The structural basis of fatty acid elongation by the ELOVL elongases

Abstract

Very long chain fatty acids (VLCFAs) are essential building blocks for synthesis of the ceramides and sphingolipids required for nerve, skin and retina function and 3-keto acyl-CoA synthases (ELOVL elongases) perform the first step in the FA elongation cycle. 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 includes an inverted transmembrane barrel structure surrounding a 35 Å long tunnel containing a covalently-attached product analogue. The structure reveals the substrate binding sites in the tunnel and an active site deep in the membrane including the canonical ELOVL HxxHH sequence. This indicates a ping-pong mechanism for catalysis, involving unexpected covalent histidine adducts. The unusual substrate-binding arrangement and chemistry suggest mechanisms for selective ELOVL inhibition, relevant for diseases where VLCFAs accumulate such as X-linked adrenoleukodystrophy. MainThe seven human 3-keto acyl-CoA synthases (elongation of very long chain fatty acids proteins: ELOVL1-7 elongases) catalyse the first, rate-limiting step in the cycle that adds two carbon units to the acyl chains of fatty acids (FAs) with 12 or more carbons per chain (Fig. 1a).These long and very long chain FAs (LCFAs: 12C:20C and VLCFAs: >20C) 1,2 are the precursors for synthesis of ceramides, sphingolipids and sphingolipid signalling molecules 3 .VLCFAs are essential for the myelin sheaths of nerves 4,5 , the skin permeability barrier 6,7 , retina 8 and liver function 4,9 . Mutations in ELOVL elongases cause severe genetic diseases

TMEM120A contains a specific coenzyme A-binding site and might not mediate poking- or stretch-induced channel activities in cells

“…Recently, it has been reported that TMEM120 protein shares structural similarities with a membrane-embedded enzyme named elongation of very long chain fatty acid (ELOVL) protein ( Niu et al, 2021 ; Xue et al, 2021 ). ELOVLs catalyze a condensation reaction between acyl-coA and malonyl-CoA to produce 3-keto acyl-CoA and release CoASH as well as CO 2 as byproducts ( Nie et al, 2021 ). Although TMEM120A did not exhibit ELOVL-like enzymatic activity when malonyl-CoA and stearoyl-CoA were supplied as substrates ( Niu et al, 2021 ), it is possible that TMEM120A may utilize different substrates or catalyze a reaction distinct from that of ELOVLs if it functions as an enzyme.…”

Structure, mechanism, and inhibition of Hedgehog acyltransferase

“…Values of dn/dc = 0.1926 mL g -1 and ε 280 3.198 mL (mg cm) -1 were used to calculate HHAT molecular mass. Protein conjugate analysis was performed with dn/dc = 0.1270 mL g -1 for OGNG ( Nie et al., 2021 ).…”

Cryo-EM structures of human TMEM120A and TMEM120B

“…A search of TMEM120A protomer in the DALI 7 server identified a structurally homologous protein ELOVL7 6 , an endoplasmic reticulum embedded fatty acid elongase involves in the elongation of very long chain fatty acid. ELOVL7 catalyzes the condensation reaction step between an acyl-CoA and malonyl-CoA to form a 3keto acyl-CoA, followed by three other steps to yield a product acyl-CoA with two extra carbons.…”

“…Unexpectedly, the almost identical structures between TMEM120A and TMEM120B, and our electrophysiological characterizations do not support the role of TMEM120A as an MSC. Instead, the TMD of TMEM120A/B share similar fold with ELOVL7, a member of the ELOVL family elongase catalyzing the first step in the fatty acid elongation cycle 6 . These clues suggest TMEM120A/B are likely enzymes involved in lipid metabolism, although its detailed role remains to be investigated.…”