Biology:Diglyceride acyltransferase
| diacylglycerol O-acyltransferase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC number | 2.3.1.20 | ||||||||
| CAS number | 9029-98-5 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
| diacylglycerol O-acyltransferase 1 | |
|---|---|
| Identifiers | |
| Symbol | DGAT1 |
| NCBI gene | 8694 |
| HGNC | 2843 |
| OMIM | 604900 |
| RefSeq | NM_012079 |
| UniProt | O75907 |
| Other data | |
| Locus | Chr. 8 q24.3 |
Diglyceride acyltransferase (or O-acyltransferase), DGAT, catalyzes the formation of triglycerides (triacylglycerols) from diacylglycerol and acyl-CoA (for a recent and comprehensive review about DGAT, see [1]). The reaction catalyzed by DGAT is considered the terminal and only committed step in the acyl-CoA-dependent triglyceride synthesis, universally important in animal, plants, and microorganisms. The conversion is essential for intestinal absorption (i.e. DGAT1) and adipose tissue formation (i.e. DGAT2) in mammalian.[2] DGAT1 are homologous to other membrane-bound O-acyltransferases, but not all other DGATs.[1]
Isoforms
Two important DGAT isozymes are encoded by the genes DGAT1[3] and DGAT2.[4] Although both isozymes catalyze similar reactions, they share no sequence homology, which is similar to other DGATs reported in various organisms.[1] The location of DGAT1 and DGAT2 in other organisms, as well as other DGATs have been reported in various literatures.[1]
DGAT1 is mainly located in absorptive enterocyte cells that line the intestine and duodenum where it reassembles triglycerides that were decomposed through lipolysis in the process of intestinal absorption. DGAT1 reconstitutes triglycerides in a committed step after which they are packaged together with cholesterol and proteins to form chylomicrons.
DGAT2 is mainly located in fat, liver and skin cells.
Knockout studies in mice
Mice with genetic disruption of the DGAT1 or DGAT2 genes have been made by the Farese laboratory at UCSF. Surprisingly, DGAT1−/− mice[5] are healthy and fertile and have no changes in triglyceride levels. These mice are also lean and resistant to diet-induced obesity, consequently generating interest in DGAT1 inhibitors for the treatment of obesity. However, these mice also fail to lactate, showing a complete lack of milk production due to their inability to produce milk lipid droplets.[5] In contrast, DGAT2−/− mice[6] have reduced triglyceride levels but are lipopenic, suffer from skin barrier abnormalities (including the inability to retain moisture), and die shortly after birth.
Therapeutic application
DGAT1 inhibitors have potential for the treatment of obesity[7][8] and a number of DGAT-1 inhibitors are in clinical trials for this indication.[9]
DGAT is also important in lipid biotechnology in plants, microorganisms, and animals.[1]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Chen, Guanqun; Harwood, John L.; Lemieux, M. Joanne; Stone, Scot J.; Weselake, Randall J. (November 2022). "Acyl-CoA:diacylglycerol acyltransferase: Properties, physiological roles, metabolic engineering and intentional control". [Progress in Lipid Research] 88: 101181. doi:10.1016/j.plipres.2022.101181. PMID 35820474.
- ↑ Yen, Chi-Liang Eric; Stone, Scot J.; Koliwad, Suneil; Harris, Charles; Farese, Robert V. (2008). "Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis". Journal of Lipid Research 49 (11): 2283–2301. doi:10.1194/jlr.R800018-JLR200. PMID 18757836.
- ↑ "Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes". The Journal of Biological Chemistry 273 (41): 26765–71. October 1998. doi:10.1074/jbc.273.41.26765. PMID 9756920.
- ↑ "Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members". The Journal of Biological Chemistry 276 (42): 38870–6. October 2001. doi:10.1074/jbc.M106219200. PMID 11481335.
- ↑ 5.0 5.1 "Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat". Nature Genetics 25 (1): 87–90. May 2000. doi:10.1038/75651. PMID 10802663.
- ↑ "Lipopenia and skin barrier abnormalities in DGAT2-deficient mice". The Journal of Biological Chemistry 279 (12): 11767–76. March 2004. doi:10.1074/jbc.M311000200. PMID 14668353.
- ↑ "Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice". Arteriosclerosis, Thrombosis, and Vascular Biology 25 (3): 482–6. March 2005. doi:10.1161/01.ATV.0000151874.81059.ad. PMID 15569818.
- ↑ "Acylation of acylglycerols by acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1). Functional importance of DGAT1 in the intestinal fat absorption". The Journal of Biological Chemistry 283 (44): 29802–11. October 2008. doi:10.1074/jbc.M800494200. PMID 18768481.
- ↑ "Pfizer, Bristol finalize deal on metabolic drugs". Reuters. 2007-08-27. https://www.reuters.com/article/health-SP/idUSN2743563720070827. Retrieved 2007-08-27.
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