Structural highlights
Disease
DGAT1_HUMAN Congenital chronic diarrhea with protein-losing enteropathy. The disease is caused by mutations affecting the gene represented in this entry.
Function
DGAT1_HUMAN Catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. In contrast to DGAT2 it is not essential for survival. May be involved in VLDL (very low density lipoprotein) assembly. In liver, plays a role in esterifying exogenous fatty acids to glycerol. Functions as the major acyl-CoA retinol acyltransferase (ARAT) in the skin, where it acts to maintain retinoid homeostasis and prevent retinoid toxicity leading to skin and hair disorders.[1] [2]
Publication Abstract from PubMed
Inhibitors of triacylglycerol (TG) synthesis have been developed to treat metabolism-related diseases, but we know little about their mechanisms of action. Here, we report cryo-EM structures of the TG-synthesis enzyme acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a membrane bound O-acyltransferase (MBOAT), in complex with two different inhibitors, T863 and DGAT1IN1. Each inhibitor binds DGAT1's fatty acyl-CoA substrate binding tunnel that opens to the cytoplasmic side of the ER. T863 blocks access to the tunnel entrance, whereas DGAT1IN1 extends further into the enzyme, with an amide group interacting with more deeply buried catalytic residues. A survey of DGAT1 inhibitors revealed that this amide group may serve as a common pharmacophore for inhibition of MBOATs. The inhibitors were minimally active against the related MBOAT acyl-CoA:cholesterol acyltransferase 1 (ACAT1), yet a single-residue mutation sensitized ACAT1 for inhibition. Collectively, our studies provide a structural foundation for developing DGAT1 and other MBOAT inhibitors.
Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis.,Sui X, Wang K, Song K, Xu C, Song J, Lee CW, Liao M, Farese RV Jr, Walther TC Nat Commun. 2023 May 29;14(1):3100. doi: 10.1038/s41467-023-38934-3. PMID:37248213[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Orland MD, Anwar K, Cromley D, Chu CH, Chen L, Billheimer JT, Hussain MM, Cheng D. Acyl coenzyme A dependent retinol esterification by acyl coenzyme A: diacylglycerol acyltransferase 1. Biochim Biophys Acta. 2005 Oct 15;1737(1):76-82. doi:, 10.1016/j.bbalip.2005.09.003. Epub 2005 Sep 20. PMID:16214399 doi:http://dx.doi.org/10.1016/j.bbalip.2005.09.003
- ↑ Oelkers P, Behari A, Cromley D, Billheimer JT, Sturley SL. Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes. J Biol Chem. 1998 Oct 9;273(41):26765-71. doi: 10.1074/jbc.273.41.26765. PMID:9756920 doi:http://dx.doi.org/10.1074/jbc.273.41.26765
- ↑ Sui X, Wang K, Song K, Xu C, Song J, Lee CW, Liao M, Farese RV Jr, Walther TC. Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis. Nat Commun. 2023 May 29;14(1):3100. PMID:37248213 doi:10.1038/s41467-023-38934-3
