Long-chain-fatty-acid—CoA Ligase
   HOME

TheInfoList



Click Here for Items Related To - Long-chain-fatty-acid—CoA Ligase
OR:
Long-chain-fatty-acid—CoA Ligase on:   [Wikipedia]   [Google]   [Amazon]

The long chain fatty acyl-CoA ligase (or synthetase) is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
() of the
ligase In biochemistry, a ligase is an enzyme that can catalyze the joining (ligation) of two large molecules by forming a new chemical bond. This is typically via hydrolysis of a small pendant chemical group on one of the larger molecules or the enzym ...
family that activates the oxidation of complex
fatty acids In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...
. Long chain fatty acyl-CoA synthetase catalyzes the formation of fatty
acyl-CoA Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way ...
by a two-step process proceeding through an adenylated intermediate. The enzyme catalyzes the following reaction, :
Fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...
+ CoA +
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
⇌
Acyl-CoA Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way ...
+
AMP #REDIRECT Amp #REDIRECT Amp {{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
{{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
+ PPi It is present in all organisms from bacteria to humans. It catalyzes the pre-step reaction for
β-oxidation In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, ...
of fatty acids or can be incorporated in phospholipids.


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
esters In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides are ...
, which reportedly have affected
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
transport, enzyme activation, protein acylation,
cell signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
, 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 ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
to
AMP #REDIRECT Amp #REDIRECT Amp {{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
{{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
and
pyrophosphate In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among other ...
. This step uses 2 "ATP equivalents" because pyrophosphate is cleaved into 2 molecules of inorganic phosphate, breaking a high-energy phosphate
bond Bond or bonds may refer to: Common meanings * Bond (finance), a type of debt security * Bail bond, a commercial third-party guarantor of surety bonds in the United States * Chemical bond, the attraction of atoms, ions or molecules to form chemical ...
.


Mechanism and active site

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 ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
and a long chain
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...
enter the enzyme’s
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
. 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 In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among other ...
(PPi) leaves, resulting in an AMP-long chain fatty acid molecule within the enzyme’s
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
. (Step 2, Figure 2)
Coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
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)
Acyl CoA Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way ...
is formed from long chain fatty acids through an acyl substitution. In an ATP dependent reaction, the fatty acid carboxylate is converted to a
thioester In organic chemistry, thioesters are organosulfur compounds with the functional group . They are analogous to carboxylate esters () with the sulfur in the thioester playing the role of the linking oxygen in the carboxylate ester, as implied by t ...
. The final products of this reaction are
acyl-CoA Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way ...
,
pyrophosphate In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among other ...
(PPi) and
AMP #REDIRECT Amp #REDIRECT Amp {{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
{{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
.


Structure

There are several highly conserved areas and a 20-30%
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
sequence similarity between the members of this superfamily. The enzymes in the family consist of a large N-terminal and a small C-terminal domain, with the catalytic site positioned between the two domains. Substrate binding may affect the relative positions of the C- and N-terminal domains. The C-terminal domain of LC-FACS is assumed to be in an open conformation when a substrate is absent and in a closed conformation when a substrate is bound. The accessibility of the active site to solvent is reduced when the C- and N-terminal domains approach one another. 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
monomer In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification Mo ...
interacting at the N-terminal domains. A large electrostatically positive concave is located at the back of the structure in the central valley of the homodimer. Asp15 forms an intermolecular salt bridge with Arg176 in the dimer interactions. An intermolecular hydrogen bond is formed between the main chain
carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...
group of Glu16and the side chain of Arg199. At the interface, Glu175 forms an intermolecular salt bridge with Arg199. The L motif, a six-amino acid peptide linker, connects the large N-terminal domain and a small C-terminal domain of each LC-FACS monomer. The N-terminal domain is composed of two subdomains: a distorted antiparallel
β-barrel In protein structures, a beta barrel is a beta sheet composed of tandem repeats that twists and coils to form a closed toroidal structure in which the first strand is bonded to the last strand (hydrogen bond). Beta-strands in many beta-barrels are ...
and two β-sheets surrounded by α-helices forming an αβαβα sandwich. The small C-terminal globular domain consists of two-stranded β-sheet and a three-stranded antiparallel β-sheet flanked by three α-helices.


Dimer interaction

The dimerization of LC-FACS is stabilized through a
salt bridge In electrochemistry, a salt bridge or ion bridge is a laboratory device used to connect the oxidation and reduction half-cells of a galvanic cell (voltaic cell), a type of electrochemical cell. It maintains electrical neutrality within the int ...
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-teriminal domain of the LC-FACS structures are dependent on the presence of a
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
. AMP-PNP, a nonhydrolyzable ATP analogue, bound to LC-FACS results in the closed conformation with the C- and N-terminal domains directly interacting. In crystal structures, AMP-PNP is bound in a crevasse of each monomer at the interface between the N- and C-terminal domains. The closed conformation of the C-terminal domain is retained with myristroyl-AMP. 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. 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. 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.


Fatty acid-binding tunnel

Bulkier long chain fatty acids are bound by a fatty acid-binding tunnel that is located in the N-terminal
domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a partial function **Domain of holomorphy of a function * Do ...
of each
monomer In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification Mo ...
. A large
β-sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...
and an
α-helix The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues e ...
cluster surround the tunnel which extends from the concave cavity in the central valley to the site of ATP-binding. There are two distinct paths in the large central pathway of the tunnel in the complex structure, which includes the “ATP path” and the “center path,” separated by the indole ring of Trp234 in the G motif. 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. It opens up once AMP-PNP binds through hydrogen bond formation between β-phosphate and the nitrogen on the ring of Trp234. During this time, the closed conformation is adopted by the mobile C-terminal domain. 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 ATP binding site is connected to an ATP path that is a
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...
channel in the fatty acid-binding tunnel. The fatty acid enters through the center path extending from the interface of the dimer along β-strand 13 to the ATP path. The connection between the two paths is blocked by the indole ring of Trp234 in the absence of ATP. Water molecules fill the center path in the AMP-PNP and myristoyl-AMP complex structures and through the entrance of the center path, they connect to the bulk solvent regions. 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. The dead end branch contains residues 235-243 and extends from the fatty acid-binding tunnel to α-helix h. The bottom of the dead end branch consists of a hydrophilic environment from the water molecules and polar side chains.


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. 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. Cellular fatty acyl-CoA is involved in the short term regulation, but there is not a full understanding of the mechanisms. Free fatty acids inhibits the de novo fatty acid synthesis and appears to be dependent on the formation of long chain fatty acyl-CoAs. Studies have shown that long chain fatty acyl-CoAs inhibit ACC and FAS via feedback inhibition. 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. 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. It was recently found that vitamin D3 upregulates FACL3, which forms long-chain fatty acid synthesis through the use of
myristic acid Myristic acid (IUPAC name: tetradecanoic acid) is a common saturated fatty acid with the molecular formula CH3(CH2)12COOH. Its salts and esters are commonly referred to as myristates or tetradecanoates. It is named after the binomial name for nutm ...
,
eicosapentaenoic acid Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid with a 20-c ...
(EPA), and
arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
as substrates, in expression and activity levels. FACL3 contributes to vitamin D3 growth inhibitory effect in human prostate cancer LNCaP cells. 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.


Clinical significance

Adrenoleukodystrophy (ALD) is the build up of long chain fatty acids in the brain and adrenal cortex, because of the decreased activity of long chain fatty acyl coa synthetase. The
oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
of the long chain fatty acids normally occurs in the peroxisome where the long chain fatty acyl coa synthetase is found. Long chain fatty acids enter the peroxisome via a transporter protein, ALDP, which creates a gate in the membrane of the
peroxisome A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen pero ...
. In ALD the gene for this peroximal membrane transporter, ALDP, is defective, preventing long chain fatty acids from entering the peroxisome.


Examples

Human genes encoding long-chain-fatty-acid—CoA ligase enzymes (also known as acyl-CoA synthetase long-chain, or ACSL) include: *
ACSL1 Long-chain-fatty-acid—CoA ligase 1 is an enzyme that in humans is encoded by the ''ACSL1'' gene. Structure Gene The ACSL1 gene is located on the 4th chromosome, with its specific location being 4q35.1. The gene contains 28 exons. ...
* ACSL3 *
ACSL4 Long-chain-fatty-acid—CoA ligase 4 is an enzyme that in humans is encoded by the ''ACSL4'' gene. The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, ...
*
ACSL5 Long-chain-fatty-acid—CoA ligase 5 is an enzyme that in humans is encoded by the ''ACSL5'' gene. The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, ...
*
ACSL6 Acyl-CoA synthetase long-chain family member 6 is an enzyme that in humans is encoded by the ''ACSL6'' gene. Long fatty acyl CoA synthetase, Long-chain acyl-CoA synthetases such as ACSL6, catalyze the formation of acyl-CoA from fatty acids, Adenos ...
*
SLC27A2 Very long-chain acyl-CoA synthetase is an enzyme that in humans is encoded by the ''SLC27A2'' gene. The protein encoded by this gene is an isozyme of long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subc ...


See also

* Fatty acyl-CoA synthase *
Triacsin C Triacsin C is an Enzyme inhibitor, inhibitor of long fatty acyl CoA synthetase that has been isolated from ''Streptomyces aureofaciens''. It blocks β-cell apoptosis, induced by fatty acids (lipoapoptosis) in a rat model of obesity. In addition, i ...
- an inhibitor of Fatty acyl CoA synthetase


References


External links

* {{DEFAULTSORT:Long-chain-fatty-acid-CoA ligase EC 6.2.1 Oncogenes