Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4SBHI8)

• DOT Name: Purine nucleoside phosphorylase LACC1 (LACC1)
• Synonyms: EC 2.4.2.1; Adenosine deaminase LACC1; EC 3.5.4.4; Fatty acid metabolism-immunity nexus; Guanosine phosphorylase LACC1; Laccase domain-containing protein 1; S-methyl-5'-thioadenosine phosphorylase LACC1; EC 2.4.2.28
• Gene Name: LACC1
• Related Disease:
  Arthritis
  Inflammatory bowel disease
  Juvenile arthritis due to defect in LACC1
  Juvenile idiopathic arthritis
  Majeed syndrome
  Multiple sclerosis
  Ulcerative colitis
  Asthma
  Crohn disease
  Inflammation
  Leprosy
• UniProt ID: LACC1_HUMAN
• EC Number: 2.4.2.1; 2.4.2.28; 3.5.4.4
• Pfam ID: PF02578
• Sequence:
  MAEAVLIDLFGLKLNSQKNCHQTLLKTLNAVQYHHAAKAKFLCIMCCSNISYERDGEQDN
  CEIETSNGLSALLEEFEIVSCPSMAATLYTIKQKIDEKNLSSIKVIVPRHRKTLMKAFID
  QLFTDVYNFEFEDLQVTFRGGLFKQSIEINVITAQELRGIQNEIETFLRSLPALRGKLTI
  ITSSLIPDIFIHGFTTRTGGISYIPTLSSFNLFSSSKRRDPKVVVQENLRRLANAAGFNV
  EKFYRIKTHHSNDIWIMGRKEPDSYDGITTNQRGVTIAALGADCIPIVFADPVKKACGVA
  HAGWKGTLLGVAMATVNAMIAEYGCSLEDIVVVLGPSVGPCCFTLPRESAEAFHNLHPAC
  VQLFDSPNPCIDIRKATRILLEQGGILPQNIQDQNQDLNLCTSCHPDKFFSHVRDGLNFG
  TQIGFISIKE
• Function: Purine nucleoside enzyme that catalyzes the phosphorolysis of adenosine, guanosine and inosine nucleosides, yielding D-ribose 1-phosphate and the respective free bases, adenine, guanine and hypoxanthine. Also catalyzes the phosphorolysis of S-methyl-5'-thioadenosine into adenine and S-methyl-5-thio-alpha-D-ribose 1-phosphate. Also has adenosine deaminase activity. Acts as a regulator of innate immunity in macrophages by modulating the purine nucleotide metabolism, thereby regulating the metabolic function and bioenergetic state of macrophages. Enables a purine nucleotide cycle between adenosine and inosine monophosphate and adenylosuccinate that prevents cytoplasmic acidification and balances the cytoplasmic-mitochondrial redox interface. The purine nucleotide cycle consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. Participates in pattern recognition receptor (PRR)-induced cytokines in macrophages: associates with the NOD2-signaling complex and promotes optimal NOD2-induced signaling, cytokine secretion and bacterial clearance. Localizes to the endoplasmic reticulum upon PRR stimulation of macrophages and associates with endoplasmic reticulum-stress sensors, promoting the endoplasmic reticulum unfolded protein response (UPR). Does not show laccase activity.
• Tissue Specificity: Ubiquitously expressed, with higher expression levels in immune-related tissues such as lymph nodes and spleen . Expressed in both intestinal and peripheral myeloid-derived cells .
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Cysteine and methionine metabolism (hsa00270)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Strong	Biomarker	[1]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[1]
Juvenile arthritis due to defect in LACC1	DISLMBNW	Strong	Autosomal recessive	[2]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[3]
Majeed syndrome	DIS8AI2U	Strong	Biomarker	[4]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[5]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[6]
Asthma	DISW9QNS	moderate	Genetic Variation	[7]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[8]
Inflammation	DISJUQ5T	Limited	Genetic Variation	[9]
Leprosy	DISAA4UI	Limited	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Purine nucleoside phosphorylase LACC1 (LACC1).	[10]

15 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 Purine nucleoside phosphorylase LACC1 (LACC1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[18]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Purine nucleoside phosphorylase LACC1 (LACC1).	[24]

References

• [1] LACC1 Regulates TNF and IL-17 in Mouse Models of Arthritis and Inflammation.J Immunol. 2019 Jan 1;202(1):183-193. doi: 10.4049/jimmunol.1800636. Epub 2018 Dec 3.
• [2] Association of a mutation in LACC1 with a monogenic form of systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 2015 Jan;67(1):288-95. doi: 10.1002/art.38877.
• [3] Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis.Sci Rep. 2019 Mar 14;9(1):4579. doi: 10.1038/s41598-019-40874-2.
• [4] Pattern and diagnostic evaluation of systemic autoinflammatory diseases other than familial Mediterranean fever among Arab children: a multicenter study from the Pediatric Rheumatology Arab Group (PRAG).Rheumatol Int. 2020 Jan;40(1):49-56. doi: 10.1007/s00296-019-04478-3. Epub 2019 Nov 18.
• [5] Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
• [6] Functional Analyses of the Crohn's Disease Risk Gene LACC1.PLoS One. 2016 Dec 13;11(12):e0168276. doi: 10.1371/journal.pone.0168276. eCollection 2016.
• [7] Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia.Eur J Hum Genet. 2011 Apr;19(4):458-64. doi: 10.1038/ejhg.2010.191. Epub 2010 Dec 8.
• [8] Using genes to triangulate the pathophysiology of granulomatous autoinflammatory disease: NOD2, PLCG2 and LACC1.Int Immunol. 2018 Apr 25;30(5):205-213. doi: 10.1093/intimm/dxy021.
• [9] Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes.Nat Commun. 2017 Jun 8;8:15614. doi: 10.1038/ncomms15614.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [17] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [21] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [22] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [23] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [24] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.