How Does Fatty Acid Add Two Carbons

Biochemistry of Lipids, Lipoproteins and Membranes

Lisa Grand. Salati , Alan Yard. Goodridge , in New Comprehensive Biochemistry, 1996

4.3 Production of NADPH

Fatty acid synthesis utilizes two molecules of NADPH for each molecule of acetate incorporated into long-chain fat acids. In liver, glucose-6-phosphate dehydrogenase and half-dozen-phosphogluconate dehydrogenase ( Fig. 1) probably furnish about half of the NADPH used in fatty acid synthesis, with the other half coming from malic enzyme. The activities of the two dehydrogenases of the pentose phosphate pathway and of malic enzyme correlate positively with the charge per unit of fatty acrid synthesis under a wide variety of conditions. Even so, the rate of production of NADPH does not regulate fat acrid synthesis. In liver, each of these enzymes is commonly near equilibrium with respect to its substrates and products, and thus, changes in the activities of these enzymes do not change the charge per unit of product of NADPH. The charge per unit of production of NADPH is thus a function of its utilization.

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Coenzyme A

M.D. Lane , in Encyclopedia of Biological Chemistry (2d Edition), 2013

Fatty Acid Synthase

Fat acid synthesis in animals is catalyzed by a single large (molecular weight, five  ×   10⁵, a dimer consisting of two identical ~   2.5   ×   10⁵ subunits) multifunctional enzyme. All eight steps and thus all eight catalytic centers that deport out fatty acrid synthesis occur with the intermediates tethered to the FAS. The intermediates are covalently linked by thioester bonds to the –SH group of the long 4′-PP sidearm which facilitates translocation of intermediates from one catalytic eye to the next in sequence until the multiple steps of long-chain fatty acid synthesis are completed. Each circular of elongation lengthens the concatenation past two carbons, a process that is repeated 7 or 8 times for the synthesis of a sixteen- or eighteen-carbon-containing fatty acids.

The process is initiated by the transfer of an acetyl group to iv′-PP from acetyl-Due south–CoA. The acetyl grouping linked to 4′-PP serves every bit the primer onto which the long-concatenation fatty acid is congenital. Malonyl units from malonyl-CoA, which serve as the chain-elongating group, condenses with the acetyl-primer concomitant with decarboxylation to produce a four-carbon intermediate that and then undergoes two reductive and 1 dehydration steps. Successive malonyl groups are transferred to FAS from malonyl-CoA to provide the bones units for successive steps in the elongation process. The terminal step is catalyzed by a thioesterase releasing the long-chain fatty acid product.

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Fatty Acid Structure and Synthesis

S.D. Clarke , M.T. Nakamura , in Encyclopedia of Biological Chemistry (Second Edition), 2013

Abstruse

Fatty acid synthesis involves the de novo associates of acetate into saturated fatty acids too as the desaturation and elongation of the dietary essential fatty acids – linoleic acid (C18:2n-6) and α-linolenic acrid (C18:3n-3) – to highly unsaturated twenty- and 22-carbon fatty acids essential to reproduction, cell differentiation, inflammation, and cognition. Curt-chain fatty acids are derived largely from bacterial fermentation such as that which occurs in the gut or rumen. Medium-chain fatty acids are characteristic of milk fat and are absorbed from the intestine direct into the portal blood, and subsequently metabolized largely by the liver. Fatty acids containing xiv or more carbons are absorbed from the intestine and transported to the periphery every bit chylomicrons. Very long chain fatty acids are largely establish in neural tissue and used for myelin formation. Internet fatty acid synthesis by humans is relatively small, simply the de novo fat acrid biosynthetic pathway is essential for the production of malonyl-coenzyme A, a metabolite inhibitor of carnitine palmitoyltransferase. Consequently, substrate flux through the de novo lipogenic pathway plays a key role in determining if a fatty acid is partitioned to fatty acid oxidation or triglyceride absorption.

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Biochemistry and Metabolism of Toxoplasma gondii

Isabelle Coppens , ... Stanislas Tomavo , in Toxoplasma Gondii (2nd Edition), 2014

8.v.1.1 Fatty Acid Biosynthetic Pathways – Generalities

Fatty acrid synthesis is a critical anabolic pathway in most organisms. In addition to being the major component of membranes, fatty acids are important energy storage molecules, and fatty acyl derivatives possess a variety of physiological functions, including post-translational modification of numerous proteins. The cardinal process of fatty acid biosynthesis is highly conserved amid species. The key feature is the sequential extension of an alkanoic concatenation, two carbons at a time, past a series of decarboxylative condensation reactions. This procedure is generally initiated with the carboxylation of acetyl-CoA to yield malonyl-CoA ( Smith et al., 2003). The malonate grouping of malonyl-CoA is transferred to the phosphopantetheine prosthetic group of a small, acidic poly peptide or protein domain, called the acyl carrier protein (ACP). Malonyl-ACP is then condensed with acetyl-CoA, reduced, dehydrated and reduced once again yielding an acyl-ACP. The elongation of the chain occurs by condensing another malonyl-ACP with the acyl-ACP and repeating the reaction bicycle.

In nature, at that place are two basic types of fat acid synthesis (FAS) architectures. The prototypical FASI is constitute in vertebrates and fungi. This pathway is an associated system since information technology consists of a single gene that produces a multifunctional protein, which contains all of the reaction centres required to produce a fatty acid molecule (Smith et al., 2003). Past dissimilarity, plants, bacteria and lower eukaryotes such equally yeast and some protozoa, contain ii genes that are implicated in fat acid production, and whose polypeptide products coalesce to form a multifunctional complex (White et al., 2005). This dissociated system named FASII is characterized by the encoding of each component by a divide gene that produces a unique poly peptide, which catalyses a single step in the pathway.

The Type I FAS is idea to accept evolved by the fusion of a Blazon II complex into a single protein. The multifunctional protein of FASI is localized in the cytosol. In plants, FASII takes place in the plastid (chloroplast) that is derived from a cyanobacterial endosymbiont. The genes for these enzymes are all encoded in the nuclear genome, and the proteins are post-translationally targeted to the plastid as is common with plastid enzymes in plants and algae (McFadden, 1999). FASI is unremarkably considered more than efficient than FAII because the enzymatic activities are fused into a single polypeptide template and the intermediates practise non diffuse from the complex. However, FASI produces only palmitate whereas FASII is capable of producing a large diversity of fatty acids with different chain lengths. Unsaturated fatty acids, iso- and anteiso-branched-chain fat acids, and hydroxy fatty acids are generated by FASII. In addition, some FASII intermediates are used in the synthesis of key cellular constituents, such as lipoic acid and quorum-sensing molecules. This enormous diversity of products is possible because the ACP intermediates in the type II pathway are diffusible entities that can be diverted into other biosynthetic pathways.

Finally, pregnant amounts of the fatty acids tin further be elongated into very long chain fatty acids by individual membrane-leap enzymes, named elongases located in the endoplasmic reticulum (ER). The synthesis of very long chain fatty acids is a ubiquitous organisation found in unlike organisms and jail cell types (reviewed in Jakobsson et al., 2006; Uttaro et al., 2006). These specific fatty acids serve commonly equally building blocks of sphingolipids, simply they are also of import constituents of glycerophospholipids, triacylglycerols, steryl- and wax-esters.

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Lipid Biosynthesis

D. de Mendoza , G.E. Schujman , in Encyclopedia of Microbiology (Third Edition), 2009

The Type II Fatty Acid Biosynthetic Pathway

Fat acid synthesis is essential for the formation of membranes and hence for the viability of all cells except Archaea, in which the membranes are composed of glycerol–ether lipids instead of glycerol–ester lipids and are based on isoprenoid side chains.

Fatty acrid synthesis in leaner is achieved past a highly conserved fix of genes that each encodes an individual footstep in the blazon II fatty acid biosynthetic pathway (FASII) ( Figure 1 ). Each protein of the pathway is located in the cytosol, and reaction intermediates are covalently attached to acyl carrier protein (ACP). The ACPs are a group of highly related pocket-sized acidic proteins with molecular weights of about 9.0   kDa. The acyl intermediates of fat acrid biosynthesis are bound to ACP through a thioester linkage attached to the terminal sulfhydril of the 4′-phosphopantetheine prosthetic grouping.

Figure 1. Initiation and elongation cycle of fat acid biosynthesis. Malonyl-CoA, the production of the acetyl-CoA carboxylase (ACC) reaction, is converted to malonyl-ACP by malonyl-CoA transacylase (FabD). The following step is catalyzed by β-ketoacyl ACP synthase Three (FabH), which is able to utilize brusk acyl-CoA primers as substrates. The elongation of the growing acyl chains is accomplished in four successive steps catalyzed past the post-obit enzymes: β-ketoacyl ACP synthase I or Ii (FabB or FabF, respectively), β-ketoacyl ACP reductase (FabG), β-hydroxyacyl-ACP dehydrase (FabZ), and enoyl reductase (FabI).

Malonyl-CoA is required for all the elongation steps of the fatty acid biosynthetic pathway and is formed by carboxylation of acetyl-CoA past acetyl-CoA carboxylase (ACC). ACC is constructed from four separate proteins and requires biotin every bit a cofactor. Malonyl-CoA is made bachelor to the enzymes of fatty acid biosynthesis by its conversion to malonyl-ACP past malonyl transacylase (FabD). The concatenation elongation stride in fatty acrid biosynthesis consists of the condensation of acyl groups, which are derived from acyl-ACP or acyl-coenzyme A (acyl-CoA), with malonyl-ACP by the β-ketoacyl-ACP synthases (often referred every bit condensing enzymes). These enzymes are divided into two groups. The FabH class of condensing enzymes is responsible for the initiation of fatty acid elongation and utilizes acyl-CoA primers. Escherichia coli produces directly chain and unsaturated fatty acids (UFA), and Eastward. coli FabH selectively uses acetyl-CoA to initiate the pathway. In contrast, Bacillus subtilis produces mainly branched-chain fatty acids and contains 2 FabH isozymes (named FabHA and FabHB) that differ from the E. coli enzyme in that they are selective for branched-chain acyl-CoAs. The FabF–FabB class of condensing enzymes is responsible for the subsequent rounds of fat acid elongation in the pathway. These enzymes condense malonyl-ACP with acyl-ACP to extend the acyl chain by two carbons. The FabF isoform is universally expressed in bacteria, and in B. subtilis is the sole condensing enzyme able to comport out the subsequent elongation reactions in fatty acid synthesis. E. coli, and another bacteria, also have the FabB isoform, which plays a special role in the synthesis of UFA (see 'Biosynthesis of UFAs'). FabG is the β-ketoacyl-ACP reductase and only a single isoform of this enzyme has been identified so far in bacteria. The adjacent step in the elongation cycle is the aridity of β-hydroxyacyl-ACP to trans-2-enoyl-ACP. 2 isoforms, FabZ and FabA, catalyze the dehydration of β-hydroxyacyl-ACPs, admitting with different substrate specificities. FabZ is universally expressed in bacteria, whereas FabA is restricted to organisms that use the FabA/B system to introduce double bonds into the growing acyl concatenation (see 'Biosynthesis of UFAs'). Although most FAS II enzymes are relatively conserved in leaner, an exception is the last step of the elongation bike, where a saturated acyl-ACP is formed by a NAD(P)H-dependent reduction of the enoyl-ACP double bond. In Eastward. coli, this reaction is catalyzed by FabI, while B. subtilis contains two isozymes, a FabI homologue and FabL that, similar FabI, is a member of the short concatenation reductase superfamily. Vibrio cholerae contains FabV, a NADH-dependent member of the short chain reductase superfamily, while Streptococcus pneumoniae contains a single enoyl reductase, FabK, unrelated to this last superfamily of enzymes.

E. coli and mostly of Gram-negative bacteria synthesize straight-chain fatty acids, but at that place can be a major variation of this image. Branched-chain fatty acids are produced in several Gram-positive bacteria, such every bit Bacillus, Streptomyces, and Listeria, and exist in two forms that are characterized by the presence of either iso and anteiso branches at their termini. The primer carbons for the synthesis of branched-chain fatty acids are 2-ketoacids derived from valine, leucine, and isoleucine. While isoleucine is the precursor of anteiso-branched-concatenation fatty acids, leucine and valine give raise to the primers for iso-branched chain fatty acids. The enzyme responsible for the germination of the branched-chain acyl-CoAs is a specialized branched-chain α-ketoacid dehydrogenase complex. These branched-chain acyl-CoAs are then introduced into the FASII pathway past FabH enzymes of the appropriate substrate specificity.

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Exchangers

Magnus Monné , Ferdinando Palmieri , in Current Topics in Membranes, 2014

ii.6 The plant dicarboxylate–tricarboxylate carrier

Fatty acid synthesis, nitrogen assimilation, and the shuttling of reducing equivalents in plants are processes thought to involve the dicarboxylate–tricarboxylate carrier (DTC) that shares a substantial sequence identity with OGC only displays a broader substrate specificity ( Picault et al., 2002). DTC from A. thaliana and Nicotiana tabacum was expressed in E. coli, purified, reconstituted into liposomes, and shown to transport both dicarboxylates (such every bit malate, oxaloacetate, oxoglutarate, and maleate) and tricarboxylates (such as citrate, isocitrate, cis-aconitate, and trans-aconitate). The Chiliad _m of DTC for α-ketoglutarate, malate, and citrate is in the micromolar range. The expression of DTC is constitute in all establish tissues.

DTC transport of citrate and α-ketoglutarate is pH dependent. The K _m values for the dissimilar charged species of citrate and malate were calculated from kinetic transport experiments at different pH values, demonstrating that the K _m was constant for the species with two negative charges (Picault et al., 2002). This finding suggests that H⁺  +   citrate^{3   −} and malate^{2   −} are the main substrates for DTC (Fig. 8.2C). Furthermore, the influence of the membrane potential on DTC transport in proteoliposomes was investigated by applying a Thou⁺ improvidence potential in the presence of valinomycin (Fig. 8.2A). The results demonstrated that the DTC-mediated citrate/oxoglutarate exchange was contained of the Δψ. Therefore, DTC was suggested to catalyze the electroneutral, ΔpH-dependent i:1 substrate exchange of H⁺  +   citrate^{3   −}, α-ketoglutarate^{2   −}, or malate^{2   −}.

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Lipids

Gerald Litwack PhD , in Human Biochemistry (2nd Edition), 2022

Fatty Acid Synthesis

Fatty acid synthesis occurs in the liver and in adipose cells. The rate-limiting reaction in fatty acid biosynthesis is that of acetyl-CoA carboxylase (ACC) that catalyzes the reaction of acetyl-CoA to malonyl-CoA in two steps shown in Fig. 9.45.

Figure 9.45. The formation of malonyl-CoA from acetyl-CoA catalyzed past the enzyme acetyl-CoA carboxylase. The enzyme–biotin complex is carboxylated biotin (the coenzyme) from bicarbonate and ATP at one site in the get-go step. This is followed by the transfer of the carboxyl grouping to acetyl-CoA at a second site. The overall reaction is ${\mathrm{HCO}}_{\mathrm{three}}^{-}+\mathrm{ATP}+\mathrm{acetyl}-\mathrm{CoA}\to \mathrm{ADP}+{\mathrm{P}}_{\mathrm{i}}+{\mathrm{H}}^{+}+\mathrm{malonylCoA}$ . ATP, adenosine triphosphate; CoA, Coenzyme A.

The coenzyme, biotin, is fastened to the epsilon (ε) amino group of a lysine residual in the enzyme. Lysine has half-dozen carbons (Fig. iv.nine) and the epsilon amino group is the final amino group farthest from the α-carbon, the α-carbon being the cantlet that is substituted past the carboxyl grouping and the amino group of the amino acid. The terminal carbon containing the ε-amino group is four carbons from the α-carbon, therefore, α, β, δ, γ, and ε. The structure of biotin showing its attachment to the enzyme ACC is shown in Fig. 9.46. 2 subunits of the enzyme are located opposite each other with a biotin carboxyl carrier protein connecting both at their apex. 1 subunit is the carboxylase subunit and the other is the transcarboxylase subunit. In the class of the enzymatic reaction, biotin, extending from the carrier protein, swings beginning to the active site of the carboxylase subunit where biotin is carboxylated and and so swings across to the transcarboxylase subunit's active site where it reacts with acetyl-CoA to grade malonyl-CoA.

Figure ix.46. The structure of the coenzyme biotin and its attachment to acetyl-CoA carboxylase through the ε-amino grouping of a lysine residue in the enzyme.

The regulation of ACC is complex. There exist 2 isozymes, ACC1 and ACC2, and these derive from ii different genes. Each enzyme in the active grade consists of 2 subunits, α and β. There are ii atoms of magnesium bound per subunit. The regulation of both isozymes appears to be the same. They produce 2 pools of malonyl-CoA. I of these (ACC2) inhibits β-oxidation, whereas the other (ACC1) stimulates lipid biosynthesis. ACC is inactivated by phosphorylation. The phosphorylation is catalyzed by AMP poly peptide kinase. Phosphorylation causes the enzyme to dissociate into ii inactive monomers. ACC1 is a cytosolic enzyme, whereas ACC2 has twenty N-terminal hydrophobic amino acids that direct this isozyme to the mitochondria. ACC1 stimulates lipid biosynthesis by supplying malonyl-CoA and ACC2 inhibits β-oxidation by inhibition through malonyl-CoA of mitochondrial carnitine palmitoyltransferase 1. The inactive grade can exist reversed by dephosphorylation catalyzed by PP′ase 2. Notably, the inactive phosphorylated form of ACC (ACC-P) can bind citrate that acts as an allosteric activator binding to a site remote from the catalytic centre. This produces a phosphorylated enzyme that has partial activity. This system is as well controlled by hormones. When the blood glucose level is low, epinephrine and glucagon stimulate the phosphorylation of ACC but when blood glucose is high insulin stimulates the dephosphorylation of ACC-P. Insulin enhances the activity of PP′ase 2 (Fig. 6.30). These overall activities are summarized in Fig. 9.47.

Figure 9.47. ACC consists of two isozymes, ACC1 and ACC2 (left, middle). There are ii pools of the product of the enzymatic reaction, malonyl-CoA. 1 pool suppresses β-oxidation of fatty acids and the other puddle stimulates lipid biosynthesis. ACCs are inhibited by phosphorylation (at multiple sites) catalyzed by AMPPK. The inactive, phosphorylated (P) form tin be reversed to generate the active form by PP'ase2. The phosphorylated inactive enzyme (AAC-P) is able to bind the citrate that acts every bit an allosteric activator and so that the citrate-jump phosphorylated enzyme (AAC-P-citrate) is partially active. Citrate binds at a site on the enzyme remote from the catalytic center and its binding may generate a favorable conformational change. Palmitoyl-CoA, one of the end products of lipid biosynthesis, can catechumen a partially active grade of the enzyme to the inactivated form. Hormones also regulate the activeness of ACC. Epinephrine and glucagon stimulate the phosphorylation of ACC, whereas insulin stimulates the dephosphorylation of ACC-P by enhancing the action of PP'ase2. ACC, Acetyl-CoA carboxylase; AMPPK, adenosine monophosphate protein kinase; CoA, coenzyme A; PP'ase2, protein phosphatase two.

It should be noted that the linkage between biotin and the ε-lysine of ACC involves the concluding carboxyl group of biotin. The length of this biotin side concatenation is sufficient to let for the transit of biotin betwixt the 2 active sites on the enzyme.

In the eye, which does not synthesize fatty acids, malonyl-CoA inhibits fat acid oxidation. When the concentration of ATP is depression and AMP is loftier, the product of malonyl-CoA is reduced allowing for fat acid oxidation, the production of acetyl-CoA, and energy from the TCA bicycle.

Malonyl-CoA is produced as shown in Figs. 9.44–nine.46. Malonyl-CoA synthesis is summarized:

${\mathrm{HCO}}_{\mathrm{three}}^{-}+\mathrm{ATP}+\mathrm{acetyl}-\mathrm{CoA}\to \mathrm{ADP}+{\mathrm{P}}_{\mathrm{i}}+\mathrm{malonylCoA}$

As AAC generates malonyl-CoA representing the committed step in fatty acid synthesis, it is a highly regulated enzyme and the regulation is complex as described in Fig. 9.46. The remaining pathway of fatty acid synthesis is carried out past cytoplasmic fatty acid synthase (FAS). FAS is a dimer of two multifunctional polypeptides. Information technology is a unmarried enzyme that has resulted from gene fusion of several individual enzymes. The substrates are acetyl-CoA and malonyl-CoA, linked as thioester derivatives of CoA through the β-mercaptoethylamine of the coenzyme. At that place are three catalytic domains in the N-terminus and four catalytic domains in the C-terminus (one of which is a carrier protein) as shown in Fig. ix.48 that is a diagram of one of two popular models.

Figure 9.48. One of two models of the FAS enzyme. FAS is a multienzyme with ii identical multifunctional polypeptides of 272   kDa (some reports betoken 250   kDa) connected in antiparallel way. The two-component proteins are bundled from head (tiptop) to tail (or foot) on the left and from tail (human foot) to caput on the right. Substrates are moved from one functional domain to the next. In the North-terminus (head), proceeding downwards, the activities are KS, MAT, and DH. Interposed is a core region (Torso) of 600 amino acid residues followed by four functions in the C-terminal domain: ER, KR, ACP, and TE. The ACP is shown on the right-hand partner to the left of KR. The reactions catalyzed by each component activity are shown on the left and are recapitulated below in the text. ACP, Acyl carrier protein; DH, dehydrase; ER, enoyl reductase; FAS, fat acid synthase; KR, ketoacyl reductase; KS, ketoacyl synthase; MAT, malonyl/acetyltransferase; TE, thioesterase.

Reproduced from http://en.wikipedia.org/wiki/File:FASmodel2.jpg.

Pantothenic acid, a vitamin, is the cofactor in the FAS enzyme system. Information technology is too a component of CoA. Phosphopantetheine (Pant) (Fig. 9.29) is attached covalently through a phosphate ester to a serine hydroxyl on the acyl carrier protein (Fig. 9.49). Pant has a long flexible arm that allows its thiol to move from one active site to another within FAS.

Figure nine.49. Phosphopantetheine is covalently linked through a phosphate ester to a serine hydroxyl of the acyl carrier protein component of FAS. FAS, fatty acid synthase.

The initial substrates of FAS are acetyl-CoA and malonyl-CoA. The individual steps of the FAS sequential reactions are shown in Fig. 9.50.

Effigy 9.fifty. Private steps in fatty acid synthesis. Pant, phosphopantethiene. Colored structures are cocky-described. Each pace is detailed to the left of each set of reactions. NADPH, Reduced nicotinamide dinucleotide phosphate.

Reproduced from http://rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/fasynthesis.htm.

In this set of reactions, after all the cycles accept been completed, the concluding production is palmitate, a 16-carbon fat acid. If the fat acid to be synthesized is larger than 16 carbons, the lengthening is carried out in the mitochondria and the endoplasmic reticulum. To accomplish elongation, the fatty acid oxidation system runs in contrary and malonyl-CoA is the two-carbon fragment donor. The final electrons are donated by NADPH. In the synthesis of palmitate, the overall reaction (accounting for the ATP synthesis of malonate) is summarized every bit follows:

$8\mathrm{acetyl}-\mathrm{CoA}+\mathrm{xiv}\mathrm{NADPH}+\mathrm{fourteen}{\mathrm{H}}^{+}+7\mathrm{ATP}=\mathrm{palmitate}+14{\mathrm{NADP}}^{+}+8\mathrm{CoA}+\mathrm{seven}\mathrm{ADP}+\mathrm{vii}{\mathrm{P}}_{\mathrm{i}}$

FAS set of reactions can be represented equally a bicycle in which each step is delineated (Fig. 9.51).

Figure 9.51. Fatty acid synthase reactions shown, stepwise, leading to the synthesis of palmitate. The reactions are numbered starting in the upper right middle. For convenience, simply one of the two subunits of fatty acrid synthase is represented. NADPH, reduced nicotinamide dinucleotide phosphate.

Redrawn with permission from McGraw-Hill, McKee, Biochemistry, 1996, DuBuque, Iowa.

Proceeding from the N-terminus of FAS toward the C-terminus, the active centers are condensing enzyme, malonyl/acetyl-CoA transacylase, dehydrase, enoyl reductase (ER), β-ketoyl reductase, acyl carrier protein, and thioesterase. The complex enzyme is regulated at the level of Dna past upstream stimulatory gene and the SREBP. Transcription of FAS is blunted past polyunsaturated fatty acids through suppression of SREBP-ane. In adipose cells in white adipose tissue, leptin (130 amino acid–containing proteins) is produced and amount of leptin in blood is proportional to the total body fatty. In liver and muscle mitochondria, leptin stimulates the oxidation of fatty acids, decreasing fatty storage in those tissues. Leptin enters the central nervous organization proportionally to its plasma concentration and interacts with leptin receptors on neurons in the mediobasal hypothalamus that are involved in energy intake and expenditure. Activation of certain leptin receptors leads to the production of α-melanocyte-stimulating hormone that causes ambition suppression. In the arcuate nucleus, leptin binds to neuropeptide Y (NPY)-producing neurons and decreases their activity, resulting in satiety. Leptin can prevent the secretion of anandamide, an endogenous cannabinoid, which binds to its receptors and stimulates feeding. Leptin and NPY are polypeptides and anandamide (cannabinoid) is derived from arachidonic acid (Fig. 9.52).

Figure 9.52. Anandamide is arachidonylethanolamide, an endogenous cannabinoid derived from arachidonic acid.

Homozygous mutations in the leptin gene effect in the constant desire for food and resultant obesity. Mutations in the leptin gene can pb to obesity; however, it is uncertain that all obesity is the issue of leptin gene mutation. Consumption of big amounts of fructose (eastward.g., corn sirup and dearest) tin can pb to leptin resistance, the height of triglycerides, and gain in body weight. Leptin volition undoubtedly play an important part in the regulation of body weight.

At that place is evidence in the human being for a cytokine called resistin (~12.5   kDa polypeptide). It is secreted from adipose tissue and likewise from immune and epithelial cells. Information technology has been proposed that resistin is linked to insulin resistance in obesity and in type 2 diabetes. Its concentration in serum increases with obesity. Resistin also is thought to play a role in inflammation and energy residuum.

Double bonds are introduced at specific positions in the chain by desaturases. This requires enzymes of the endoplasmic reticulum: NADH cytochrome b₅ reductase, cytochrome b_v, and desaturase. The desaturases are mixed-function oxidases that catalyze iv-electron reduction of oxygen to course ii h2o molecules as a double bond is introduced into the fat acid. For introduction of a double bail in stearate (18:0; indicating eighteen carbons in length with no double bonds) to form oleate (18:ane cis Δ-9), the overall reaction is as follows:

$\mathrm{stearate}+\mathrm{NADH}+{\mathrm{H}}^{+}+{\mathrm{O}}_2=\mathrm{oleate}+{\mathrm{NAD}}^{+}+2{\mathrm{H}}_2\mathrm{O}$

Oleic acid has a double bail at C9–10 and other fatty acids have double bonds in different positions. Certain fatty acids demand to be ingested through the diet as humans have a limited chapters for synthesizing long-chain fatty acids. Therefore the ingestion of linoleic and α-linolenic acids is essential. Linoleic acid is an ω-6 (omega-6) fatty acid, containing a double bail located at the sixth carbon from the methyl end of the molecule. The showtime carbon (α-carbon) is numbered from carbon bearing the concluding carboxyl group then the omega carbon would be the terminate carbon at the last methyl grouping. Linolenic acrid is a component of fish oils and is an ω-three fatty acrid, having a double bond at the third carbon from the last methyl group. Arachidonic acid (twenty:iv) tin can be formed from linoleic acid (xviii:2); yet, fiddling arachidonic acid is formed in this fashion. Arachidonic acid has to be ingested and is therefore essential. The structures of essential fatty acids and other important fatty acids are shown in Fig. 9.53.

Figure 9.53. Structures of important fatty acids, including essential* fatty acids in the human.

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Polyketides and Other Secondary Metabolites Including Fatty Acids and Their Derivatives

Akihiko Kawaguchi , ... Norihiro Sato , in Comprehensive Natural Products Chemistry, 1999

1.02.2.1.1 Acetyl-CoA carboxylase

Fatty acid synthesis starts with the carboxylation of acetyl-CoA to malonyl-CoA, as shown in Equation (1). This reaction is catalyzed past acetyl-CoA carboxylase, which contains a biotin prosthetic grouping. The carboxyl group of biotin is covalently leap to the ɛ-amino group of a specific lysine balance. Acetyl-CoA is carboxylated through two partial reactions. First, a carboxybiotin intermediate is formed at the expense of ATP (Equation (2)). The activated CO₂ group in this intermediate is then transferred to acetyl-CoA to give malonyl-CoA (Equation (3)).

(ane) ${\text{CH}}_3\text{COSCoA}+{\text{HCO}}_{\mathrm{three}}^{-}+\text{ATP}\to {}^{-}\text{O}{\text{OCCH}}_2\text{COSCoA}+\text{ADP}+\text{Pi}+{\text{H}}^{+}$

(2) ${\text{HCO}}_3^{-}+\text{ATP}+\text{Biotin}-\text{Enzyme}\to {\text{CO}}_2^{-}-\text{Biotin}-\text{Enzyme}+\text{ADP}+\text{Pi}$

(3) ${\text{CO}}_2^{-}-\text{Biotin}-\text{Enzyme}+{\text{CH}}_{\mathrm{iii}}\text{COSCoA}\to {}^{-}\text{O}{\text{OCCH}}_2\text{COSCoA}+\text{Biotin}-\text{Enzyme}$

(iii) Acetyl-CoA carboxylase consists of three different functional components, biotin carboxylase (BC), biotin-carboxyl-carrier protein (BCCP), and carboxyl transferase (CT). In fact, the acetyl-CoA carboxylase of Escherichia coli consists of three respective dissociable components. Poly peptide fractionation of the E. coli carboxylase initially gives ascent to two protein fractions, Eastward _a and E _b , which catalyze Equations (two) and (3), respectively. ^three,4 Purified Eastward _a can exist separated further into 2 proteins by gel electrophoresis. Therefore, the bacterial carboxylase dissociates into iii components: BC (molecular weight, 102 kDa), BCCP (22.v kDa), and CT (130 kDa). They may function as an enzyme complex in the cell.

A single subunit of eukaryotic acetyl-CoA carboxylase exhibits the functions of BC, BCCP, and CT. The eukaryotic enzyme has a highly integrated structure, representing a multifunctional protein (polypeptide). ^five Effigy 2 shows a schematic model of the eukaryotic enzyme. The biotinyl lysine has a long arm attached to a ureido band. The length and flexibility of the link betwixt biotin and its carrier protein enable the activated carboxyl group to motion between the active domains of BC and CT. Therefore, eukaryotic and prokaryotic acetyl-CoA carboxylases accept unlike structural organizations. The former are composed of multiple monofunctional polypeptides, whereas the latter consist of a single, integrated multifunctional polypeptide.

Figure 2. Schematic model of eukaryotic acetyl-CoA carboxylase.

The biotin-dependent carboxylases, which include acetyl-CoA carboxylase, propionyl-CoA carboxylase, oxalacetate decarboxylase, pyruvate carboxylase, and transcarboxylase, share mutual catalytic mechanisms. Biotin-dependent carboxylases other than oxalacetate decarboxylase and transcarboxylase, which lack biotin carboxylase, exert their catalytic activities through the three functional domains. ^v The three functional domains of the enzymes are encoded on the genome in various ways (Effigy 3). In some enzymes (prokaryotic acetyl-CoA carboxylase and transcarboxylase), the three components are encoded past three dissimilar genes. In other enzymes, two functional components are encoded by a single cistron, the other component beingness encoded by a different gene. In eukaryotic acetyl-CoA carboxylase and pyruvate carboxylase, all components are encoded past a unmarried gene. Even when two or 3 components are encoded by a single gene, both the order and the combination of functional domains in the primary construction differ from enzyme to enzyme.

Figure 3. Schematic diagram of the domains and/or subunit structures of various biotin-dependent carboxylases. Boxes signal functional domains and confined connecting the boxes indicate that the functional domains are fused to be encoded past a gene. The social club of the connected boxes corresponds to the order of the functional domains in the gene. CTac or CTox show whether CT uses acyl-CoA or 2-oxo acid equally its acceptor molecule (after Toh et al. ^five ).

The amino acid sequence of BCCP is similar to those of the lipoyl domains of various enzymes. The lipoyl domain also contains a specific lysine residuum, at which a lipoic acid is covalently leap to class a lipoamide. ⁶ The lipoyl domain is found in the subunits of enzyme complexes such as pyruvate dehydrogenase, 2-oxoglutamate dehydrogenase, and branched-concatenation α-keto acrid dehydrogenase. ⁷ The lipoyl domain is also found in a subunit of the glycine cleavage enzyme. ⁸ The lipoamide transfers acetyl, succcinyl, or aminomethyl moiety betwixt two different active sites in the enzyme complex.

The amino acid sequence of BC is similar to those of the duplicated domains of carbamoyl-phosphate synthetases, which are involved in the metabolic pathway for arginine and pyrimidine biosynthesis. ^6,nine,10 The N-terminal half of carbamoyl-phosphate synthetases is homologous to the C-terminal one-half. The repeats in carbamoyl-phosphate synthetases catalyze similar just distinct reactions, ^xi which are likewise like to the reactions catalyzed by BC.

There are two types of CT. One of them uses acyl-CoA (acetyl-CoA, propionyl-CoA, or iii-methylcrotonyl-CoA) every bit the acceptor of CO₂, and the other uses ii-oxo acid. In Figure 3, the former is referred to as CTac, and the latter equally CTox. The amino-acid sequences of CTac do not testify any similarity to that of CTox. ⁵ The CTac domains of eukaryotic acetyl-CoA carboxylases are considered to be carried on the C-final regions. However, significant sequence similarity has not been detected between these regions and Eastward. coli CT. It is difficult, on amino-acid sequence comparison, to determine whether prokaryotic and eukaryotic carboxyl transferases share a common bequeathed gene or have different origins.

Toh

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Man Adipose Tissue Dynamics and Regulation

Per Björntorp , Jan Östman , in Advances in Metabolic Disorders, 1971

(2) Obesity

Information on fatty acid synthesis in obesity is rather limited. Fatty acrid synthesis in obesity without diabetes was constitute to be normal while it was extinguished in obesity with diabetes ( Goldrick and Hirsch, 1964; Hood and Björntorp, 1966).

In the hyperglycemic, obese mouse certain metabolic aberrations seem to resemble those observed in human obesity. Thus, both are fat, have often hyperglycemia and hyperinsulinemia and do not hands develop ketosis during fasting (Mayer, 1964). The obese mouse has an increased fatty acid synthesis and an agile glycerokinase in adipose tissue, only obese human being has non (Goldrick and Hirsch, 1964; Hood and Björntorp, 1966). Thus, the similarity between the obesity of these mice and of man might therefore exist more apparent than real.

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Obesity

Laura L. Gathercole , ... Jeremy W. Tomlinson , in Vitamins & Hormones, 2013

2.two De novo lipogenesis

During fatty acid synthesis, carbons from acetyl-CoA are incorporated into a growing fat acrid chain. The first and rate-limiting step is the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA past acetyl-CoA carboxylase i (ACC1) ( Lane, Moss, & Polakis, 1974). ACC1 requires the vitamin biotin equally a coenzyme, which is covalently bound to a lysyl residue of the carboxylase. The malonyl-CoA produced is subsequently converted past a multistep reaction to the 16-carbon fat acid palmitate past fatty acrid synthase (FAS) (Ruderman, Saha, & Kraegen, 2003). FAS is a multicatalytic, dimeric enzyme, conveying out several reactions and requires the reducing power of nicotinamide adenine dinucleotide phosphate (NADPH).

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How Does Fatty Acid Add Two Carbons,

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