Long-chain-fatty-acid—CoA ligase

Long chain fatty acyl-CoA synthetase, LC-FACS, plays a role in the physiological regulation of various cellular functions via the production of long chain fatty acyl-CoA esters, which reportedly have affected protein transport, enzyme activation, protein acylation, cell signaling, and transcriptional regulation.

In step one, ATP and a long chain fatty acid enter the enzyme's active site.

(Step 2, Figure 2) Coenzyme A now enters the enzyme and another intermediate is formed which consists of AMP-long chain fatty acid-Coenzyme A.

[1] The N-terminal domain is composed of two subdomains: a distorted antiparallel β-barrel and two β-sheets surrounded by α-helices forming an αβαβα sandwich.

[1] AMP-PNP, a nonhydrolyzable ATP analogue, bound to LC-FACS results in the closed conformation with the C- and N-terminal domains directly interacting.

[1] An extensive hydrogen bond network is used by the AMP moiety of the bound ATP molecule to hold the C- and N-terminal domains together.

[1] A large β-sheet and an α-helix cluster surround the tunnel which extends from the concave cavity in the central valley to the site of ATP-binding.

[1] There is also another branch of the central pathway known as the “dead and branch.” The indole ring of Trp234 closes the fatty acid-binding tunnel in the uncomplexed structure.

There is a shift in the flexible loop of the G motif in the closed structures of LC-FACS, resulting in a wider dead end branch compared to the uncomplexed forms.

The basic residues from each monomer, Lys219, Arg296, Arg297, Arg321, Lys350, and Lys 354, cause the entrance of the center path to generate a positive electrostatic potential.

[4][10][11][12] Cellular fatty acyl-CoA is involved in the short term regulation, but there is not a full understanding of the mechanisms.

[19] Long-chain fatty-acid-CoA ligase in cells catalytically synthesizes long chain fatty acyl-CoAs.

[21] FACL3 contributes to vitamin D3 growth inhibitory effect in human prostate cancer LNCaP cells.

In ALD the gene for this peroximal membrane transporter, ALDP, is defective, preventing long chain fatty acids from entering the peroxisome.

[24] Human genes encoding long-chain-fatty-acid—CoA ligase enzymes (also known as acyl-CoA synthetase long-chain, or ACSL) include:

Figure 1. Long chain Fatty acyl-CoA synthetase asymmetric unit showing active site residues Trp 234, Tyr504, and Glu540, along with the potentially supporting Asn450 residue. [ 1 ]
Figure 2. Mechanism of long chain fatty acyl-CoA synthetase.
Figure 3. Dimerization of LC-FACS.
Figure 4. Active site of long chain fatty acyl-CoA synthetase with a long chain fatty acid. Trp444, Lys435 and Lys439 are the important residues
Figure 5.
Figure 6.