Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome

Abstract

Acyl-coenzyme A synthetases (ACSs) catalyze the fundamental, initial reaction in fatty acid metabolism. "Activation" of fatty acids by thioesterification to CoA allows their participation in both anabolic and catabolic pathways. The availability of the sequenced human genome has facilitated the investigation of the number of ACS genes present. Using two conserved amino acid sequence motifs to probe human DNA databases, 26 ACS family genes/proteins were identified. ACS activity in either humans or rodents was demonstrated previously for 20 proteins, but 6 remain candidate ACSs. For two candidates, cDNA was cloned, protein was expressed in COS-1 cells, and ACS activity was detected. Amino acid sequence similarities were used to assign enzymes into subfamilies, and subfamily assignments were consistent with acyl chain length preference. Four of the 26 proteins did not fit into a subfamily, and bootstrap analysis of phylograms was consistent with evolutionary divergence. Three additional conserved amino acid sequence motifs were identified that likely have functional or structural roles. The existence of many ACSs suggests that each plays a unique role, directing the acyl-CoA product to a specific metabolic fate. Knowing the full complement of ACS genes in the human genome will facilitate future studies to characterize their specific biological functions.-Watkins, P. A., D. Maiguel, Z. Jia, and J. Pevsner. Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome. J. Lipid Res.

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

“…The difference between the v1 and v2 isoforms resides in their N-termini. The N-terminus of ACSL4 v1 is 41 amino acids shorter than that of v2 [7].…”

“…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.…”

“…The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity [7] (Fig. 1A): the ACS short-chain (ACSS) subfamily (ACSS1, ACSS2, and ACSS3; substrates, C2 to C4 FAs), ACS medium-chain (ASCM) subfamily (ACSM1, ACSM2A, ACSM2B, ACSM3-5; substrates, C6 to C10 FAs), ACS long-chain (ACSL) subfamily (ACSL1 and ACSL3-6; substrates, C12 to C18 FAs), ACS very long-chain (ACSVL) subfamily (ACSVL1-6; substrates, C20 to C26 FAs), ACS bubblegum (ACSBG) subfamily (ACSBG1 and ACSBG2), and ACSF subfamily (ACSF1-4).…”

“…ACSBG1 is active toward LCFAs and VLCFAs [8,9], and ACSBG2 exhibits activities toward C18:1 and C18:2 FAs, but not toward C16:0 [10]. The substrate of ACSF2 is C8:0 FA, whereas those of ACSF3 are malonate and methylmalonate [7]. The substrates of ACSF1 and ACSF4 have not been identified.…”

Role of trans fatty acids in the nutritional regulation of mammary lipogenesis in ruminants

“…Long-chain fatty acids are esterified to CoA esters in the inner surface of the plasma membrane before entering intracellular metabolic pathways. Activation of fatty acids occurs primarily via an ATP-dependent mechanism involving the action of ACSL isoforms (Watkins et al, 2007). Measurements in lactating cows have shown that several ACSL (ACSL1, 3, 4 and 5) and FABP (FABP 1,3,4,5 and 6) isoforms are transcribed in mammary tissue (Bionaz and Loor, 2008a) and demonstrated that the expression of ACSL1, FABP3, FABP4 and FABP5 increases several-fold during lactation, whereas changes in the relative abundance of ACBP mRNA are much lower suggesting a minor role in mammary lipogenesis in the bovine (Bionaz and Loor 2008b).…”