DGAT

Diglyceride acyltransferase (or O-acyltransferase), DGAT, catalyzes the formation of triglycerides from diacylglycerol and Acyl-CoA. The reaction catalyzed by DGAT is considered the terminal and only committed step in triglyceride synthesis and to be essential for the formation of adipose tissue. The protein is homologous to other membrane-bound O-acyltransferases.

1031336-60-3
ABT-046
1031336-60-3
1109276-89-2
PF-04620110
1109276-89-2
1166827-44-6
AZD7687
1166827-44-6
124083-20-1
Etomoxir
124083-20-1
1449779-49-0
DGAT1-IN-1
1449779-49-0
1469284-78-3
PF-06424439
1469284-78-3
JNJ DGAT2-A
1962931-71-0
701232-20-4
T863
701232-20-4
828934-41-4
828934-41-4
AZD 3988
892489-52-0
942999-61-3
DGAT-1 inhibitor 2
942999-61-3
956136-95-1
LCQ-908
956136-95-1
959122-11-3
A922500
959122-11-3

Background


An Overview of DGAT

Diacylgycerol acyltransferase (DGAT, or O-acyltransferase) is a microsomal enzyme for the synthesis of triacylglycerols. Its main function is to catalyze the formation of triacylglycerols (TAG) by the addition of diacylglycerols and fatty acid acyl groups. TAG is the most important form of oil storage in most plants and animals.

Major Types of DGAT

DGAT is classified into four types based on the differences in structure, cell or subcellular localization of DGAT: DGAT1, DGAT2, WS/DGAT (wax ester synthase/acyl coenzyme A (acyl-CoA): diacylglycerol acyltransferase), and intracytoplasmic DGAT (CytoDGAT). DGAT1 belongs to the acyl CoA: cholesterol acyltransferase (ACAT), while DGAT2 belongs to the GAT2 superfamily. The DGAT1 and DGAT2 proteins are mainly bound to the endoplasmic reticulum membrane and microsomal enzymes. WS /DGAT and CytoDGAT are new types discovered in recent years.

DGAT and Diseases

DGAT in humans is a key enzyme that catalyzes the final synthesis of TAG. When the gene of DGAT is deleted or the activity of DGAT is inhibited, the body does not become obese due to the high-fat diet, and the sensitivity to insulin is enhanced. Therefore, DGAT can be used as a target for the treatment of obesity and diabetes. It was reported that the DGAT1 inhibitor (A-922500) was significantly effective in improving hypertriglyceridemia in congenital obese Zucher diabetic rats and diet-induced hamsters.

The Inhibition of DGAT

DGAT inhibitors are mainly derived from fungi, plants and chemical synthesis. The amidepsines, roselipins and phenylpyropenes were isolated from the fungi Humicola sp FO, Gliocladium roseum KF-1040, Penicillium griseo-fulvum F1959, and the IC50 of DGAT activity was 10-70mmol/L. Some DGAT inhibitors (Xanthohumols, quinolone alkaloids, tanshinones, polyacetylenes, prenylflavonoids, terpenoids and sesquiterpenoids) were isolated from natural plants, like Sophora flavescent, Piper nigrum, and Humulus lupulus. At present, the development of DGAT inhibitors is focused on small molecule inhibitors for obesity, lipid metabolism disorders and diabetes, such as AZD-7687, PF-04620110. There are currently no drugs targeting at DGAT, and finding DGAT inhibitors is very promising.

Reference:

Yen, L.E., Stone, S.J., Koliwad, S., Harris, C., Farese, R.V. (2008) DGAT enzymes and triacylglycerol biosynthesis. Journal of lipid research, 49 (11): 2283-2301