Transcriptional regulation of acaca is effected by three promoters (pi, pii, and piii which are located upstream of exons 1, 2, and 5A, respectively. The pi promoter is a constitutive promoter, the pii promoter is regulated by various hormones, and the piii promoter is expressed in a tissue-specific manner. The presence of the alternatively spliced exons does not alter the translation of the acc1 protein which starts from an aug present in exon. The acc2 gene (symbol: acacb) is located on chromosome 12q24.11 and is composed of 56 exons that encode a precursor protein of 2,458 amino acids. Acc1 is strictly cytosolic and is enriched in liver, adipose tissue and lactating mammary tissue. Acc2 was originally discovered in rat heart but is also expressed in liver and skeletal muscle.
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Back to the top Regulation by Acetyl-coa carboxylase: acc one must consider the global organismal energy requirements in order to effectively understand how the synthesis and summary degradation of fats (and also carbohydrates) needs to be exquisitely regulated. The blood is the carrier of triacylglycerols in the form of vldls and chylomicrons, fatty acids bound to albumin, amino acids, lactate, ketone bodies and glucose. The pancreas is the primary organ involved in sensing the organisms dietary and energetic states via glucose concentrations in the blood. In response to low blood glucose, glucagon is secreted, whereas, in response to elevated blood glucose insulin is secreted. The regulation of fat metabolism occurs via two distinct mechanisms. One is short term regulation which is regulation effected by events such as substrate availability, allosteric effectors and/or enzyme modification. Acc is the rate-limiting (committed) step in fatty acid synthesis. There are two major isoforms of acc in mammalian tissues. These are identified as acc1 (also called accα) and acc2 (also called accβ). The acc1 gene (symbol: acaca) is located on chromosome 17q12 and is composed of 63 exons that undergo alternative splicing to yield five splice variant mRNAs that generate precursor proteins from 2268 to 2383 amino acids in length.
In these circumstances, the pyruvate generated by the actions of ME2 and/or ME3 come from fumarate precursors such as glutamine. In neurons, as well as in numerous types of tumor cells, mitochondrial malic enzymes allow for the utilization of the amino acid glutamine as a fuel source. When glutamine is de-aminated by glutaminase the resulting glutamate can also be de-aminated by glutamate dehydrogenase yielding 2-oxoglutarate (α-ketoglutarate) which can then be shunted to malate synthesis in the tca cycle. The malate can then be decarboxylated to pyruvate via mitochondrial malic enzyme. The pyruvate can then be decarboxylated by the pdhc and the resulting acetyl-coa can enter the tca cycle ultimately allowing for glutamine carbons to be oxidized for atp synthesis. Within β-cells of the pancreas, this process driven by mitochondrial malic enzyme serves as an important means for the use of amino acid carbon oxidation for the stimulated british secretion of insulin. Indeed, this process is energetically equal to glucose-stimulated insulin secretion (gsis).
The malate produced by this pathway can undergo oxidative decarboxylation by cytoplasmic malic enzyme (ME1). The co-enzyme for this reaction is nadp generating nadph. The advantage of this series of reactions for converting mitochondrial acetyl-coa into cytoplasmic acetyl-coa is that the nadph produced by the malic enzyme reaction can be a major source of reducing co-factor for the fatty acid synthase activities. Humans express three malic enzymes, one cytoplasmic that requires nadp and two mitochondrial enzymes, one that requires nadp and one that requires nad. The cytoplasmic enzyme is called malic enzyme 1 and is encoded by the me1 gene that is located on chromosome 6q14.2 and is composed of 14 exons that encode a protein of 572 amino acids. The nad-dependent mitochondrial enzyme is called malic enzyme 2 and is encoded by the me2 gene located on chromosome 18q21.2 and is composed of 16 exons that generate two isoforms from alternatively spliced mRNAs. The nadp-dependent mitochondrial enzyme is called malic enzyme 3 and is encoded by the me3 gene located on chromosome 11q14.2 and is composed of 22 exons that generate four alternatively spliced mRNAs that all encode the same 604 amino acid protein. The role of the mitochondrial malic enzymes is principally to provide the cell with an alternate source of pyruvate under conditions where glycolytic flux in reduced.
Slc25A1 is the citrate transporter (also called the dicarboxylic acid transporter). Transport of pyruvate across the plasma membrane is catalyzed by the slc16A1 protein (also called the monocarboxylic acid transporter 1, mct1) and transport across the outer mitochondrial membrane involves a voltage-dependent porin transporter. Transport across the inner mitochondrial membrane requires a heterotetrameric transport complex (mitochondrial pyruvate carrier) consisting of the mpc1 gene and mpc2 gene encoded proteins. Note that the cytoplasmic malic enzyme (encoded by the me1 gene) catalyzed reaction generates nadph which can be used for reductive biosynthetic reactions such as those of fatty acid and cholesterol synthesis. Acetyl-coa enters the cytoplasm in the form of citrate via the tricarboxylate transport system (encoded by the slc25A1 gene; see figure). In the cytoplasm, citrate is converted to oxaloacetate and acetyl-coa by the atp driven atp-citrate lyase reaction. This reaction is essentially the reverse of that catalyzed by the tca enzyme citrate synthase except it requires the energy of atp hydrolysis to drive it forward. The resultant oxaloacetate is converted to malate by cytoplasmic malate dehydrogenase (encoded by the mdh1 gene). Atp-citrate lyase is encoded by the acyl gene which is located on chromosome 17q21.2 and is composed of 30 exons that generate four alternatively spliced mRNAs, each of which encoded a unique protein isoform.
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This butyryl group mga is then transferred to the cys-sh ( 8 ) as for the case of the activating acetyl group. At this point another malonyl group is attached to the acp-sh ( 3b ) and the process bags begins again. Reactions 4 through 8 are repeated another six times, each beginning with a new malonyl group being added. At the completion of synthesis the saturated 16 carbon fatty acid, palmitic acid, is released via the action of the thioesterase activity of fas (palmitoyl acp thioesterase) located in the c-terminal end of the enzyme. Not shown are the released coash groups. Back to the top Acetyl-coa is generated in the mitochondria primarily from two sources, the pyruvate dehydrogenase (PDH) reaction and fatty acid oxidation.
In order for these acetyl units to be utilized for fatty acid synthesis they must be present in the cytoplasm. The shift from fatty acid oxidation and glycolytic oxidation occurs when the need for energy diminishes. This results in reduced oxidation of acetyl-coa in the tca cycle and the oxidative phosphorylation pathway. Under these conditions the mitochondrial acetyl units can be stored as fat for future energy demands. Pathway for the movement of acetyl-coa units from within the mitochondrion to the cytoplasm. Under high energy charge mitochondrial acetyl-coa and citrate accumulate due to allosteric inhibition of the tca cycle. Due to accumulating acetyl-coa, pyruvate carboxylase is highly activated allowing for continued synthesis of oxaloacetate ensuring the eventual sysnthesis of citrate.
The primary fatty acid synthesized by fas is palmitic acid (palmitate). Palmitate is then released from the enzyme via the thioesterase activity of fas (contained in a domain composed of amino acids 22422487). Once released, palmitate can then undergo separate elongation and/or unsaturation to yield other fatty acid molecules. Reactions of fatty acid synthesis catalyzed by fatty acid synthase, fas. Only half of the normal head-to-tail (head-to-foot) dimer of functional fas is shown.
Synthesis of malonyl-coa from CO2 and acetyl-coa is carried out by acc as described. Fas is initially activated by the incorporation of the acetyl group from acetyl-coa. The acetyl group is initially attached to the sulfhydryl of the 4'-phosphopantothenate of the acyl carrier protein portion of fas (acp-sh). This is catalyzed by malonyl/acetyl-coa acp transacetylase ( 1 and 2 ; also called malonyl/acetyltransferase, mat). This activating acetyl group represents the omega (ω) end of the newly synthesized fatty acid. Following transfer of the activating acetyl group to a cysteine sulfhydryl in the β-ketoacyl-acp synthase portion of fas, the three carbons from a malonyl-coa are attached to acp-sh ( 3 ) also catalyzed by malonyl/acetyl-coa acp transacetylase. The acetyl group attacks the methylene group of the malonyl attached to acp-sh catalyzed β-ketoacyl-acp synthase ( 4 ) which also liberates the co2 that was added to acetyl-coa by acc. The resulting 3-ketoacyl group then undergoes a series of three reactions catalyzed by the β-ketoacyl-acp reductase ( 5 3-hydroxyacyl-acp dehydratase ( 6 and enoyl-coa reductase ( 7 ) activities of fas that reduce, dehydrate, and reduce the substrate. This results in a saturated four carbon (butyryl) group attached to the acp-sh.
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The active fas enzyme short exists as a head-to-tail homodimer. All of the reactions of fatty acid synthesis are carried out by the multiple enzymatic activities of fas. Like fat oxidation, fat synthesis involves four primary enzymatic activities. These are (in order of reaction β-ketoacyl-acp synthase (contained in a domain composed of amino acids 2404 β-ketoacyl-acp reductase (contained in a domain composed of amino acids 18762112 3-hydroxyacyl-acp dehydratase (contained in a domain composed of amino acids 8741106) and enoyl-coa reductase (contained. The two reduction reactions require nadph oxidation to nadp. The domain that is great required for attachment and transfer of acetyl-coa and malonyl-coa (acyltransferase domain) is composed of amino acids 493810. The phosphopantetheine arm of fas is attached to a domain composed of amino acids.
The carrier of acetyl groups (and elongating acyl groups) during fatty acid synthesis is keywords also a phosphopantetheine prosthetic group, however, it is attached a serine hydroxyl in the synthetic enzyme complex. The carrier portion of the synthetic complex is called acyl carrier protein, acp. This is somewhat of a misnomer in eukaryotic fatty acid synthesis since the acp portion of the synthetic complex is simply one of many domains of a single polypeptide. The acetyl-coa and malonyl-coa are transferred to acp by the action of the malonyl/acetyltransferase activity (also called acetyl-coa transacylase and malonyl-coa transacylase). The attachment of these carbon atoms to acp allows them to enter the fatty acid synthesis cycle. The synthesis of fatty acids from acetyl-coa and malonyl-coa is carried out by fatty acid synthase, fas. Fatty acid synthase is encoded by the fasn gene which is located on chromosome 17q25.3 and is composed of 43 exons that encode a protein of 2511 amino acids.
acetyl-coa to synthesize malonyl-coa. The rate of fatty acid synthesis is controlled by the equilibrium between monomeric acc and polymeric acc. The activity of acc requires this polymerization process. This conformational change is enhanced by citrate and inhibited by long-chain fatty acids. Acc is also controlled through hormone mediated phosphorylation (see below ). The acetyl groups that are the products of fatty acid oxidation are linked to coash. As outlined in the. Vitamins page, coash contains a phosphopantetheine group coupled to amp.
Both oxidation and synthesis proposal of fats utilize an activated two carbon intermediate, acetyl-coa. However, the activated form of acetyl-coa in fat synthesis exists temporarily bound to the enzyme complex as malonyl-coa. The synthesis of malonyl-coa is the first committed step of fatty acid synthesis and the enzyme that catalyzes this reaction, acetyl-coa carboxylase (acc is the major site of regulation of fatty acid synthesis. Like other enzymes that transfer CO2 to substrates, acc requires a biotin co-factor. Acetyl-coa carboxylase is called. Abc enzyme due to the requirements for. A tp, b iotin, and, c O2 for the reaction. The details of the two different forms of acc in human cells are described below in the. Acetyl-coa carboxylase regulation section.
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Return to The medical biochemistry page llc info @ one might predict that the pathway for the synthesis of fatty acids would paperwork be the reversal of the oxidation pathway. However, this would not allow distinct regulation of the two pathways to occur even given the fact that the pathways are separated within different cellular compartments. The pathway for fatty acid synthesis occurs in the cytoplasm, whereas, oxidation occurs in the mitochondria. The other major difference is the use of nucleotide co-factors. Oxidation of fats involves the reduction of fad and nad. Synthesis of fats involves the oxidation of nadph. However, the essential chemistry of the two processes are reversals of each other.