Long-chain-fatty-acid—CoA ligase
Long-chain-fatty-acid—CoA ligase | |||||||||
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ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Chr. 4 q35 | |||||||
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The long chain fatty acyl-CoA ligase (or synthetase) is an
It is present in all organisms from bacteria to humans. It catalyzes the pre-step reaction for
Function
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
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.
Mechanism and active site
The mechanism for Long Chain Fatty Acyl-CoA Synthetase is a “bi uni uni bi ping-pong” mechanism.[1] 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 2) 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 2) Coenzyme A now enters the enzyme and another intermediate is formed which consists of AMP-long chain fatty acid-Coenzyme A. (Step 3, Figure 2) At the end of this mechanism two products are released, AMP and acyl coa product. (Step 4, Figure 2)
Structure
There are several highly conserved areas and a 20-30%
The structure-function relationship between LC-FACS and the formation and processing of the acyl-AMP intermediate was still unclear. A domain swapped dimer is formed by LC-FACS, with
Dimer interaction
The dimerization of LC-FACS is stabilized through a salt bridge between Asp15 of sequence A and Arg176 of sequence B. Figure 3 shows this salt bridge between these two amino acids. The yellow line between Asp15 and Arg176 shows the salt bridge present.
ATP binding to the C-terminal domain
The conformations of the C-terminal domain of the LC-FACS structures are dependent on the presence of a ligand.[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] In crystal structures, AMP-PNP is bound in a crevasse of each monomer at the interface between the N- and C-terminal domains.[1] The closed conformation of the C-terminal domain is retained with myristroyl-AMP.[1] Three residues in the C-terminal domain, Glu443, Glu475, and Lys527, interact noncovalently with L motif residues and the N-terminal domain to stabilize the closed conformation.[1] There are two types of open conformations in the C-terminal domains of the uncomplexed structure. The C- and N-terminal domains do not interact directly for both monomers of the dimer.[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]
Fatty acid-binding tunnel
Bulkier long chain fatty acids are bound by a fatty acid-binding tunnel that is located in the N-terminal
The ATP binding site is connected to an ATP path that is a
Domains
The domains founds in Long chain fatty acyl CoA synthetase are shown both in the enzyme view (figure 5) and sequence view (figure 6). LC-FACS has five domains. After searching 1v26 in Entrez, the location of the 5 domains was shown and was used to create figure 5 and 6. The ribbons colors in figure 5 correspond to the colors of the figure 6.
Inhibition by long chain fatty acyl-CoAs
A long term and short term regulation controls fatty acid synthesis.[4] Long term fatty acid synthesis regulation is dependent on the rate of acetyl-CoA carboxylase (ACC) synthesis, the rate-limiting enzyme and first enzyme of the fatty acid synthesis, and fatty acid synthase (FAS), the second and major enzyme of the fatty acid synthesis.[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.[13]
Free fatty acids inhibits the de novo fatty acid synthesis and appears to be dependent on the formation of long chain fatty acyl-CoAs.[14] Studies have shown that long chain fatty acyl-CoAs inhibit ACC and FAS via feedback inhibition.[15][16][17][18] Long chain fatty acyl-CoA's inhibitory effect on the fatty acid synthesis may be a result of its regulation of lipogenic enzymes in a feedback manner through gene transcription suppression.[19]
Long-chain fatty-acid-CoA ligase in cells catalytically synthesizes long chain fatty acyl-CoAs. Long-chain fatty-acid-CoA ligase may be involved in an important role in the suppression of fatty acid synthesis and it has been reported that it played a part in fatty acid synthesis inhibition.[20] It was recently found that vitamin D3 upregulates FACL3, which forms long-chain fatty acid synthesis through the use of myristic acid, eicosapentaenoic acid (EPA), and arachidonic acid as substrates, in expression and activity levels.[21] FACL3 contributes to vitamin D3 growth inhibitory effect in human prostate cancer LNCaP cells.[21] A current study reports that the feedback inhibition of FAS expression by long chain fatty acyl-CoAs causes the downregulation of FAS mRNA by vitamin D3.[4][22]
Clinical significance
Examples
Human genes encoding long-chain-fatty-acid—CoA ligase enzymes (also known as acyl-CoA synthetase long-chain, or ACSL) include:
See also
- Fatty acyl-CoA synthase
- Triacsin C - an inhibitor of Fatty acyl CoA synthetase
References
- ^ PMID 15145952.
- PMID 18375835.
- ISBN 978-0-9514171-7-1.
- ^ S2CID 25190904.
- ^ PMID 9250661.
- PMID 12021428.
- PMID 8805533.
- PMID 12221282.
- PMID 12627952.
- PMID 5806590.
- PMID 5044513.
- PMID 4981792.
- PMID 4145797.
- PMID 237919.
- PMID 4638549.
- PMID 5875764.
- PMID 5082134.
- S2CID 8678424.
- PMID 9173866.
- PMID 11085947.
- ^ PMID 15178414.
- S2CID 54296796.
- ^ "Adrenoleukodystrophy Information Page". National Institute of Neurological Disorders and Stroke (NINDS). 2009-03-18. Archived from the original on 2006-05-10. Retrieved 2010-01-16.
- ^ Kemp S, Watkins P (2009-03-03). "very long-chain fatty acids and X-ALD". X-linked Adrenoleukodystrophy Database. Archived from the original on December 21, 2009. Retrieved 2010-01-16.
External links
- ACSL6+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)