Which Of The Following Are Components Of Animal Fatty Acid Synthase

Natural Products Structural Variety-I Secondary Metabolites: Arrangement and Biosynthesis

Tyler Paz Korman , ... Shiou-Chuan (Sheryl) Tsai , in Comprehensive Natural Products II, 2010

one.08.iii.i Similarities and Differences betwixt FAS and PKS

FAS and PKS share many structural and functional similarities:

ane.

Both FAS and PKS tin can be grouped into type I and type 2, depending on whether the complex is a single polypeptide with multiple domains, or numerous stand-lonely proteins.

2.

In both FAS and PKS, the KS catalyzes concatenation elongation using small, 2 to iv carbon building blocks attached to ACP.

3.

Both employ KR, DH, and ER to modify the growing concatenation after each elongation cycle.

4.

Structural conservation seen in high-resolution structures of isolated type I and type II PKS and FAS domains suggest that both FAS and PKS may course similar mega complexes.

Withal, subtle differences in reduction patterns between PKS and FAS lead to the staggering variety of polyketide natural products compared to the simplicity of fatty acids ( Effigy 7 ) due to the following features: (i) Chain modification. FAS uses KR, ER, and DH afterwards each elongation pace to fully reduce every carbon. In comparison, the chain-modification events are much more complicated in PKS. In some type II and iterative type I PKSs, the polyketide is left completely unreduced due to the lack of KR, every bit in the instance of Tcm C ( 3 ) ⁶³ and norsolorinic acid ⁶⁴ biosynthesis. In other cases (such as act ( 1 ) and doxorubicin ( 2 )), the PKS KR catalyzes a regio- and stereospecific reduction at a single position, ¹ as opposed to reducing every carbonyl grouping in FAS KR. (ii) An altered regiospecificity: in PKS, the activeness of the KR is not necessarily followed by DH or ER. Therefore, from a production standpoint, polyketides frequently comprise multiple hydroxyl groups that undergo further reactions such as cyclization, aromatization, glycosylation, and methylation, leading to the huge chemical diversity observed in nature ( Figures one and 7 ). How ketoreduction and cyclization are controlled, especially in blazon Ii PKSs remains a mystery, and the lack of information has and so far prevented rational command of reduction and cyclization during polyketide biosynthesis. Therefore, understanding the substrate specificities and molecular mechanisms governing the ketoreduction and cyclization events in type 2 PKS systems will exist scientifically pregnant by filling in the noesis gaps and providing a structural guide for manipulating these proteins to produce polyketides with new reduction and cyclization patterns.

Effigy vii. A full general scheme for the biosynthesis of polyketides and fatty acids. Fat acid biosynthesis is primed with an acetyl starter unit, and the chain extended via iterative condensations with malonyl-ACP. In dissimilarity, polyketide biosynthesis can exist initiated with acetyl, propionyl, or other acyl groups that can be coupled with malonyl-ACP or methylmalonyl-ACP. In the FAS, the β-carbonyl is fully reduced after each concatenation elongation round to produce an aliphatic fatty acid. The large diversity of polyketide structures is a result of partial reduction after each chain elongation round.

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Regulation of Fat Synthesis and Adipose Differentiation

Hei Sook Sul , ... Li Chen , in Progress in Nucleic Acid Research and Molecular Biology, 1998

A Hormonal and Nutritional Regulation of Fat Acid Synthase Gene Transcription

Fat acid synthase (FAS) (7) plays a central role in de novo lipogenesis in mammals and birds. By the action of its vii active sites, FAS catalyzes all the reaction steps in the conversion of acetyl-CoA and malonyl-CoA to palmitate. Mitochondrial glycerol-three-phosphate acyltransferase (GPAT) catalyzes the first committed stride in glycerophospholipid biosynthesis by catalyzing acylation of glycerol-3-phosphate using fatty acyl-CoA to generate 1-acyl-glycerol-three-phosphate (lysophosphatidic acid). Lysophosphatidic acrid is further acylated to form triacylglycerol for storage. FAS activity is non known to be regulated by allosteric effectors or covalent modification. Notwithstanding, FAS concentration is exquisitely sensitive to nutritional, hormonal, and developmental condition; the concentration or activity of FAS in lipogenic tissues, i.e., liver and adipose tissue, changes dramatically when animals are subjected to different nutritional and hormonal manipulations. The charge per unit of FAS synthesis declines when rats are fasted for ane−2 days, whereas refeeding a high-carbohydrate, fat-free diet increases synthesis of FAS (8, 9). FAS provided a good model system to study potential transcriptional regulation. We cloned the murine FAS cDNA sequence by differential screening, exploiting the fact that FAS is induced past fasting/refeeding (10). Nosotros also cloned the cDNA sequence for mitochondrial GPAT, which catalyzes the first acylation in triacylglycerol biosynthesis and whose regulation had non been studied previously. Regulation of the FAS and mitochondrial GPAT genes by hormones and nutrients, especially by insulin, was examined.

Both FAS and mitochondrial GPAT mRNAs are present at high levels in lipogenic tissues, i.e., liver and adipose tissue (x). FAS and GPAT mRNAs were not detectable in liver of normal fasted mice, and refeeding with a high-saccharide diet increased the levels two orders of magnitude. However, in streptozotocin-diabetic mice, the mRNA levels for these enzymes did not increase after refeeding, indicating that insulin is required for the fasting/ refeeding induction of these mRNAs. Dibutyryl cAMP, administered to normal fasted mice at the time of refeeding, inhibited the induction of these mRNAs by 90%. This indicates that the barely detectable levels of these mRNAs during fasting may exist partly due to the increased plasma glucagon that increases intracellular military camp. The effect of insulin can be further demonstrated past administering insulin to streptozotocin-diabetic mice fed a loftier-carbohydrate, fat-free diet. The consecration of FAS and GPAT mRNAs by insulin was rapid and marked. Transcriptional run-on analyses were carried out in isolated liver nuclei from normal and diabetic mice. The transcription rates of the FAS and mitochondrial GPAT genes increased when previously fasted mice were refed a loftier-carbohydrate diet (11, 12). The maximal increase of 39-fold for FAS was attained at half-dozen   hr after refeeding and was maintained up to xvi   60 minutes whereas the transcriptional increase for the mitochondrial GPAT cistron was substantially slower in that information technology was 2.5-fold at half dozen   hr, 7-fold at nine   hr, and reached 22-fold after 16   hour of refeeding (Fig. 1). However, there was no detectable transcription of FAS and mitochondrial GPAT genes in fasted or fast-ed/refed streptozotocin-diabetic mice, indicating that insulin is required for transcriptional induction by fasting/refeeding. Administration of cAMP at the start of feeding in normal mice prevented a feeding-induced increase in the transcription of these genes. Furthermore, there was a rapid and marked increase in the transcription rates of the FAS and GPAT genes when insulin was given to diabetic mice; the rates increased approximately 4-fold after 0.five   hr, with a maximal increase of 7- to eight-fold at two   hour (Fig. ane). The results demonstrate that these genes are highly regulated at the transcriptional level by nutritional and hormonal stimuli. The molecular mechanisms underlying the regulation need to be elucidated.

Fig. ane. Effects of fastmg/refeeding and insulin on the FAS and mitochondrial GPAT gene transcription in liver. (A) Nuclei isolated from livers of normal mice fasted (0) or fasted/refed with a high-sugar, fat-complimentary diet for 6, ix, or 16 hr were subjected to nuclear run-on transcription and hybridization with pFAS-1 (FAS), pl3 (mGPAT), pAM91 (actin), and pBR322 vector sequence fixed on nitrocellulose. Dibutyryl cAMP (Bt₂cAMP) was given at the starting time of refeeding. (B) Liver nuclei from streptozotocin-diabetic mice or diabetic mice treated with insulin for up to 6 hr were used for run-on analysis as in A.

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Cancer metabolism

Tomas Koltai MD, PhD , ... Salvador Harguindey Doctor, PhD , in An Innovative Arroyo to Agreement and Treating Cancer: Targeting pH, 2020

Fatty acid synthase

FAS is a key enzymatic complex in FA synthesis from acetyl-CoA and malonyl-CoA, in the presence of NADPH, into long-chain saturated FAs ¹⁵⁵ and it is expressed at high levels in liver and adipose tissue, but at low levels in other tissues. FAS is not a unmarried enzyme simply a whole enzymatic organisation composed of two identical 272   kDa multifunctional polypeptides, with seven functional domains each, in which substrates are passed from one functional domain to the next. ^156–158 Its main function is to catalyze the synthesis of palmitate. ¹⁵⁹

Under a nutrition with a relatively high fat content (40%), and even after a carbohydrate-rich diet for three days, FAS activeness remained low in humans. Nether normal dietary conditions, de novo lipogenesis in human is negligible. ¹⁶⁰ The source of long concatenation saturated FAs is either de novo synthesis (mediated by FAS), ingested food, or both.

FAS is the single human being enzymatic circuitous responsible for the conversion of dietary sugar to fat and it is the simply eukaryotic enzyme capable of synthesizing palmitate, the precursor of the majority of nonessential FAs. Information technology is down-regulated in most normal cells, except in lipogenic tissues such as liver, lactating breast, fetal lung, and adipose tissue. Conversely, several human cancers, over-express FAS, which has been associated with poor prognosis. ^161–163

FAs are aliphatic acids primal for free energy production and storage, building blocks for cellular structures as membranes and intermediates in the biosynthesis of hormones and other biologically important molecules.

The metabolism and homeostasis of FAS are transcriptionally regulated by upstream stimulatory factors and sterol regulatory element binding protein-1c (SREBP-1c) in response to feeding and insulin in living animals ^{164, 165} (Fig. 10).

SREBP-1c is a transcription factor regulated by environmental factors, external and internal signaling pathways and hormones and it can be modified past unlike pharmaceuticals (Fig. xi).

Fig. eleven. Factors influencing FAS production and inhibition.

FAS has been investigated as a possible oncogene. ¹⁶⁶ Increased retinoblastoma aggressiveness was associated with FAS activation and Camassei postulated that FAS inhibition could correspond an alternative treatment strategy in advanced and resistant retinoblastoma. ¹⁶⁷

A molecular link was identified between FAS and the HER2 oncogene, a marker for poor prognosis that is over-expressed in 30% of breast and ovarian cancers. Pharmacologic FAS inhibitors were found to suppress p185(HER2) oncoprotein expression and tyrosine kinase action in chest and ovarian cancers over-expressing HER2. ¹⁶⁸ Like suppression was observed when FAS gene expression was silenced past RNA interference.

Metformin is not commonly considered a FAS inhibitor, however it blocks the stimulation of a loftier energy nutrition on colon carcinoma growth in vivo and is associated with a reduction of FAS expression. ¹⁶⁹ Free energy deficiency induced by metformin inhibits lipogenesis in prostate cancer cells. ¹⁷⁰ Wahdan-Alaswad et al. ¹⁷¹ plant that MIRNA 193b is induced past metformin and it inhibits FAS through a postranslational block of the 3 UTR region of the transcript. We believe that part of the anti-tumoral behavior of metformin is linked to its ability to acidify the intracellular milieu.

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Hydrocarbon pheromone production in insects

Matthew D. Ginzel , ... Gary J. Blomquist , in Insect Pheromone Biochemistry and Molecular Biological science (2d Edition), 2021

7.three.3 Formation of fat acrid precursors

Fatty acrid synthase (FAS) has 7 enzymatic activities on each protein and exists as a dimer. The enzyme activities on each monomer office in combination with the other monomer to effectively synthesize 2 fat acids at the aforementioned time on each dimer. FAS activity has been measured in insect extracts for many years, but merely recently accept the genetics been studied, and data on which FAS is involved in methyl-branched hydrocarbons is becoming available by using knockdown techniques and then analyzing the hydrocarbons the insect produces.

The carbon skeletons of leucine and valine tin can exist metabolized to isovaleryl-CoA and isobutyryl-CoA which are the chain initiator molecules for odd chain and fifty-fifty concatenation, respectively, 2-methylalkanes (reviewed in Blomquist, 2010). D. melanogaster has 3 FAS genes, and knockdown of one of these, FASN^CG3524, markedly decreased production of 2-methylalkanes (Chung et al., 2014) but non of n-alkanes or alkenes. This provides potent show that a specific FAS is required for ii-methylalkane synthesis. An alternate FAS, FASN^CG3523, is expressed in the fatty body merely not the oenocytes, suggesting that all the enzymes necessary for hydrocarbon production are localized to the oenocytes, but that some fatty acids are imported to oenocytes for due north-methane series product (Wicker-Thomas et al., 2015).

The 3-methyl- and internally methyl-branched hydrocarbons arise from the incorporation of propionate equally a methylmalonyl-CoA derivative during concatenation elongation (reviewed in Blomquist, 2010) (Fig. 7.2). The labeled carbon from [ane–^thirteenC]propionate was plant exclusively in the 4-position of 3-methylpentacosane as demonstrated by carbon-xiii NMR in the P. americana (Dwyer et al., 1981b), indicating that information technology was the second grouping added to the growing chain. If the propionate, as methylmalonyl-CoA, was added toward the end of synthesis by elongases, the labeled carbon would have been institute in the two-position. Tracing the incorporation of [ane–^thirteenC]propionate into mono- and dimethylalkanes in M. domestica (Dillwith et al., 1982) and B. germanica (Chase et al., 1990) by mass spectrometry indicated that the methyl group was put on early in chain synthesis rather than toward the cease of the process, thus implicating a FAS rather than an elongase in their synthesis. The propionate group for methylalkanes is inserted as a methylmalonyl-CoA unit, and is derived from valine, isoleucine or methionine in the housefly (Dillwith et al., 1982) in identify of a malonyl-CoA at specific points during chain elongation (Fig. 7.2). These are essential amino acids for nigh insects, and thus requires a higher price for their use. An examination of the methyl-branched fatty acids from the integument of the German cockroach (Juarez et al., 1992) and the housefly (Blomquist et al., 1994) showed that modest amounts of some of the fat acids with the appropriate methyl branch positions to serve as precursors to hydrocarbons are present in both species.

Figure seven.2. Biosynthetic pathways for hydrocarbons in insects.

The fatty acrid synthase of most animals is a soluble enzyme. Yet, a microsomal FAS was observed in the German cockroach (Juarez et al., 1992) and the housefly (Gu et al., 1995), in addition to a soluble FAS. Assays of each FAS showed that methylmalonyl-CoA was incorporated into the growing fatty acrid more than efficiently by the microsomal FAS than the soluble FAS. This suggested that there may exist a specific FAS that inserts methylmalonyl-CoA at specific points during the formation of the methyl-branched fatty acid precursors to the internally branched hydrocarbons. Pei et al. (2019) identified 3 functional fatty acrid synthase genes from B. germanica, and using RNAi knockdown for each 1, showed that knockdown of BgFas1 resulted in less methyl-branched hydrocarbon product. Similarly, Rhodinus prolixus has three FAS genes and knockdown of FASN3 resulted in less methyl branched hydrocarbons compared to controls, and less resistance to desiccation (Moriconi et al., 2019). It will exist interesting to make up one's mind the sub-cellular location of the corresponding enzymes from these FAS genes to run into if they are membrane bound. In two sympatric grasshopper species, it is proposed that the development of fatty acrid synthases can lead to different isomers of methyl-branched hydrocarbons with the methyl branch position differing by two carbons (Finck et al., 2016).

The desaturases involved in producing unsaturated hydrocarbons have been studied in D. melanogaster. Desaturase i (desat1) in Drosophila accepts both palmitic acid and stearic acid to form palmitoleic (Δ9   C_16:ane) and oleic (Δ9   C_18:1) acids. This gene is expressed in both fat body and oenocytes and appears to play a office in general lipid metabolism and in hydrocarbon product (Wicker-Thomas and Chertemps, 2010). A desat2encoded factor converts myristic (C_fourteen:0) to myristoleic (Δ9   C_14:1, an n-v double bail) in flies that produce a 5,9-alkadiene (Dallerac et al., 2000). A 2d desaturation is required for females that produce five,nine- and vii,11-diene. RNA interference was used to written report this gene (Chertemps et al., 2007). This desaturase was institute simply in females and thus was named desatF (reviewed in Wicker-Thomas and Chertemps, 2010). The role of desaturases in insect hydrocarbon production is covered in depth in Chapter 4 of this book.

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Fatty Acrid Handling in Mammalian Cells

Richard Lehner , Ariel D. Quiroga , in Biochemistry of Lipids, Lipoproteins and Membranes (Sixth Edition), 2016

two.2 Fatty Acid Synthase

Mammalian FAS is a soluble cytosolic protein. Like to ACC1-deficient mice, global ablation of Fasn factor (encoding FAS) expression in mice results in embryonic lethality. On the other hand, liver or adipose-specific FAS-scarce mice are viable. Functional FAS is a homodimer of 273   kDa subunits. Each monomer contains seven catalytic elements that are required for the biosynthetic process. The acyltransferase component 'loads' acetyl-CoA and malonyl-CoA onto the FAS complex, resulting in the formation of thioester-enzymeintermediates; acyl carrier protein translocates the diverse thioester intermediates amidst the catalytic sites of β-ketoacyl reductase, β-hydroxylacyl dehydratase and enoyl reductase. Thioesterase is a chain-terminating enzyme that releases the production (mainly palmitic acid).

Similarly to Acaca, Fasn cistron expression is transcriptionally regulated by SREBP-1c, LXR and ChREBP. In addition, binding of upstream stimulatory factors one and 2 to East-boxes in Fasn proximal promoter is required for insulin-dependent upregulation of Fasn expression. Fasting rapidly reduces Fasn expression; however, in mice fasted for 14   h, FAS activity remains similar to ad-lib fed mice, possibly because of the long half-life of the protein. Counterintuitively, FAS activity is initially inhibited past insulin for a menses of up to fifteen   min after insulin administration before an insulin-stimulated increase in action is observed. This suggests acute regulation of the protein, possibly by posttranslational modification. Phosphorylation and acetylation of FAS have been reported simply the physiological result of these modifications remains to be elucidated.

Attenuation of hepatic FAS activity would exist expected to be protective against hepatic lipid accumulation. Withal, liver-specific FAS-deficient mice instead adult severe hepatic steatosis when fed a zero-fatty diet or on prolonged fasting. This phenotype can be corrected by activation of peroxisome proliferator-activated receptor (PPAR)-α with a synthetic agonist, which suggests that FAS provides a ligand for this of import transcription factor that regulates fatty acid oxidation and mitochondrial biogenesis. Semenkovich's grouping has identified 16:0/18:1-glycerophosphocholine as an endogenous ligand for PPARα, and the production of this phospholipid molecular species was establish to exist dependent on FAS activity (Chakravarthy et al., 2009).

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Mechanisms of chemoresistance and approaches to overcome its impact in gynecologic cancers

Nirupama Sabnis , ... Andras G. Lacko , in Overcoming Drug Resistance in Gynecologic Cancers, 2021

Targeting fat acid metabolism

Fatty acid synthase (FASN), an enzyme responsible for the production of long-chain fatty acids from saccharide-derived glycolytic precursors, just in cancers, its effects are multifaceted. FASN expression was correlated to tumor progression in multiple cancers, including endometrial and high-grade ovarian tumors [243, 244]. As previously discussed, dissemination of ovarian cancer is influenced by multiple factors, apparently including enhanced FASN expression [245]. In prison cell culture studies, FASN inhibition by cerulenin did subtract cell viability and apoptosis while sequential treatment of a cisplatin-resistant OC prison cell line commencement with cerulenin and and so with cisplatin reduced the IC_l of cisplatin, suggesting sensitization [246]. In another study, assessing cisplatin resistance in OC, FASN inhibition by orlistat led to significant delay of tumor growth [244]. These findings lend support to the possible utility of FASN inhibitors for drug-resistant tumors. Alternatively, using methods discussed earlier, knockdown of FASN via shRNA significantly decreased resistance in breast cancer cells to both Adriamycin and mitoxantrone. Although there exist multiple studies utilizing FASN knockdown via siRNA and shRNA in gynecologic cancers, the effects of chemotherapy resistance were not yet studied [247–249]. A new generation of FASN inhibitors has displayed reduced systemic toxicity in the colorectal and breast cancer models [250, 251]. These findings may use to gynecologic cancers also.

Fatty acid oxidation (FAO) is a pathway involving several enzymes catalyzed steps, including the rate limiting enzyme Carnitine Palmitoyltransferase 1A. Alteration of this pathway is observed in many cancers, including OC, posing information technology as a suitable target for therapeutic intervention [252]. The use of etomoxir and Ranolazine, which ultimately inhibit FAO, sensitized human leukemia cells to apoptosis past ABT-737 or cytosine arabinoside [253]. The effect was replicated even when the cancer cells were cultured on bone marrow-derived mesenchymal stromal cells (MSCs), which are known to heighten cancerous potential. In a nasopharyngeal carcinoma model, etomoxir was found to sensitize cancer cells to radiations. It was postulated that etomoxir impaired fatty acid influx, essentially starving the prison cell and leaving it decumbent to radiations [254]. Although there is a dearth of literature directly detailing the effects of CPT1A or FAO inhibition of drug resistance, specifically in the area of gynecologic cancers, this may nowadays an opening for future research.

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Coenzyme A

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

CoA every bit Donor of four′-PP for Fat Acid Synthase

Fatty acrid synthase (FAS) is a big multifunctional enzyme that catalyzes all steps in fatty acid synthesis, catalysis being facilitated by a covalently linked iv′-PP prosthetic group. The 4′-PP group, which is derived from CoA ( Figure 1 ), is enzymatically transferred to the FAS apoenzyme where it becomes covalently linked to the enzyme. The 4′-PP prosthetic grouping acts as a long sidearm to which intermediates of the pathway are covalently linked. The 4′-PP sidearm allows translocation of the growing fatty acyl chain intermediate from one catalytic site on FAS complex to the side by side in the circadian sequence, which leads to formation of a long-concatenation fatty acid.

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Chemical and Synthetic Biology Approaches To Understand Cellular Functions – Office B

Andrew J. Schaub , ... Shiou-Chuan Tsai , in Methods in Enzymology, 2019

one.2 Introduction to enzymatic mechanism

FAS, PKS and NRPS are large, multi-domain enzyme complexes (Fig. 2). Their intermediate products, often highly unstable, are shuttled between the catalytic domains via acyl carrier proteins (ACPs; in FAS and PKS) or peptidyl carrier proteins (PCPs; in NRPS) in a well-choreographed order that results in the biosynthesis of natural products with high fidelity. ACP and PCP are sequential and structural homologs that share the four-helix bundle fold. The growing intermediate is covalently fastened to a conserved serine on the carrier poly peptide (CP). The mature production is ultimately released from the PPant-CP by cleaving the thioester bail through enzyme-catalyzed hydrolysis or cyclization to generate the final production (Fig. 2) (Du & Lou, 2010).

Fig. 2. Examples of assembly line biosynthesis of (A) not-ribosomal peptides in Type A NRPS systems and (B) polyketides in Type I modular PKS systems.

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Marine Microbial Secondary Metabolites

Daniela Giordano , ... Cinzia Verde , in Advances in Microbial Physiology, 2015

three.4 Fatty Acid Synthase

FASs are found ubiquitously across all groups of organisms and are probably steps of very ancient biochemical pathways. These enzymatic machineries are equivalent to PKSs, because they operate post-obit the same strategy (see Department 2.ane). FAS and PKS share similarities in domain organisation, catalytic reactions, precursor usage and overall architectural organization, suggesting an evolutionary connection between these two biochemical pathways.

Like to PKSs, bacteria are able to perform fatty acid biosynthesis, essential for membrane phospholipids, in 3 dissimilar means. The majority of bacteria produce fatty acids via type Two FAS (like to type II PKS) past which distinct enzymes, encoded by separate genes, catalyse specific steps of the biosynthetic pathway (White, Zheng, Zhang, & Rock, 2005). The ascendant cellular fatty acids produced via type II FAS typically incorporate xiv–18 carbon atoms. An culling style, the type I FAS system (like to blazon I PKS and typical of eukaryotic organisms), is found in sure coryneform bacteria of the order Actinomycetales and consists of multifunctional enzyme complexes harbouring catalytic activities every bit detached functional domains (Schweizer & Hofmann, 2004).

Although FASs and PKSs apply the same enzymatic strategy, in contrast to type I and II PKSs, in which the 'catalytic domains' are optional, these are always nowadays in type I and II FASs.

A third bacterial mechanism of de novo fat acid synthesis occurs in a narrow group of predominately marine γ-Proteobacteria that includes species of the Shewanella, Photobacterium, Moritella, Colwellia and Vibrio genera (Donadio et al., 2007; Nichols, 2003; Nichols & McMeekin, 2002). It proceeds via a novel type I iterative fatty acid FAS/PKS enzyme complex (Metz et al., 2001), herein referred to as 'Pfa synthase', and is responsible for bacterial PUFA biosynthesis. In improver to the archetypal Pfa synthase gene products in marine bacteria, homologous type I FAS/PKS factor clusters (20 singled-out types), with high functional conservation within distinct biosynthetic pathways, have been identified in microbial lineages spanning 45 genera representing 10 phyla, suggesting that HGT has contributed to the dissemination of specialised lipid biosynthetic activities amongst different microbial lineages (Shulse & Allen, 2011).

In addition to PUFA, big-calibration analysis of sequenced microbial genomes has revealed a variety of analogous iterative type I FAS/PKS mechanisms that synthesise other long-chain fat acids having more than than 20 carbon atoms. Two examples are the C₂₆–C₃₂ alkyl bondage, containing hydroxyl and ketone functional groups plant in heterocyst glycolipids of filamentous cyanobacteria (Bauersachs et al., 2009; Campbell, Cohen, & Meeks, 1997), and the C₂₂–C₂₆ chains of phenolic lipids of dormant cysts of the Gram-negative bacterium Azotobacter vinelandii (guild Pseudomonadales) (Miyanaga, Funa, Awakawa, & Horinouchi, 2008).

The pathways in which FASs/PKSs biosynthesise bondage of more than 20 carbon atoms are usually referred to every bit 'secondary lipid biosynthesis', in club to distinguish these products from those obtained by the core (or chief) FAS mechanisms.

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Regulation of Body Weight by Malonyl-CoA in the CNS

S. Rodriguez , M.J. Wolfgang , in Encyclopedia of Biological Chemistry (2d Edition), 2013

Hypothalamic Malonyl-CoA

Inhibiting FASN either pharmacologically or genetically reduces body weight. The inhibition of FASN causes an increase in its substrate malonyl-CoA. Since malonyl-CoA serves a signaling role in muscle, it was hypothesized that malonyl-CoA could be serving a signaling office in the hypothalamus to regulate body weight. Indeed, the simultaneous inhibition of ACC and FASN reverses the weight-reducing effects of FASN inhibitors. Furthermore, exogenous addition of malonyl-CoA decarboxylase to the hypothalamus results in an increase in body weight. Finally, malonyl-CoA is dynamically regulated by meal state. Fasting suppresses hypothalamic malonyl-CoA and refeeding causes a spike in hypothalamic malonyl-CoA concentration. These experiments strongly propose that malonyl-CoA is a major nexus for the regulation of body weight ( Figure 1 ).

Figure i. Phenotypic outcomes of modulating de novo fatty acrid synthesis in the CNS. Inhibition of FASN results in weight loss, and promoting malonyl-CoA decarboxylation results in weight gain. Loss of CPT1c results in mice with a reduction in nutrient intake and weight loss.

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