to a lesser extent, in the kidneys; Functions in L-arginine homeostasis in nonhepatic tissues characterized by the competition between nitric oxide synthase (NOS) and arginase for the available intracellular substrate arginine. Arginine metabolism is a critical regulator of innate and adaptive immune responses. Involved in an antimicrobial effector pathway in polymorphonuclear granulocytes (PMN). Upon PMN cell death is liberated from the phagolysosome and depletes arginine in the microenvironment leading to suppressed T cell and natural killer (NK) cell proliferation and cytokine secretion. In group 2 innate lymphoid cells (ILC2s) promotes acute type 2 inflammation in the lung and is involved in optimal ILC2 proliferation but not survival. In humans, the immunological role in the monocytic/macrophage/dendritic cell (DC) lineage is unsure.
• Tissue Specificity: Within the immune system initially reported to be selectively expressed in granulocytes (polymorphonuclear leukocytes [PMNs]) . Also detected in macrophages mycobacterial granulomas . Expressed in group2 innate lymphoid cells (ILC2s) during lung disease .
• 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)
  Neutrophil degranulation (R-HSA-6798695)
• BioCyc Pathway: MetaCyc:HS04231-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
Arginase 1 deficiency	DISAGUMY	Definitive	Autosomal recessive	[1]

31 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 Arginase-1 (ARG1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Arginase-1 (ARG1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Arginase-1 (ARG1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Arginase-1 (ARG1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Arginase-1 (ARG1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Arginase-1 (ARG1).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Arginase-1 (ARG1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Arginase-1 (ARG1).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Arginase-1 (ARG1).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Arginase-1 (ARG1).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Arginase-1 (ARG1).	[10]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Arginase-1 (ARG1).	[11]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Arginase-1 (ARG1).	[12]
Bicalutamide	DMZMSPF	Approved	Bicalutamide decreases the expression of Arginase-1 (ARG1).	[13]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol increases the expression of Arginase-1 (ARG1).	[14]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Arginase-1 (ARG1).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Arginase-1 (ARG1).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Arginase-1 (ARG1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Arginase-1 (ARG1).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Arginase-1 (ARG1).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Arginase-1 (ARG1).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Arginase-1 (ARG1).	[19]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Arginase-1 (ARG1).	[20]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Arginase-1 (ARG1).	[13]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Arginase-1 (ARG1).	[7]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos decreases the expression of Arginase-1 (ARG1).	[22]
Rutin	DMEHRAJ	Investigative	Rutin decreases the expression of Arginase-1 (ARG1).	[23]
NSC-1771	DMNXDGQ	Investigative	NSC-1771 decreases the expression of Arginase-1 (ARG1).	[22]
CYCLOPAMINE	DMEM2SW	Investigative	CYCLOPAMINE increases the expression of Arginase-1 (ARG1).	[24]
S-(2-boronoethyl)-L-cysteine	DMMZQB5	Investigative	S-(2-boronoethyl)-L-cysteine decreases the activity of Arginase-1 (ARG1).	[25]
Trypanothione	DMDUGQ1	Investigative	Trypanothione decreases the activity of Arginase-1 (ARG1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Manganese	DMKT129	Investigative	Manganese affects the binding of Arginase-1 (ARG1).	[21]

References

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• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [12] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [13] Androgen-regulated expression of arginase 1, arginase 2 and interleukin-8 in human prostate cancer. PLoS One. 2010 Aug 11;5(8):e12107.
• [14] Oral vitamin D rapidly attenuates inflammation from sunburn: an interventional study. J Invest Dermatol. 2017 Oct;137(10):2078-2086.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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• [20] Comparison of base-line and chemical-induced transcriptomic responses in HepaRG and RPTEC/TERT1 cells using TempO-Seq. Arch Toxicol. 2018 Aug;92(8):2517-2531.
• [21] Synthesis of (2S)-2-amino-7,8-epoxyoctanoic acid and structure of its metal-bridging complex with human arginase I. Org Biomol Chem. 2008 Sep 21;6(18):3240-3. doi: 10.1039/b811797g. Epub 2008 Aug 6.
• [22] RNA-protein correlation of liver toxicity markers in HepaRG cells. EXCLI J. 2020 Jan 17;19:135-153. doi: 10.17179/excli2019-2005. eCollection 2020.
• [23] Combination of metabolomics and network pharmacology analysis to decipher the mechanisms of total flavonoids of Litchi seed against prostate cancer. J Pharm Pharmacol. 2023 Jul 5;75(7):951-968. doi: 10.1093/jpp/rgad035.
• [24] M2 macrophage-derived IL6 mediates resistance of breast cancer cells to hedgehog inhibition. Toxicol Appl Pharmacol. 2019 Feb 1;364:77-82. doi: 10.1016/j.taap.2018.12.013. Epub 2018 Dec 19.
• [25] Inhibition profile of Leishmania mexicana arginase reveals differences with human arginase I. Int J Parasitol. 2011 Apr;41(5):545-52. doi: 10.1016/j.ijpara.2010.12.006. Epub 2011 Jan 11.