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The structural basis of fatty acid elongation by the ELOVL elongases

DOI: 10.1038/s41594-021-00605-6 DOI Help

Authors: Laiyin Nie (Structural Genomics Consortium, University of Oxford) , Tomas C. Pascoa (Structural Genomics Consortium, University of Oxford) , Ashley C. W. Pike (Structural Genomics Consortium, University of Oxford) , Simon R. Bushell (Structural Genomics Consortium, University of Oxford) , Andrew Quigley (Diamond Light Source; Research Complex at Harwell) , Gian Filippo Ruda (Structural Genomics Consortium, University of Oxford) , Amy Chu (Structural Genomics Consortium, University of Oxford) , Victoria Cole (Structural Genomics Consortium, University of Oxford) , David Speedman (Structural Genomics Consortium, University of Oxford) , Tiago Moreira (Structural Genomics Consortium, University of Oxford) , Leela Shrestha (Structural Genomics Consortium, University of Oxford) , Shubhashish M. M. Mukhopadhyay (Structural Genomics Consortium, University of Oxford) , Nicola A. Burgess-Brown (Structural Genomics Consortium, University of Oxford) , James D. Love (Albert Einstein College of Medicine) , Paul E. Brennan (Structural Genomics Consortium, Centre for Medicines Discovery, University of Oxford; Alzheimer’s Research UK Oxford Drug Discovery Institute, Target Discovery Institute) , Elisabeth P. Carpenter (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 28 , PAGES 512 - 520

State: Published (Approved)
Published: June 2021
Diamond Proposal Number(s): 19301

Abstract: Very long chain fatty acids (VLCFAs) are essential building blocks for the synthesis of ceramides and sphingolipids. The first step in the fatty acid elongation cycle is catalyzed by the 3-keto acyl-coenzyme A (CoA) synthases (in mammals, ELOVL elongases). Although ELOVLs are implicated in common diseases, including insulin resistance, hepatic steatosis and Parkinson’s, their underlying molecular mechanisms are unknown. Here we report the structure of the human ELOVL7 elongase, which comprises an inverted transmembrane barrel surrounding a 35-Å long tunnel containing a covalently attached product analogue. The structure reveals the substrate-binding sites in the narrow tunnel and an active site deep in the membrane. We demonstrate that chain elongation proceeds via an acyl-enzyme intermediate involving the second histidine in the canonical HxxHH motif. The unusual substrate-binding arrangement and chemistry suggest mechanisms for selective ELOVL inhibition, relevant for diseases where VLCFAs accumulate, such as X-linked adrenoleukodystrophy.

Journal Keywords: Enzyme mechanisms; Membrane lipids; X-ray crystallography

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry

Diamond Offline Facilities: Membrane Protein Laboratory (MPL)
Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 14/06/2021 09:40

Discipline Tags:

Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)