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.

TMEM120A is a coenzyme A-binding membrane protein with structural similarities to ELOVL fatty acid elongase

“…Here we present the single particle cryo-EM structure of TMEM120A which exhibits no obvious feature of a channel protein. Instead, TMEM120A shares several common features with the recently determined ELOVL7 structure (Nie et al, 2021), a member of ELOVL family elongases important for the biosynthesis of very long-chain fatty acid. The ELOVL elongases (ELOVL1-7) are ER membrane enzymes that catalyze a condensation reaction between a longchain acyl-CoA and malonyl-CoA to produce a 3-keto acyl-CoA, free CoA and CO 2 (Deak et al, 2019;Jakobsson et al, 2006;Leonard et al, 2004;Pereira et al, 2004), which is the first step in the four-step elongation process of very long-chain fatty acid.…”

“…The overall structure TMEM120A shows no clear feature of a channel protein and has no discernible ion conduction pathway. We performed structure homology search using DALI, a protein structure comparison server (http://ekhidna2.biocenter.helsinki.fi/dali/) (Holm and Rosenstrom, 2010), and identified the human ELOVL7 structure (PDB code: 6Y7F) (Nie et al, 2021) to share the same fold as TMEM120A at the TMD region. ELOVL7 is an ER membrane enzyme and belongs to ELOVL family elongases that catalyze the condensation reaction step in the elongation process of very long-chain fatty acid (Jakobsson et al, 2006).…”

Analysis of the mechanosensor channel functionality of TACAN

“…It is noteworthy that CoASH binds with different conformations in TACAN from ELOVL7 (Figure 5 -figure supplement 1A, B) (Nie et al, 2021). In addition, no enzymatic activity was observed for TACAN using a free-CoA detection assay (details see Methods) which demonstrated robust activity for ELOVL7 (Figure 5 -figure supplement 1C), thus TACAN does not appear to catalyze the same reaction as ELOVL7.…”

“…The two protomers of TACAN dimer bury an extensive surface area of 3049 Å 2 , mediated through the TM domain as well as two long N-terminal helices that form a coiled coil (Figure 3A, The DALI 3-dimensional structure comparison server (Holm and Rosenstrom, 2010) identified a homologous protein called ELOVL7, a long-chain fatty acid (FA) elongase (Figure 4) (Nie et al, 2021). This enzyme catalyzes the first step in the FA elongation cycle by transferring an acetyl group from malonyl-CoA onto long chain FA-CoA (Naganuma et al, 2011).…”

Pain or gain?

“…Several recent reports have shown that C. elegans and mammalian cells need it to accumulate fat, and that disrupting the gene for TMEM120A leads to metabolic defects in mice fed a high-fat diet ( Czapiewski et al, 2021 ; Li et al, 2021 ). In addition, its structure also resembles that of ELOVL7, a membrane-embedded enzyme that helps to elongate fatty acids ( Nie et al, 2020 ; Niu et al, 2021 ; Xue et al, 2021 ). However, TMEM120A does not catalyze the same reactions as ELOVL7, and the possible substrates and end products of TMEM120A remain unknown ( Niu et al, 2021 ).…”