Cargando…

Structure and catalytic mechanism of a human triglyceride synthesis enzyme

Triglycerides (triacylglycerols, TGs) store metabolic energy in organisms and have industrial uses for foods and fuels. Excessive accumulation of TGs in humans causes obesity and is associated with metabolic diseases(1). TG synthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enz...

Descripción completa

Detalles Bibliográficos
Autores principales: Sui, Xuewu, Wang, Kun, Gluchowski, Nina L., Elliott, Shane D., Liao, Maofu, Walther, Tobias C., Farese, Robert V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398557/
https://www.ncbi.nlm.nih.gov/pubmed/32433611
http://dx.doi.org/10.1038/s41586-020-2289-6
_version_ 1783565983417368576
author Sui, Xuewu
Wang, Kun
Gluchowski, Nina L.
Elliott, Shane D.
Liao, Maofu
Walther, Tobias C.
Farese, Robert V.
author_facet Sui, Xuewu
Wang, Kun
Gluchowski, Nina L.
Elliott, Shane D.
Liao, Maofu
Walther, Tobias C.
Farese, Robert V.
author_sort Sui, Xuewu
collection PubMed
description Triglycerides (triacylglycerols, TGs) store metabolic energy in organisms and have industrial uses for foods and fuels. Excessive accumulation of TGs in humans causes obesity and is associated with metabolic diseases(1). TG synthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes(2–4) whose structures and catalytic mechanisms are 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 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 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 center 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 an acyl-acceptor molecule, is located within the reaction center, orthogonal to acyl-CoA. Insights provided by the DGAT1 structures, together with mutagenesis and functional studies, give rise to a model of catalysis for DGAT’s generation of TGs.
format Online
Article
Text
id pubmed-7398557
institution National Center for Biotechnology Information
language English
publishDate 2020
record_format MEDLINE/PubMed
spelling pubmed-73985572020-11-13 Structure and catalytic mechanism of a human triglyceride synthesis enzyme Sui, Xuewu Wang, Kun Gluchowski, Nina L. Elliott, Shane D. Liao, Maofu Walther, Tobias C. Farese, Robert V. Nature Article Triglycerides (triacylglycerols, TGs) store metabolic energy in organisms and have industrial uses for foods and fuels. Excessive accumulation of TGs in humans causes obesity and is associated with metabolic diseases(1). TG synthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes(2–4) whose structures and catalytic mechanisms are 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 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 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 center 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 an acyl-acceptor molecule, is located within the reaction center, orthogonal to acyl-CoA. Insights provided by the DGAT1 structures, together with mutagenesis and functional studies, give rise to a model of catalysis for DGAT’s generation of TGs. 2020-05-13 2020-05 /pmc/articles/PMC7398557/ /pubmed/32433611 http://dx.doi.org/10.1038/s41586-020-2289-6 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Sui, Xuewu
Wang, Kun
Gluchowski, Nina L.
Elliott, Shane D.
Liao, Maofu
Walther, Tobias C.
Farese, Robert V.
Structure and catalytic mechanism of a human triglyceride synthesis enzyme
title Structure and catalytic mechanism of a human triglyceride synthesis enzyme
title_full Structure and catalytic mechanism of a human triglyceride synthesis enzyme
title_fullStr Structure and catalytic mechanism of a human triglyceride synthesis enzyme
title_full_unstemmed Structure and catalytic mechanism of a human triglyceride synthesis enzyme
title_short Structure and catalytic mechanism of a human triglyceride synthesis enzyme
title_sort structure and catalytic mechanism of a human triglyceride synthesis enzyme
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398557/
https://www.ncbi.nlm.nih.gov/pubmed/32433611
http://dx.doi.org/10.1038/s41586-020-2289-6
work_keys_str_mv AT suixuewu structureandcatalyticmechanismofahumantriglyceridesynthesisenzyme
AT wangkun structureandcatalyticmechanismofahumantriglyceridesynthesisenzyme
AT gluchowskininal structureandcatalyticmechanismofahumantriglyceridesynthesisenzyme
AT elliottshaned structureandcatalyticmechanismofahumantriglyceridesynthesisenzyme
AT liaomaofu structureandcatalyticmechanismofahumantriglyceridesynthesisenzyme
AT walthertobiasc structureandcatalyticmechanismofahumantriglyceridesynthesisenzyme
AT fareserobertv structureandcatalyticmechanismofahumantriglyceridesynthesisenzyme