Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7FOIK2)

• DOT Name: Polyunsaturated fatty acid 5-lipoxygenase (ALOX5)
• Synonyms: EC 1.13.11.-; Arachidonate 5-lipoxygenase; 5-LO; 5-lipoxygenase; EC 1.13.11.34
• Gene Name: ALOX5
• UniProt ID: LOX5_HUMAN
• PDB ID: 3O8Y; 3V92; 3V98; 3V99; 6N2W; 6NCF; 7TTJ; 7TTK; 7TTL
• EC Number: 1.13.11.-; 1.13.11.34
• Pfam ID: PF00305 ; PF01477
• Sequence:
  MPSYTVTVATGSQWFAGTDDYIYLSLVGSAGCSEKHLLDKPFYNDFERGAVDSYDVTVDE
  ELGEIQLVRIEKRKYWLNDDWYLKYITLKTPHGDYIEFPCYRWITGDVEVVLRDGRAKLA
  RDDQIHILKQHRRKELETRQKQYRWMEWNPGFPLSIDAKCHKDLPRDIQFDSEKGVDFVL
  NYSKAMENLFINRFMHMFQSSWNDFADFEKIFVKISNTISERVMNHWQEDLMFGYQFLNG
  CNPVLIRRCTELPEKLPVTTEMVECSLERQLSLEQEVQQGNIFIVDFELLDGIDANKTDP
  CTLQFLAAPICLLYKNLANKIVPIAIQLNQIPGDENPIFLPSDAKYDWLLAKIWVRSSDF
  HVHQTITHLLRTHLVSEVFGIAMYRQLPAVHPIFKLLVAHVRFTIAINTKAREQLICECG
  LFDKANATGGGGHVQMVQRAMKDLTYASLCFPEAIKARGMESKEDIPYYFYRDDGLLVWE
  AIRTFTAEVVDIYYEGDQVVEEDPELQDFVNDVYVYGMRGRKSSGFPKSVKSREQLSEYL
  TVVIFTASAQHAAVNFGQYDWCSWIPNAPPTMRAPPPTAKGVVTIEQIVDTLPDRGRSCW
  HLGAVWALSQFQENELFLGMYPEEHFIEKPVKEAMARFRKNLEAIVSVIAERNKKKQLPY
  YYLSPDRIPNSVAI
• Function: Catalyzes the oxygenation of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) to 5-hydroperoxyeicosatetraenoate (5-HPETE) followed by the dehydration to 5,6- epoxyeicosatetraenoate (Leukotriene A4/LTA4), the first two steps in the biosynthesis of leukotrienes, which are potent mediators of inflammation. Also catalyzes the oxygenation of arachidonate into 8-hydroperoxyicosatetraenoate (8-HPETE) and 12-hydroperoxyicosatetraenoate (12-HPETE). Displays lipoxin synthase activity being able to convert (15S)-HETE into a conjugate tetraene. Although arachidonate is the preferred substrate, this enzyme can also metabolize oxidized fatty acids derived from arachidonate such as (15S)-HETE, eicosapentaenoate (EPA) such as (18R)- and (18S)-HEPE or docosahexaenoate (DHA) which lead to the formation of specialized pro-resolving mediators (SPM) lipoxin and resolvins E and D respectively, therefore it participates in anti-inflammatory responses. Oxidation of DHA directly inhibits endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor gamma (PPARgamma). It does not catalyze the oxygenation of linoleic acid and does not convert (5S)-HETE to lipoxin isomers. In addition to inflammatory processes, it participates in dendritic cell migration, wound healing through an antioxidant mechanism based on heme oxygenase-1 (HO-1) regulation expression, monocyte adhesion to the endothelium via ITGAM expression on monocytes. Moreover, it helps establish an adaptive humoral immunity by regulating primary resting B cells and follicular helper T cells and participates in the CD40-induced production of reactive oxygen species (ROS) after CD40 ligation in B cells through interaction with PIK3R1 that bridges ALOX5 with CD40. May also play a role in glucose homeostasis, regulation of insulin secretion and palmitic acid-induced insulin resistance via AMPK. Can regulate bone mineralization and fat cell differentiation increases in induced pluripotent stem cells.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
  Efferocytosis (hsa04148)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Serotonergic sy.pse (hsa04726)
  Ovarian steroidogenesis (hsa04913)
  Toxoplasmosis (hsa05145)
• Reactome Pathway:
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)
  Synthesis of Lipoxins (LX) (R-HSA-2142700)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Neutrophil degranulation (R-HSA-6798695)
  Interleukin-18 signaling (R-HSA-9012546)
  Biosynthesis of D-series resolvins (R-HSA-9018676)
  Biosynthesis of maresins (R-HSA-9018682)
  Biosynthesis of E-series 18(S)-resolvins (R-HSA-9018896)
  Biosynthesis of aspirin-triggered D-series resolvins (R-HSA-9020265)
  Biosynthesis of E-series 18(R)-resolvins (R-HSA-9023661)
  Biosynthesis of DPAn-3-derived protectins and resolvins (R-HSA-9026286)
  Biosynthesis of DPAn-3-derived maresins (R-HSA-9026290)
  Biosynthesis of DPAn-3-derived 13-series resolvins (R-HSA-9026403)
  Biosynthesis of electrophilic -3 PUFA oxo-derivatives (R-HSA-9027604)
  Synthesis of 5-eicosatetraenoic acids (R-HSA-2142688)
• BioCyc Pathway: MetaCyc:HS00336-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Polyunsaturated fatty acid 5-lipoxygenase (ALOX5) affects the response to substance of Methotrexate.	[40]

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
LTB4	DME26RS	Phase 2	Polyunsaturated fatty acid 5-lipoxygenase (ALOX5) increases the chemical synthesis of LTB4.	[41]
5S-HETE	DM3Z6G4	Investigative	Polyunsaturated fatty acid 5-lipoxygenase (ALOX5) increases the chemical synthesis of 5S-HETE.	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
LTD4	DMIUZX3	Investigative	Polyunsaturated fatty acid 5-lipoxygenase (ALOX5) increases the abundance of LTD4.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[3]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[10]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[11]
Fructose	DM43AN2	Approved	Fructose increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[12]
Masoprocol	DMMVNZ0	Approved	Masoprocol decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[13]
Loratadine	DMF3AN7	Approved	Loratadine decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[14]
Meclofenamic acid	DM05FXR	Approved	Meclofenamic acid decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[15]
Zileuton	DMVRIC2	Approved	Zileuton decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[18]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[19]
Tenidap	DMHQRYE	Phase 3	Tenidap decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[21]
SPI-1005	DM6XFHS	Phase 2 Trial	SPI-1005 decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[22]
AZD-4877	DMFVL5J	Phase 2	AZD-4877 decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[23]
BIM23A760	DM6EIZG	Phase 2	BIM23A760 decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[20]
Tepoxalin	DMVS61L	Phase 2	Tepoxalin decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[27]
JWH-015	DMGTSCP	Patented	JWH-015 decreases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[28]
Benoxaprofen	DM5ZOX8	Withdrawn from market	Benoxaprofen decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[20]
OX-NLA	DMPEHBJ	Discontinued in Phase 3	OX-NLA decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[14]
CJ-13610	DM1CDNS	Discontinued in Phase 2	CJ-13610 decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[29]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[30]
AA-861	DMPEB0Z	Terminated	AA-861 decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[31]
BW A4C	DMNUMDG	Terminated	BW A4C decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[32]
FPL-55712	DMF1CDK	Terminated	FPL-55712 decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[31]
REV-5901	DMI94L1	Terminated	REV-5901 decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[24]
BW755C	DMQM3P4	Terminated	BW755C decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[15]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[33]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[34]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[12]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[35]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[36]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[37]
2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One	DMDN12L	Investigative	2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One decreases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[28]
PAF	DMRZAQW	Investigative	PAF increases the expression of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[38]
ICI-211965	DMYRILU	Investigative	ICI-211965 decreases the activity of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine monophosphate	DMNIJT0	Approved	Adenosine monophosphate affects the binding of Polyunsaturated fatty acid 5-lipoxygenase (ALOX5).	[17]

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