Mammalian Long-Chain Acyl-CoA Synthetases

Abstract

Acyl-CoA synthetase enzymes are essential for de novo lipid synthesis, fatty acid catabolism, and remodeling of membranes. Activation of fatty acids requires a two-step reaction catalyzed by these enzymes. In the first step, an acyl-AMP intermediate is formed from ATP. AMP is then exchanged with CoA to produce the activated acyl-CoA. The release of AMP in this reaction defines the superfamily of AMP-forming enzymes. The length of the carbon chain of the fatty acid species defines the substrate specificity for the different acyl-CoA synthetases (ACS). On this basis, five sub-families of ACS have been characterized. The purpose of this review is to report on the large family of mammalian long-chain acyl-CoA synthetases (ACSL), which activate fatty acids with chain lengths of 12 to 20 carbon atoms. Five genes and several isoforms generated by alternative splicing have been identified and limited information is available on their localization. The structure of these membrane proteins has not been solved for the mammalian ACSLs but homology to a bacterial form, whose structure has been determined, points at specific structural features that are important for these enzymes across species. The bacterial form acts as a dimer and has a conserved short motif, called the fatty acid Gate domain, that seems to determine substrate specificity. We will discuss the characterization and identification of the different spliced isoforms, draw attention to the inconsistencies and errors in their annotations, and their cellular localizations. These membrane proteins act on membrane-bound substrates probably as homo-and as heterodimer complexes but have often been expressed as single recombinant isoforms, apparently purified as monomers and tested in Triton X-100 micelles. We will argue that such studies have failed to provide an accurate assessment of the activity and of the distinct function of these enzymes in mammalian cells.

Identification of acyl-CoA synthetases involved in the mammalian sphingosine 1-phosphate metabolic pathway

“…Therefore, ACSs responsible for S1P metabolism should also be localized in the ER for efficient metabolic flow. It has been reported that each ACS isozyme exhibits characteristic intracellular localization, such as in the ER, plasma membrane, mitochondria, and peroxisome [7,13,14]. However, the precise localization of most ACS isozymes remains unclear since inconsistent localization patterns have been reported among researchers using different approaches.…”

ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis

“…VLCFAs are produced from certain LCFAs, provided through diet or generated by FA synthase, or they are elongated from shorter VLCFAs by endoplasmic reticulum (ER) membranebound enzymes, which lengthen each chain with carbon units from FAs that have been converted to substrate-form acyl-CoAs (7). The FA elongase machinery comprises four distinct enzymes.…”

Dual Functions of the Trans-2-Enoyl-CoA Reductase TER in the Sphingosine 1-Phosphate Metabolic Pathway and in Fatty Acid Elongation

“…Because trans-2-hexadecenoyl-CoA is classified as a trans-2-enoyl-CoA, the enzyme involved is trans-2-enoyl-CoA reductase. All known enzymes involved in the S1P metabolic pathway are localized in the endoplasmic reticulum (20,(31)(32)(33). Therefore, we expected the candidate trans-2-enoyl-CoA reductase to be localized in the endoplasmic reticulum.…”