diacylglycerol O-acyltransferase 1

Target id: 2821

Nomenclature: diacylglycerol O-acyltransferase 1

Family: 2.3.1.- Acyltransferases

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for diacylglycerol O-acyltransferase 1 in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 488 8q24.3 DGAT1 diacylglycerol O-acyltransferase 1
Mouse - 498 15 D3 Dgat1 diacylglycerol O-acyltransferase 1
Rat - 498 7q34 Dgat1 diacylglycerol O-acyltransferase 1
Previous and Unofficial Names
ARGP1 | DGAT
Database Links
BRENDA
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 2.3.1.20
Description Reaction Reference
Conversion of diacylglycerol and fatty acyl CoA to triacylglycerol. Acyl-CoA + 1,2-diacylglycerol <=> CoA + triacylglycerol

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
compound 5B [PMID: 25349648] Hs Inhibition 8.4 pIC50 10
pIC50 8.4 (IC50 3.9x10-9 M) [10]
T863 Hs Inhibition 7.8 pIC50 2
pIC50 7.8 (IC50 1.5x10-8 M) [2]
PF-04620110 Hs Inhibition 7.7 pIC50 9
pIC50 7.7 (IC50 1.9x10-8 M) [9]
compound 23n [PMID: 24900877] Hs Inhibition 7.2 pIC50 13
pIC50 7.2 (IC50 6.4x10-8 M) [13]
AZD7687 Hs Inhibition 7.1 pIC50 1
pIC50 7.1 (IC50 8x10-8 M) [1]
Description: Measured using purified human DGAT1
Clinically-Relevant Mutations and Pathophysiology
Disease:  Diarrhea 7; DIAR7
Synonyms: Congenital chronic diarrhea with protein-losing enteropathy [Orphanet: ORPHA329242]
OMIM: 615863
Orphanet: ORPHA329242
General Comments
DGAT1 catalyzes the final committed step in triglyceride synthesis and is believed to play a key role in whole body energy homeostasis [6]. Inhibition of DGAT1 represents a novel approach to treat metabolic disease and obesity [5,12] and as such has become the focus of intense interest from the pharmaceutical industry [3-4,8,11]. Their efforts have lead to the development of many novel DGAT1 inhibitors, some of which are reaching the clinic. Unfortunately many of the lead compounds are associated with adverse gastrointestinal events [7], so medicinal chemists are working to elucidate the underlying mechanism to develop novel compounds which will circumvent this undesireable action.

References

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1. Barlind JG, Bauer UA, Birch AM, Birtles S, Buckett LK, Butlin RJ, Davies RD, Eriksson JW, Hammond CD, Hovland R et al.. (2012) Design and optimization of pyrazinecarboxamide-based inhibitors of diacylglycerol acyltransferase 1 (DGAT1) leading to a clinical candidate dimethylpyrazinecarboxamide phenylcyclohexylacetic acid (AZD7687). J. Med. Chem.55 (23): 10610-29. [PMID:23116186]

2. Birch AM, Birtles S, Buckett LK, Kemmitt PD, Smith GJ, Smith TJ, Turnbull AV, Wang SJ. (2009) Discovery of a potent, selective, and orally efficacious pyrimidinooxazinyl bicyclooctaneacetic acid diacylglycerol acyltransferase-1 inhibitor. J. Med. Chem.52 (6): 1558-68. [PMID:19256504]

3. Birch AM, Buckett LK, Turnbull AV. (2010) DGAT1 inhibitors as anti-obesity and anti-diabetic agents. Curr Opin Drug Discov Devel13 (4): 489-96. [PMID:20597032]

4. Cao J, Zhou Y, Peng H, Huang X, Stahler S, Suri V, Qadri A, Gareski T, Jones J, Hahm S et al.. (2011) Targeting Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases. J. Biol. Chem.286 (48): 41838-51. [PMID:21990351]

5. Chen HC, Farese Jr RV. (2000) DGAT and triglyceride synthesis: a new target for obesity treatment?. Trends Cardiovasc. Med.10 (5): 188-92. [PMID:11282293]

6. Cheng D, Iqbal J, Devenny J, Chu CH, Chen L, Dong J, Seethala R, Keim WJ, Azzara AV, Lawrence RM et al.. (2008) Acylation of acylglycerols by acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1). Functional importance of DGAT1 in the intestinal fat absorption. J. Biol. Chem.283 (44): 29802-11. [PMID:18768481]

7. Denison H, Nilsson C, Löfgren L, Himmelmann A, Mårtensson G, Knutsson M, Al-Shurbaji A, Tornqvist H, Eriksson JW. (2014) Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial. Diabetes Obes Metab16 (4): 334-43. [PMID:24118885]

8. DeVita RJ, Pinto S. (2013) Current status of the research and development of diacylglycerol O-acyltransferase 1 (DGAT1) inhibitors. J. Med. Chem.56 (24): 9820-5. [PMID:23919406]

9. Dow RL, Li JC, Pence MP, Gibbs EM, LaPerle JL, Litchfield J, Piotrowski DW, Munchhof MJ, Manion TB, Zavadoski WJ et al.. (2011) Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1. ACS Med Chem Lett2 (5): 407-12. [PMID:24900321]

10. He S, Hong Q, Lai Z, Yang DX, Ting PC, Kuethe JT, Cernak TA, Dykstra KD, Sperbeck DM, Wu Z et al.. (2014) Discovery of a Potent and Selective DGAT1 Inhibitor with a Piperidinyl-oxy-cyclohexanecarboxylic Acid Moiety. ACS Med Chem Lett5 (10): 1082-7. [PMID:25349648]

11. Zammit VA, Buckett LK, Turnbull AV, Wure H, Proven A. (2008) Diacylglycerol acyltransferases: Potential roles as pharmacological targets. Pharmacol. Ther.118 (3): 295-302. [PMID:18508126]

12. Zhao G, Souers AJ, Voorbach M, Falls HD, Droz B, Brodjian S, Lau YY, Iyengar RR, Gao J, Judd AS et al.. (2008) Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor. J. Med. Chem.51 (3): 380-3. [PMID:18183944]

13. Zhou G, Zorn N, Ting P, Aslanian R, Lin M, Cook J, Lachowicz J, Lin A, Smith M, Hwa J et al.. (2014) Development of novel benzomorpholine class of diacylglycerol acyltransferase I inhibitors. ACS Med Chem Lett5 (5): 544-9. [PMID:24900877]

How to cite this page

2.3.1.- Acyltransferases: diacylglycerol O-acyltransferase 1. Last modified on 13/08/2015. Accessed on 17/12/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2821.