The structural basis of fatty acid elongation by the ELOVL elongases

Nat Struct Mol Biol. 2021 Jun;28(6):512-520. doi: 10.1038/s41594-021-00605-6.

Laiyin Nie ^# ¹ ², Tomas C Pascoa ^# ¹, Ashley C W Pike ^# ¹, Simon R Bushell ¹ ³, Andrew Quigley ⁴ ⁵, Gian Filippo Ruda ¹ ⁶, Amy Chu ¹ ⁷, Victoria Cole ¹ ⁸, David Speedman ¹, Tiago Moreira ¹, Leela Shrestha ¹, Shubhashish M M Mukhopadhyay ¹, Nicola A Burgess-Brown ¹, James D Love ⁹ ¹⁰, Paul E Brennan ¹ ¹¹, Elisabeth P Carpenter ¹² ¹³

Affiliations

1 Structural Genomics Consortium, Centre for Medicines Discovery, University of Oxford, Oxford, UK.
2 CRELUX GmbH, Planegg-Martinsried, Germany.
3 Orbit Discovery, Oxford, UK.
4 Membrane Protein Laboratory, Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot, UK.
5 Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, UK.
6 Evotec Ltd, Milton, Abingdon, UK.
7 Department of Biochemistry, Oxford University, Oxford, UK.
8 Genomics Centre, South African Medical Research Council, Cape Town, South Africa.
9 Albert Einstein College of Medicine, Department of Biochemistry, Bronx, NY, USA.
10 Novo Nordisk A/S, Måløv, Denmark.
11 Alzheimer's Research UK Oxford Drug Discovery Institute, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
12 Structural Genomics Consortium, Centre for Medicines Discovery, University of Oxford, Oxford, UK. liz.carpenter@cmd.ox.ac.uk.
13 Vertex Pharmaceuticals Ltd, Milton, Abingdon, UK. liz.carpenter@cmd.ox.ac.uk.
# Contributed equally.

PMID: 34117479 DOI: 10.1038/s41594-021-00605-6

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.

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