The long chain fatty acyl-CoA ligase (or synthetase) is an enzyme of the ligase family that activates the breakdown of complex fatty acids. Long chain fatty acyl-CoA synthetase catalyzes the formation of fatty acyl-CoA by a two-step process proceeding through an adenylated intermediate. The enzyme catalyzes the following reaction:

It is present in all organisms from bacteria to humans. It catalyzes the pre-step reaction for β-oxidation of fatty acids or can be incorporated in phospholipids.

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. The formation of fatty acyl-CoA is catalyzed in two steps: a stable intermediate of fatty acyl-AMP molecule and then the product is formed—fatty acid acyl-CoA molecule.

Fatty acyl CoA synthetase catalyzes the activation of a long fatty acid chain to a fatty acyl CoA, requiring the energy of 1 ATP to AMP and pyrophosphate. This step uses 2 "ATP equivalents" because pyrophosphate is cleaved into 2 molecules of inorganic phosphate, breaking a high-energy phosphate bond.

The mechanism for Long Chain Fatty Acyl-CoA Synthetase is a “bi uni uni bi ping-pong” mechanism. The uni and bi prefixes refer to the number of substrates that enter the enzyme and the number of products that leave the enzyme; bi describes a situation where two substrates enter the enzyme at the same time. Ping-pong signifies that a product is released before another substrate can bind to the enzyme.

In step one, ATP and a long chain fatty acid enter the enzyme’s active site. Within the active site the negatively charged oxygen on the fatty acid attacks the alpha phosphate on ATP, forming an ATP-long chain fatty acid intermediate. (Step 1, Figure 3) In the second step, Pyrophosphate (PPi) leaves, resulting in an AMP-long chain fatty acid molecule within the enzyme’s active site. (Step 2, Figure 3) Coenzyme A now enters the enzyme and another intermediate is formed which consists of AMP-long chain fatty acid-Coenzyme A. (Step 3, Figure 3) At the end of this mechanism two products are released, AMP and acyl coa synthetase. (Step 4, Figure 3)

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