Structure and catalytic mechanism of a human triglyceride synthesis enzyme

By X. Sui, Kun Wang, N. Gluchowski, Shane D. Elliott, Maofu Liao, T. Walther, R. Farese. 2020

81 citations recorded by the source corpus.

Triacylglycerols store metabolic energy in organisms and have industrial uses as foods and fuels. Excessive accumulation of triacylglycerols in humans causes obesity and is associated with metabolic diseases1. Triacylglycerol synthesis is catalysed by acyl-CoA diacylglycerol acyltransferase (DGAT) enzymes2–4, the structures and catalytic mechanisms of which remain unknown. Here we determined the structure of dimeric human DGAT1, a member of the membrane-bound O-acyltransferase (MBOAT) family, by cryo-electron microscopy at approximately 3.0 Å resolution. DGAT1 forms a homodimer through N-terminal segments and a hydrophobic interface, with putative active sites within the membrane region. A structure obtained with oleoyl-CoA substrate resolved at approximately 3.2 Å shows that the CoA moiety binds DGAT1 on the cytosolic side and the acyl group lies deep within a hydrophobic channel, positioning the acyl-CoA thioester bond near an invariant catalytic histidine residue. The reaction centre is located inside a large cavity, which opens laterally to the membrane bilayer, providing lipid access to the active site. A lipid-like density—possibly representing an acyl-acceptor molecule—is located within the reaction centre, orthogonal to acyl-CoA. Insights provided by the DGAT1 structures, together with mutagenesis and functional studies, provide the basis for a model of the catalysis of triacylglycerol synthesis by DGAT. Cryo-electron microscopy structures and functional and mutagenesis studies provide insights into the catalysis of triacylglycerol synthesis by human acyl-CoA diacylglycerol acyltransferase at its intramembrane active site.

Subfields: Biochemistry, Molecular Biology, Physiology

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In Molecular Biology

1. Jonathan Kim
2. O. Clarke
3. G. Parisi
4. F. Mancia
5. Daniela Ross
6. R. Nygaard
7. Jia Yu
8. D. Virshup

Citations in the corpus

• Structure, mechanism, and inhibition of Hedgehog acyltransferase (2021, background): “The majority of MBOATs 16, 2021 Crown Copyright ª 2021 Published by Elsevier Inc. 5025 er the CC BY license (http://creativecommons.org/licenses/by/4.0/). catalyze lipid chain transfer to small-molecule lipid substrates; however, HHAT, alongside porcupine acyltransferase (PORCN) and ghrelin O-acyltr”
• Structural basis of WLS/Evi-mediated Wnt transport and secretion (2020, background): “A number of PAM-binding proteins including various MBOAT proteins and stearoyl CoA desaturase also accommodate the acyl group in the plasma membrane (Sui et al., 2020; Wang et al., 2015).”
• Structural model of PORCN illuminates disease-associated variants and drug binding sites (2021, unknown): “The homology structure based on DGAT1 (Figure 2) was deemed to be of highest quality, with 92.2% of residues in favored and another 6.1% in allowed Ramachandran regions.”