C75, a Fatty Acid Synthase Inhibitor,Inhibits Feeding Activity and Pheromone Production in a Moth,Helicoverpa zea

Fatty acid synthesis produces long-chain fatty acids that are principal forms of stored energy and essential constituents of cellular membrane lipids. In animals fatty acid synthesis is catalyzed by fatty acid synthase (FAS) from acetyl-coenyzyme A (CoA) and malonyl-CoA. Cerulenin and C75, potent FAS inhibitors, can inhibit feeding in mammals.Using these inhibitors we examined the effect of feeding inhibition during H. zea larval stage. Growth of larvae injected (30 μg/g body weight) with C75 or cerulenin was significantly delayed during the first 8 hrs after injection, but recovered to normal levels within 20 hrs. During the first 8 hr period, the amount of consumed diet in the inhibitor treated larvae was significantly less than the control group. The retardation of larval development could be caused from the reduction of food intake after injection of the inhibitor. The result indicates that C75 or cerulenin inhibits fatty acid synthesis, resulting in feeding suppression in the larval moth as demonstrated in vertebrates.Pheromone production was significantly decreased in the isolated pheromone gland of H. zea females treated with FAS inhibitors. Pheromone production was inhibited by blocking fatty acid synthesis, even though PBAN stimulated pheromone biosynthesis. After topical application of D3-16: Acid to pheromone glands the relative labeled pheromone amount was increased when the gland was incubated with C75. This result indicates that a part of the pheromone amount could be synthesized from 16: Acid directly when fatty acid synthesis was blocked. These results indicate that the inhibitors have a potential possibility to control insect feeding activity and inhibit pheromone biosynthesis in moths.     

抗肿瘤中药中脂肪酸合酶抑制剂的筛选

最新报道脂肪酸合酶(EC.2.3.1.85,Fatty acid synthase,FAS)是治疗癌症和肥胖的双重靶部位。本文对24种抗肿瘤中药进行抑制FAS活性研究。实验结果表明,这24种中药中有17种具有抑制FAS生物活性(抑制率I40%),其中9种中药抑制FAS活性较高(抑制率I70%),为寻找无毒、低成本的FAS抑制剂提供依据。     

4-Methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic Acid (C75), an Inhibitor of Fatty-acid Synthase,Suppresses the Mitochondrial Fatty Acid Synthesis Pathway and Impairs Mitochondrial Function

4-Methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic acid (C75) is a synthetic fatty-acid synthase (FASN) inhibitor with potential therapeutic effects in several cancer models. Human mitochondrial β-ketoacyl-acyl carrier protein synthase (HsmtKAS) is a key enzyme in the newly discovered mitochondrial fatty acid synthesis pathway that can produce the substrate for lipoic acid (LA) synthesis. HsmtKAS shares conserved catalytic domains with FASN, which are responsible for binding to C75. In our study, we explored the possible effect of C75 on HsmtKAS and mitochondrial function. C75 treatment decreased LA content, impaired mitochondrial function, increased reactive oxygen species content, and reduced cell viability. HsmtKAS but not FASN knockdown had an effect that was similar to C75 treatment. In addition, an LA supplement efficiently inhibited C75-induced mitochondrial dysfunction and oxidative stress. Overexpression of HsmtKAS showed cellular protection against low dose C75 addition, whereas there was no protective effect upon high dose C75 addition. In summary, the mitochondrial fatty acid synthesis pathway has a vital role in mitochondrial function. Besides FASN, C75 might also inhibit HsmtKAS, thereby reducing LA production, impairing mitochondrial function, and potentially having toxic effects. LA supplements sufficiently ameliorated the toxicity of C75, showing that a combination of C75 and LA may be a reliable cancer treatment.     

Structure of the Human Fatty Acid Synthase KS-MAT Didomain as a Framework for Inhibitor Design

The human fatty acid synthase (FAS) is a key enzyme in the metabolism of fatty acids and a target for antineoplastic and antiobesity drug development. Due to its size and flexibility, structural studies of mammalian FAS have been limited to individual domains or intermediate-resolution studies of the complete porcine FAS. We describe the high-resolution crystal structure of a large part of human FAS that encompasses the tandem domain of β-ketoacyl synthase (KS) connected by a linker domain to the malonyltransferase (MAT) domain. Hinge regions that allow for substantial flexibility of the subdomains are defined. The KS domain forms the canonical dimer, and its substrate-binding site geometry differs markedly from that of bacterial homologues but is similar to that of the porcine orthologue. The didomain structure reveals a possible way to generate a small and compact KS domain by omitting a large part of the linker and MAT domains, which could greatly aid in rapid screening of KS inhibitors. In the crystal, the MAT domain exhibits two closed conformations that differ significantly by rigid-body plasticity. This flexibility may be important for catalysis and extends the conformational space previously known for type I FAS and 6-deoxyerythronolide B synthase.     

The mTOR Inhibitor Rapamycin Synergizes with a Fatty Acid Synthase Inhibitor to Induce Cytotoxicity in ER/HER2-Positive Breast Cancer Cells

Patients with ER/HER2-positive breast cancer have a poor prognosis and are less responsive to selective estrogen receptor modulators; this is presumably due to the crosstalk between ER and HER2. Fatty acid synthase (FASN) is essential for the survival and maintenance of the malignant phenotype of breast cancer cells. An intimate relationship exists between FASN, ER and HER2. We hypothesized that FASN may be the downstream effector underlying ER/HER2 crosstalk through the PI3K/AKT/mTOR pathway in ER/HER2-positive breast cancer. The present study implicated the PI3K/AKT/mTOR pathway in the regulation of FASN expression in ER/HER2-positive breast cancer cells and demonstrated that rapamycin, an mTOR inhibitor, inhibited FASN expression. Cerulenin, a FASN inhibitor, synergized with rapamycin to induce apoptosis and inhibit cell migration and tumorigenesis in ER/HER2-positive breast cancer cells. Our findings suggest that inhibiting the mTOR-FASN axis is a promising new strategy for treating ER/HER2-positive breast cancer.     

脂肪酸合酶—特异性肿瘤治疗靶点

脂肪酸合成的产物———脂肪酸为肿瘤生长的物质和能量来源。脂肪酸合成的关键酶———脂肪酸合酶(fattyacidsynthase ,FAS)在肿瘤组织中高表达而在正常组织中含量较低 ,表明FAS可成为肿瘤治疗靶点。现就近年来有关FAS、FAS与肿瘤的关系以及FAS抑制剂等问题的研究进展进行综述。     

p63 Promotes Cell Survival through Fatty Acid Synthase

There is increasing evidence that p63, and specifically ΔNp63, plays a central role in both development and tumorigenesis by promoting epithelial cell survival. However, few studies have addressed the molecular mechanisms through which such important function is exerted. Fatty acid synthase (FASN), a key enzyme that synthesizes long-chain fatty acids and is involved in both embryogenesis and cancer, has been recently proposed as a direct target of p53 family members, including p63 and p73. Here we show that knockdown of either total or ΔN-specific p63 isoforms in squamous cell carcinoma (SCC9) or immortalized prostate epithelial (iPrEC) cells caused a decrease in cell viability by inducing apoptosis without affecting the cell cycle. p63 silencing significantly reduced both the expression and the activity of FASN. Importantly, stable overexpression of either FASN or myristoylated AKT (myr-AKT) was able to partially rescue cells from cell death induced by p63 silencing. FASN induced AKT phosphorylation and a significant reduction in cell viability was observed when FASN-overexpressing SCC9 cells were treated with an AKT inhibitor after p63 knockdown, indicating that AKT plays a major role in FASN-mediated survival. Activated AKT did not cause any alteration in the FASN protein levels but induced its activity, suggesting that the rescue from apoptosis documented in the p63-silenced cells expressing myr-AKT cells may be partially mediated by FASN. Finally, we demonstrated that p63 and FASN expression are positively associated in clinical squamous cell carcinoma samples as well as in the developing prostate. Taken together, our findings demonstrate that FASN is a functionally relevant target of p63 and is required for mediating its pro-survival effects.     

脂肪酸合成酶在肿瘤中表达的调节机制

脂肪酸合成酶（fatty acid synthase,FASN）是肿瘤脂质生成的一种关键酶,在催化脂肪酸合成的最后一步中发挥重要作用。FASN在许多肿瘤细胞中过表达而在相应的正常细胞中却不表达。有证据表明FASN是一个代谢性癌基因,在癌细胞中高表达,在肿瘤生长和存活中有重要的作用。FASN在肿瘤中的表达调节是一个很复杂的过程,包括转录水平、翻译后控制和微环境状态的影响。正确认识FASN在肿瘤中的表达调节机制和研究新的FASN抑制剂,为成功治疗肿瘤提供一种新的思路。     

何首乌提取物对脂肪酸合酶的抑制作用

最新报道脂肪酸合酶 (FAS)是治疗肥胖症的潜在靶部位 ,但目前已知的FAS抑制剂还很少 .测定表明 ,中药何首乌提取物对FAS同时具有很强的快结合可逆抑制和慢结合不可逆抑制作用 .萃取的最佳溶剂为 4 0 %乙醇水溶液 .该提取物对FAS全反应的半抑制浓度为 0 .0 0 5mg ml(以萃取时中药重量计 ) ;不可逆抑制过程为两相 ,在 0 4 6mg ml浓度下在 0 5min内快相失活超过 5 0 % ,慢相在 32min时失活达 90 % .该提取物对FAS中的酮酰还原反应有强抑制 ,半抑制浓度为 0 0 18mg ml,对烯酰还原反应有弱抑制作用 .抑制动力学分析表明 ,何首乌提取物对FAS的抑制和底物NADPH之间呈非竞争性关系 ,和丙二酰辅酶A接近竞争性关系 ,而与乙酰辅酶A为反竞争性关系 .推测何首乌还含有作用于FAS中的丙二酰转酰酶的抑制剂 .用何首乌提取物口服饲喂大鼠 ,可明显减低大鼠摄食量和降低大鼠体重 ;实验结束时实验组大鼠肝脏FAS活性低于对照组 .以上结果表明 ,中药何首乌提取物对FAS有很强的抑制作用 ,其抑制能力明显强于已知抑制剂 ,其动力学表现也和已知抑制剂完全不同 ,预计为新的抑制剂 ,对研究FAS的作用机理及在防治肥胖症的应用上可能具有重要的价值     

Fatty Acid Synthase Mediates the Epithelial-Mesenchymal Transition of Breast Cancer Cells

This study aimed to investigate the role of fatty acid synthase (FASN) in the epithelial-mesenchymal transition (EMT) of breast cancer cells. MCF-7 cells and MCF-7 cells overexpressing mitogen-activated protein kinase 5 (MCF-7-MEK5) were used in this study. MCF-7-MEK5 cells showed stable EMT characterized by increased vimentin and decreased E-cadherin expression. An In vivo animal model was established using the orthotopic injection of MCF-7 or MCF-7-MEK5 cells. Real-time quantitative PCR and western blotting were used to detect the expression levels of FASN and its downstream proteins liver fatty acid-binding protein (L-FABP) and VEGF/VEGFR-2 in both in vitro and in vivo models (nude mouse tumor tissues). In MCF-7-MEK5 cells, significantly increased expression of FASN was associated with increased levels of L-FABP and VEGF/VEGFR-2. Cerulenin inhibited MCF-7-MEK5 cell migration and EMT, and reduced FASN expression and down-stream proteins L-FABP, VEGF, and VEGFR-2. MCF-7-MEK5 cells showed higher sensitivity to Cerulenin than MCF-7 cells. Immunofluorescence revealed an increase of co-localization of FASN with VEGF on the cell membrane and with L-FABP within MCF-7-MEK5 cells. Immunohistochemistry further showed that increased percentage of FASN-positive cells in the tumor tissue was associated with increased percentages of L-FABP- and VEGF-positive cells and the Cerulenin treatment could reverse the effect. Altogether, our results suggest that FASN is essential to EMT possibly through regulating L-FABP, VEGF and VEGFR-2. This study provides a theoretical basis and potential strategy for effective suppression of malignant cells with EMT.     

来源于中药和功能性食品的脂肪酸合酶抑制剂（英文）

肥胖症及其相关疾病已成为迫切需要解决的公共卫生问题。脂肪酸合酶（fatty acid synthase,FAS）是一种多功能复合酶,对长链脂肪酸的生物合成发挥至关重要的作用,是治疗肥胖、2型糖尿病、癌症、炎症和心血管疾病等的潜在靶点。在过去的30年里,FAS抑制剂的研究受到越来越多的关注。在中国,传统中药和功能性食品广泛被应用于慢性疾病的预防和治疗,其中有多种天然产物对FAS的活性表现出很强的抑制作用。本文综述了来源于中药和功能性食品中的FAS抑制剂结构和活性特点,为天然来源的FAS抑制剂治疗肥胖症和相关疾病提供了依据。     

Evolutionary Origins of the Multienzyme Architecture of Giant Fungal Fatty Acid Synthase

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Fatty Acid Synthase Cooperates with Glyoxalase 1 to Protect against Sugar Toxicity

Fatty acid (FA) metabolism is deregulated in several human diseases including metabolic syndrome, type 2 diabetes and cancers. Therefore, FA-metabolic enzymes are potential targets for drug therapy, although the consequence of these treatments must be precisely evaluated at the organismal and cellular levels. In healthy organism, synthesis of triacylglycerols (TAGs)—composed of three FA units esterified to a glycerol backbone—is increased in response to dietary sugar. Saturation in the storage and synthesis capacity of TAGs is associated with type 2 diabetes progression. Sugar toxicity likely depends on advanced-glycation-end-products (AGEs) that form through covalent bounding between amine groups and carbonyl groups of sugar or their derivatives α-oxoaldehydes. Methylglyoxal (MG) is a highly reactive α-oxoaldehyde that is derived from glycolysis through a non-enzymatic reaction. Glyoxalase 1 (Glo1) works to neutralize MG, reducing its deleterious effects. Here, we have used the power of Drosophila genetics to generate Fatty acid synthase (FASN) mutants, allowing us to investigate the consequence of this deficiency upon sugar-supplemented diets. We found that FASN mutants are lethal but can be rescued by an appropriate lipid diet. Rescued animals do not exhibit insulin resistance, are dramatically sensitive to dietary sugar and accumulate AGEs. We show that FASN and Glo1 cooperate at systemic and cell-autonomous levels to protect against sugar toxicity. We observed that the size of FASN mutant cells decreases as dietary sucrose increases. Genetic interactions at the cell-autonomous level, where glycolytic enzymes or Glo1 were manipulated in FASN mutant cells, revealed that this sugar-dependent size reduction is a direct consequence of MG-derived-AGE accumulation. In summary, our findings indicate that FASN is dispensable for cell growth if extracellular lipids are available. In contrast, FA-synthesis appears to be required to limit a cell-autonomous accumulation of MG-derived-AGEs, supporting the notion that MG is the most deleterious α-oxoaldehyde at the intracellular level.     

AMPK-sensed cellular energy state regulates the release of extracellular Fatty Acid Synthase

Fatty Acid Synthase (FASN), a 250-kDa cytosolic multi-enzyme catalyzing eukaryotic de novo FA biogenesis, unexpectedly localizes in cancer cell culture supernatants and in the blood of cancer patients. High levels of “extracellular FASN” have recently been found in supernatants from Hepatitis C Virus-infected liver cells. The ultimate mechanism regulating FASN release, however, remained completely undefined. When the AMPK-activating drug AICAR was used to simulate an elevated AMP/ATP ratio in breast cancer cells, ELISA-based analyses revealed that extracellular FASN dramatically augmented in a dose- and time-dependent manner. Immunoblotting procedures using a battery of anti-FASN antibodies further confirmed that, in response to AMPK activation, FASN protein is depleted from the cytosol to accumulate as different FASN isoforms in the extracellular milieu. siRNA-induced blockade of AMPK expression largely attenuated AICAR-promoted FASN release. FASN release might represent a previously unrecognized mechanism through which AMPK monitor and restores cellular energy state in response to increasing AMP/ATP ratios.     

Coexpressing Escherichia coli Cyclopropane Synthase with Sterculia foetida Lysophosphatidic Acid Acyltransferase Enhances Cyclopropane Fatty Acid Accumulation

Cyclopropane fatty acids (CPAs) are desirable as renewable chemical feedstocks for the production of paints, plastics, and lubricants. Toward our goal of creating a CPA-accumulating crop, we expressed nine higher plant cyclopropane synthase (CPS) enzymes in the seeds of fad2fae1 Arabidopsis (Arabidopsis thaliana) and observed accumulation of less than 1% CPA. Surprisingly, expression of the Escherichia coli CPS gene resulted in the accumulation of up to 9.1% CPA in the seed. Coexpression of a Sterculia foetida lysophosphatidic acid acyltransferase (SfLPAT) increases CPA accumulation up to 35% in individual T1 seeds. However, seeds with more than 9% CPA exhibit wrinkled seed morphology and reduced size and oil accumulation. Seeds with more than 11% CPA exhibit strongly decreased seed germination and establishment, and no seeds with CPA more than 15% germinated. That previous reports suggest that plant CPS prefers the stereospecific numbering (sn)-1 position whereas E. coli CPS acts on sn-2 of phospholipids prompted us to investigate the preferred positions of CPS on phosphatidylcholine (PC) and triacylglycerol. Unexpectedly, in planta, E. coli CPS acts primarily on the sn-1 position of PC; coexpression of SfLPAT results in the incorporation of CPA at the sn-2 position of lysophosphatidic acid. This enables a cycle that enriches CPA at both sn-1 and sn-2 positions of PC and results in increased accumulation of CPA. These data provide proof of principle that CPA can accumulate to high levels in transgenic seeds and sets the stage for the identification of factors that will facilitate the movement of CPA from PC into triacylglycerol to produce viable seeds with additional CPA accumulation.Modified fatty acids (mFAs; sometimes referred to as unusual fatty acids) obtained from plants play important roles in industrial applications as lubricants, protective coatings, plastics, inks, cosmetics, etc. The hundreds of potential industrial uses of mFAs have led to considerable interest in exploring their production in transgenic crop plants. mFAs are produced by a limited number of species, and the transfer of genes encoding mFA-producing enzymes from source plants to heterologous hosts has generally resulted in only modest accumulation, usually less than 20% of the desired mFA in transgenic seed (Napier, 2007) compared with levels found in the natural source. For example, ricinoleic acid accounts for more than 90% of the fatty acid of castor bean (Ricinus communis) seeds, and tung (Aleuites fordii) seeds accumulate more than 80% α-eleostearic acid (Thelen and Ohlrogge, 2002; Drexler et al., 2003). In order to elevate the content of mFAs in the engineered plants to that found in the native plant, it is necessary to (1) optimize the synthesis of mFA (Mekhedov et al., 2001), (2) minimize its degradation (Eccleston and Ohlrogge, 1998), and (3) optimize its incorporation into triacylglycerol (TAG; Bafor et al., 1990; Bates and Browse, 2011; van Erp et al., 2011).Cyclic fatty acids (CFAs) are desirable for numerous industrial applications. The strained bond angles of the carbocyclic ring contribute to their unique chemistry and physical properties, and hydrogenation of CFAs results in ring opening to produce methyl-branched fatty acids. Branched chain fatty acids are ideally suited for the oleochemical industry as feedstocks for the production of lubricants, plastics, paints, dyes, and coatings (Carlsson et al., 2011). Cyclopropane fatty acids (CPAs) have been found in certain gymnosperms, Malvales, Litchi spp., and other Sapindales species. They accumulate to as much as 40% in seeds of Litchi chinensis (Vickery, 1980; Gaydou et al., 1993). Sterculia foetida accumulates the desaturated CFA (i.e. cyclopropene fatty acid) to more than 60% of its seed oil (Bohannon and Kleiman, 1978; Pasha and Ahmad, 1992). The first step in its synthesis is the formation of the CPA by the cyclopropane synthase (CPS) enzyme, which transfers a methyl group to C9 of the oleoyl-phospholipid followed by cyclization to form the cyclopropane ring (Grogan and Cronan, 1997; Bao et al., 2002, 2003). None of the known natural sources of CPA are suitable for its commercial production. Therefore, it would be desirable to create an oilseed crop plant that accumulates high levels of CPA by heterologously expressing CPS in seeds. However, to date, heterologous expression of plant cyclopropane synthase genes has led to only approximately 1.0% CPA in the transgenic seeds (Yu et al., 2011).Two pathways for the biosynthesis of TAG exist in plants (Bates and Browse, 2012; Fig. 1). The de novo biosynthesis from glycerol-3-phosphate and acyl-CoA occurs via the Kennedy pathway and includes three acyltransferases: glycerol-2-phosphate acyltransferase, acyl-CoA:lysophosphatidic acid acyltransferase (LPAT), and acyl-CoA:diacylglycerol acyltransferase (DGAT; Kennedy, 1961). Alternatively, acyl-CoAs can be redirected from phosphatidylcholine (PC) via the action of a phospholipase C, choline phosphotransferase, phosphatidylcholine:diacylglycerol cholinephosphotransferase (PDCT; Hu et al., 2012; Lu et al., 2009), or phospholipid:diacylglycerol acyltransferase (PDAT; Dahlqvist et al., 2000). An acyl group can be released from PC to generate lysophosphatidylcholine (LPC) by the back reaction of acyl-CoA:LPC acyltransferase (Stymne and Stobart, 1984; Wang et al., 2012) or a phospholipase A/acyl-CoA synthase (Chen et al., 2011).Open in a separate windowFigure 1.Schematic representation of the plant TAG biosynthesis network. Acyl editing can provide PC-modified fatty acids for de novo diacylglycerol/TAG synthesis. ACS, acyl-CoA synthase; CPT, CDP-choline:diacylglycerol choline phosphotransferase; G3P, glycerol-3-phosphate; GPAT, acyl-CoA:glycerol-3-phosphate acyltransferase; LPC acyltransferase, acyl-CoA:LPC acyltransferase; mFAS, modified fatty acid synthase (in this work, mFAS is CPS); PAP, phosphatidic acid phosphatase; PLA, phospholipase A; PLC, phospholipase C.LPAT is a pivotal enzyme controlling the metabolic flow of lysophosphatidic acid (LPA) into different phosphatidic acids (PAs) in diverse tissues. Membrane-associated LPAT activities, identified in bacteria, yeast, plant, and animal cells, catalyze the transfer of acyl groups from acyl-CoA to LPA to synthesize PA. In plants and other organisms, LPAT activities have been identified in the endoplasmic reticulum (Kim et al., 2005), plasma membrane (Bursten et al., 1991), and mitochondria (Zborowski and Wojtczak, 1969). In higher plants, endoplasmic reticulum-localized LPAT plays an essential role transferring fatty acid from CoA esters to the sn-2 position of LPA in the synthesis of PA, a key intermediate in the biosynthesis of membrane phospholipids and storage lipids in developing seeds (Maisonneuve et al., 2010). LPAT from developing seeds of flax (Linum usitatissimum), rape (Brassica napus), and castor bean preferentially incorporate oleoyl-CoA, weakly incorporate cyclopropane acyl-CoA, and were unable to incorporate methyl-branched acyl-CoA when presented with an equimolar mix of these potential substrates (Nlandu Mputu et al., 2009). Thus, LPAT activity from agronomic plants constitutes a potential bottleneck for the incorporation of branched chain acyl-CoA into PA. In this work, we investigate the utility of an LPAT from a cyclopropanoid-syntheizing plant, S. foetida, with respect to its ability to enhance CPA accumulation. In our efforts to enhance CPA accumulation in transgenic plants, we screened CPS genes from diverse sources and identified Escherichia coli CPS (EcCPS) as an effective enzyme for the production of CPA in plants. However, EcCPS is reported to prefer the sn-2 position of E. coli phospholipid (Hildebrand and Law, 1964), and the data presented here show that its expression primarily leads to the accumulation of CPA at the stereospecific numbering (sn)-1 position. Moreover, coexpression of S. foetida lysophosphatidic acid acyltransferase (SfLPAT) results in the incorporation of CPA at the sn-2 position of LPA. Thus, coexpression of EcCPS and SfLPAT enables a cycle that enriches the accumulation of CPA at both sn-1 and sn-2 positions of PC and increases the accumulation of CPA. This work underscores the utility of coexpressing an acyltransferase from mFA-accumulating species with mFA-synthesizing enzymes to help mitigate bottlenecks in mFA TAG synthesis.     

Structure and Conformational Variability of the Mycobacterium tuberculosis Fatty Acid Synthase Multienzyme Complex

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银杏叶丙酮提取物对动物脂肪酸合酶的抑制

银杏叶丙酮提取物(AEGL)对动物脂肪酸合酶(FAS)有强抑制作用。选定的萃取条件是室温下用60%丙酮搅拌萃取30~60min。该萃取液IC50值为4.66μg/mL,抑制能力明显强于已知的FAS抑制剂,有效物的初步分离显示,对FAS有抑制作用的成分可能存在于黄酮组分中。酶学动力学研究表明,抑制包含可逆抑制和不可逆抑制两部分。推测酮酰还原功能域(KR)的NADPH结合部位是其作用部位之一。标准银杏叶提取物EGb761对FAS的可逆抑制和不可逆抑制都明显比银杏叶的60%丙酮萃取液弱,后者对NADPH呈现比较明显的竞争性,不同于EGb761,这表明银杏叶还具有新的应用开发领域。     

Presence of Fatty Acid Synthase Inhibitors in the Rhizome of Alpinia officinarum Hance

The galangal (the rhizome of Alpinia officinarum, Hance) is popular in Asia as a traditional herbal medicine. The present study reports that the galangal extract (GE) can potently inhibit fatty-acid synthase (FAS, E.C.2.3.1.85). The inhibition consists of both reversible inhibition with an IC50 value of 1.73?μg?dried?GE/ml, and biphasic slow-binding inactivation. Subsequently the reversible inhibition and slow-binding inactivation to FAS were further studied. The inhibition of FAS by galangin, quercetin and kaempferol, which are the main flavonoids existing in the galangal, showed that quercetin and kaempferol had potent reversible inhibitory activity, but all three flavonoids had no obvious slow-binding inactivation. Analysis of the kinetic results led to the conclusion that the inhibitory mechanism of GE is totally different from that of some other previously reported inhibitors of FAS, such as cerulenin, EGCG (epigallocatechin gallate) and C75.