Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZM930L)

• DOT Name: Hydroxycarboxylic acid receptor 2 (HCAR2)
• Synonyms: G-protein coupled receptor 109A; G-protein coupled receptor HM74A; Niacin receptor 1; Nicotinic acid receptor
• Gene Name: HCAR2
• UniProt ID: HCAR2_HUMAN
• PDB ID: 7XK2; 7ZL9; 7ZLY; 8H2G; 8IHB; 8IHF; 8IHH; 8IHI; 8J6P; 8J6Q; 8J6R; 8JHY; 8JII; 8JIL; 8JIM; 8JZ7; 8K5B; 8K5C; 8K5D
• Pfam ID: PF00001
• Sequence:
  MNRHHLQDHFLEIDKKNCCVFRDDFIVKVLPPVLGLEFIFGLLGNGLALWIFCFHLKSWK
  SSRIFLFNLAVADFLLIICLPFLMDNYVRRWDWKFGDIPCRLMLFMLAMNRQGSIIFLTV
  VAVDRYFRVVHPHHALNKISNRTAAIISCLLWGITIGLTVHLLKKKMPIQNGGANLCSSF
  SICHTFQWHEAMFLLEFFLPLGIILFCSARIIWSLRQRQMDRHAKIKRAITFIMVVAIVF
  VICFLPSVVVRIRIFWLLHTSGTQNCEVYRSVDLAFFITLSFTYMNSMLDPVVYYFSSPS
  FPNFFSTLINRCLQRKMTGEPDNNRSTSVELTGDPNKTRGAPEALMANSGEPWSPSYLGP
  TSP
• Function: Acts as a high affinity receptor for both nicotinic acid (also known as niacin) and (D)-beta-hydroxybutyrate and mediates increased adiponectin secretion and decreased lipolysis through G(i)-protein-mediated inhibition of adenylyl cyclase. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet. Mediates nicotinic acid-induced apoptosis in mature neutrophils. Receptor activation by nicotinic acid results in reduced cAMP levels which may affect activity of cAMP-dependent protein kinase A and phosphorylation of target proteins, leading to neutrophil apoptosis. The rank order of potency for the displacement of nicotinic acid binding is 5-methyl pyrazole-3-carboxylic acid = pyridine-3-acetic acid > acifran > 5-methyl nicotinic acid = acipimox >> nicotinuric acid = nicotinamide.
• Tissue Specificity: Expression largely restricted to adipose tissue and spleen. Expressed on mature neutrophils but not on immature neutrophils or eosinophils.
• KEGG Pathway: cAMP sig.ling pathway (hsa04024)
• Reactome Pathway:
  Class A/1 (Rhodopsin-like receptors) (R-HSA-373076)
  G alpha (i) signalling events (R-HSA-418594)
  Hydroxycarboxylic acid-binding receptors (R-HSA-3296197)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]cAMP	DMZRQU7	Investigative	Hydroxycarboxylic acid receptor 2 (HCAR2) decreases the abundance of [3H]cAMP.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Hydroxycarboxylic acid receptor 2 (HCAR2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Hydroxycarboxylic acid receptor 2 (HCAR2).	[7]

7 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 Hydroxycarboxylic acid receptor 2 (HCAR2).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Hydroxycarboxylic acid receptor 2 (HCAR2).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hydroxycarboxylic acid receptor 2 (HCAR2).	[4]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Hydroxycarboxylic acid receptor 2 (HCAR2).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Hydroxycarboxylic acid receptor 2 (HCAR2).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Hydroxycarboxylic acid receptor 2 (HCAR2).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Hydroxycarboxylic acid receptor 2 (HCAR2).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cinnamic acid	DM340FH	Investigative	Cinnamic acid affects the binding of Hydroxycarboxylic acid receptor 2 (HCAR2).	[10]

References

• [1] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [2] 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.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] 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.
• [5] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] Structure-activity relationships of trans-substituted-propenoic acid derivatives on the nicotinic acid receptor HCA2 (GPR109A). Bioorg Med Chem Lett. 2011 May 1;21(9):2736-9. doi: 10.1016/j.bmcl.2010.11.091. Epub 2010 Nov 25.
• [11] Modulation of HDL metabolism by the niacin receptor GPR109A in mouse hepatocytes. Biochem Pharmacol. 2010 Nov 1;80(9):1450-7. doi: 10.1016/j.bcp.2010.07.023. Epub 2010 Jul 22.