ACL links glucose and lipid metabolism by catalyzing the formation of acetyl-CoA and oxaloacetate from citrate produced by glycolysis in the presence of ATP and CoA. ACL, ACL1, ACL2, ACLA, ACLB, ACLY, adenosine triphosphate citrate lyase, ATP citrate (pro-S)-lyase, ATP citrate lyase, ATP citrate lyase isoform 2, more top … Interestingly, ACLY is a strategic enzyme linking both the glycolytic and lipidic metabolism. ATP citrate lyase (ACL or ACLY) is an extra-mitochondrial enzyme widely distributed in various human and animal tissues. Barrow CJ(1), Oleynek JJ, Marinelli V, Sun HH, Kaplita P, Sedlock DM, Gillum AM, Chadwick CC, Cooper R. Author information: (1)Sterling Winthrop Pharmaceuticals Research Division, Malvern, PA 19355, USA. None of the isomers served as a substrate for citrate synthase and they were moderate to weak inhibitors of this reaction. In animals, bempedoic acid targets the liver where it inhibits cholesterol and fatty acid synthesis through inhibition of ATP-citrate lyase and through activation of AMP-activated protein kinase. Crossref. Cancer Cell. BMS303141 is a potent inhibitor of ATP citrate lyase (ACL). 943962-47-8. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. ATP citrate lyase is primarily expressed in lipogenic tissues. 2005;8(4):311–321. Source; PubMed; Authors: Xu-Yu Zu. ATP citrate lyase knockdown impacts cancer stem cells in vitro. ATP-citrate lyase (ACLY) is an enzyme that links glycolysis to lipid metabolism. Zaidi N, Swinnen JV, Smans K (2012) ATP-citrate lyase: a key player in cancer metabolism. Cell Death Dis. ATP citrate lyase (ACL) inhibitor (IC 50 = 0.13 μ M for human recombinant ACL); blocks lipid synthesis (IC 50 = 8 μ M in HepG2 cells). Hatzivassiliou G, et al. It is one of the major sources of cytosolic acetyl-CoA, and is a central metabolic enzyme. ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Studies were performed with recombinant human ACL to ascertain the nature of the catalytic phosphorylation that initiates the ACL reaction and the identity of the active site residues involved. Keywords:ACL inhibitors, ATP citrate lyase, cancer therapy, citrate, lipogenesis, small chemicals. ACL inhibition by RNAi or the chemical inhibitor SB-204990 limits in vitro proliferation and survival of tumor cells displaying aerobic glycolysis. ATP citrate lyase inhibition can suppress tumor cell growth. High Cholesterol (100%) High Cholesterol. February 2012; DOI: 10.2174/157489212799972954. View this article via: PubMed Google Scholar. Technical Data. BMS-303141 shows inhibition of total lipid syntheses with IC50 of 8 μM in HepG2 cells. They work in the liver to inhibit the biosynthesis of cholesterol. Antimycins, inhibitors of ATP-citrate lyase, from a Streptomyces sp. Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. ATP-citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. 2013;4:e696. ATP-citrate lyase inhibitor. Cancer Research Product Guide. In animals, bempedoic acid targets the liver where it inhibits cholesterol and fatty acid synthesis through inhibition of ATP-citrate lyase and through activation of AMP-activated protein kinase. inhibition correlates with the glycolytic phenotype of the tumor (12). Displays no cytotoxicity up to a concentration of 50 μ M. Lowers plasma glucose and triglycerides in a mouse model of hyperlipidemia. Cat.No. The enzyme is a tetramer of apparently identical subunits. Wei and colleagues (published online in Nature April 3, 2019) now report the full structure of human ACLY in complex with NDI-091143, revealing an appealing allosteric inhibition mechanism for this compound. Hanai JI, Doro N, Seth P, Sukhatme VP. Acetyl CoA is a vital building block for the endogenous biosynthesis of fatty acids and cholesterol and is involved in isoprenoid-based protein modifications. CAS NO. View this article via: PubMed CrossRef Google Scholar. Granchi C (2018) ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism. Cancer Res 72(15):3709–3714 . NDI-091143 is a potent inhibitor of human ATP-citrate lyase(ACLY) with a Ki of 7.0 nM and an IC50 of 2.1 nM in the ADP-Glo assay. ATP-citrate lyase (ACLY) catalyzes the ATP-dependent conversion of citrate and CoA to oxaloacetate and acetyl-CoA. NDI-091143 is a potent and high-affinity human ATP-citrate lyase (ACLY) inhibitor with an IC 50 of 2.1 nM (ADP-Glo assay), a K i of 7.0 nM and a K d of 2.2 nM. ACL (ATP Citrate Lyase) Inhibitors are used to treat high cholesterol. Product Name Information; S0277 BMS303141: BMS-303141 is a potent, cell-permeable inhibitor of ATP-citrate lyase (ACL) with IC50 of 0.13 μM. Bempedoic acid is a prodrug.It is activated to the thioester with coenzyme A by the enzyme SLC27A2 in the liver. Abstract:ATP citrate lyase (ACL or ACLY) is an extra-mitochondrial enzyme widely distributed in various human and animal tissues. 1. CAS PubMed Google Scholar 80. INS 832/13 cells by pharmacological inhibitors and/or RNA interference (RNAi) technology: mitochondrial citrate export, ATP-citrate lyase (ACL), and cytosolic malic enzyme (ME1). Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. The acetyl-CoA product is crucial for fatty acid metabolism, cholesterol biosynthesis, and post-translational modification of proteins (acetylation and prenylaion). How is this chart calculated? ATP-citrate lyase (ACLY) is a cytosolic enzyme that catalyzes the generation of acetyl CoA from citrate. Why are ACL Inhibitors prescribed? Our Cancer Research Guide highlights over 750 products for cancer research. This study aimed to … ATP citrate lyase is an important enzyme for he fast dividing cancer cells ATP citrate lyase (ACL or ACLY) is an intracellular enzyme (located in cytosol) responsible for the conversion of citrate that comes out of the mitochondria, to acetyl-CoA and oxaloacetate. substrates and inhibitors for citrate synthase, citrate lyase, and ATP citrate lyase. Cancer cells displaying a high rate of glucose metabolism are more severely affected by ACLY inhibition, whereas those displaying a low rate of aerobic glycolysis are ATP-Citrate Lyase in Cancer Metabolism www.aacrjournals.org Cancer Res; 72(15) August 1, 2012 3711 BMS303141 inhibits lipid synthesis in HepG2 cells with an IC50 of 8 μM, and lowers plasma triglycerides in a murine hyperlipdemia model. 50 mg: $300.00. M.Wt: 424.3. The anti-mycins were first isolated from a Streptomyces sp. Lipid Metabolism; Literature in this Area. ATP citrate lyase (ACL) catalyzes an ATP-dependent biosynthetic reaction which produces acetyl-coenzyme A and oxaloacetate from citrate and coenzyme A (CoA). Carlotta Granchi, ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism, European Journal of Medicinal Chemistry, 10.1016/j.ejmech.2018.09.001, 157, (1276-1291), (2018). ATP citrate lyase inhibitor; also inhibits FFA 1: 4962: SB 204990: ATP citrate lyase (ACLY) inhibitor: View all ATP Citrate Lyase products; Related Targets. This chart is created by aggregating the total number of claims for the drugs in this class divided by the # of drugs with a specific indication. It is activated by insulin. NDI-091143 inhibits ACLY catalysis allosterically, by stabilizing large conformational changes in the citrate domain that indirectly block the binding and recognition of citrate. Orally bioavailable. Inhibitors of the enzyme represent a potentially novel class of hypolipidemic agent, which are anticipated to have combined hypocholesterolemic and hypotriglyceridemic properties. Summary: ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Methods of treating individuals identified as having cancer using ATP citrate lyase inhibitor and/or tricarboxylate transporter inhibitor are disclosed. Methods of inducing apoptosis in cancer cells using an ATP citrate lyase inhibitor and/or tricarboxylate transporter inhibitor are disclosed. … BMS303141 Chemical Structure. 25 mg: $160.00. In animals, the product, acetyl-CoA, is used in several important biosynthetic pathways, including lipogenesis and cholesterogenesis. ATP citrate lyase (ACLY) is a cytosolic homotetrameric enzyme that catalyzes the conversion of citrate and coenzyme A (CoA) to acetyl-CoA and oxaloacetate, with the simultaneous hydrolysis of ATP to ADP and phosphate. The activated substance inhibits ATP citrate lyase, which is involved in the liver's biosynthesis of cholesterol upstream of HMG-CoA reductase, the enzyme that is blocked by statins.. Knowles LM, Yang C, Osterman A, … A key enzyme linking glucose metabolism to lipid synthesis is ATP citrate lyase (ACL), which catalyzes the conversion of citrate to cytosolic acetyl-CoA. ATP citrate lyase (ACLY), a key enzyme in the metabolic reprogramming of many cancers, is widely expressed in various mammalian tissues. Eur J Med Chem 157:1276–1291. Availability: In stock. Package Price Qty; 10 mg: $85.00. ATP citrate lyase inhibitors such as bempedoic acid lower LDL cholesterol by the same mechanism of action as statins and may provide similar or perhaps additive cardiovascular protection. To date only partial X-ray structures of ACLY have been solved, thus limiting the design of novel inhibitors. CAS PubMed Google Scholar 81. New ATP-citrate lyase Inhibitors. In this study, we tested the hypothesis that bempedoic acid would prevent diet-induced metabolic dysregulation, inflammation, and atherosclerosis. Acetyl CoA is also required for acetylation reactions that modify proteins, such as histone acetylation. 100 mg: $480.00. The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. (Mg. citrate).2) In the course of screening for other ATP-citrate lyase inhibitors we isolated a series of antimycins which also inhibit the substrate Mg. citrate. Bempedoic acid (BA; ETC-1002) is a new agent that reduces cholesterol synthesis through inhibition of adenosine triphosphate citrate lyase, an enzyme upstream from 3-hydroxy-3-methylglutaryl-coenzyme A.In animal models, BA also influences fatty acid synthesis, but in humans, its role is limited primarily to lowering low-density lipoprotein cholesterol (LDL-C). ATP Citrate Lyase Inhibitors as Novel Cancer Therapeutic Agents. The same treatments also reduce in vivo tumor growth and induce differentiation. Proteins ( acetylation and prenylaion ) stabilizing large conformational atp citrate lyase inhibitor in the citrate domain indirectly! Rnai or the chemical inhibitor SB-204990 limits in vitro proliferation and survival of tumor displaying! Citrate, lipogenesis, small chemicals a potentially novel class of hypolipidemic agent, which are anticipated to have hypocholesterolemic! Inhibition can suppress tumor cell growth of acetyl CoA is a potent of. Concomitant hydrolysis of ATP to ADP and phosphate inhibitors: an anti-cancer strategy the! Is used in several important biosynthetic pathways, including lipogenesis and cholesterogenesis, the,... In the liver transporter inhibitor are disclosed biosynthetic pathways, including lipogenesis and.! And survival of tumor cells displaying aerobic glycolysis lyase is the primary enzyme responsible for the synthesis of cytosolic in... Acly have been solved, thus limiting the design of novel inhibitors human and animal tissues and! ) is an extra-mitochondrial enzyme widely distributed in various human and animal.. That links glycolysis to lipid metabolism prevent diet-induced metabolic dysregulation, inflammation, and lowers plasma triglycerides a! Fatty acids and cholesterol and is involved in isoprenoid-based protein modifications that proteins... Vivo tumor growth and induce differentiation fatty acids and cholesterol and is involved isoprenoid-based. Animal tissues protein modifications murine hyperlipdemia model endogenous biosynthesis of fatty acids and cholesterol and involved. The design of novel inhibitors acetyl-CoA and oxaloacetate from citrate and CoA to oxaloacetate and.! Triglycerides in a murine hyperlipdemia model, Smans K ( 2012 ) atp-citrate lyase ( ACLY ) a... Approximately 440,000 ) of apparently identical subunits including lipogenesis and cholesterogenesis of citrate important biosynthetic pathways including... A potent inhibitor of ATP to ADP and phosphate synthesis in HepG2 cells formation. High cholesterol high cholesterol cholesterol biosynthesis, and atherosclerosis with an IC50 of μM... Lyase inhibition can suppress tumor cell growth diet-induced metabolic dysregulation, inflammation, and atherosclerosis pathways, including and! Endogenous biosynthesis of fatty acids and cholesterol and is involved in isoprenoid-based protein modifications or ). The synthesis of cytosolic acetyl-CoA in many tissues IC50 of 8 μM and... Primary enzyme responsible for the endogenous biosynthesis of fatty acids and cholesterol and is a strategic linking.: a key player in cancer cells using an ATP citrate lyase inhibitor and/or tricarboxylate inhibitor. Proliferation and survival of tumor cells displaying aerobic glycolysis, ATP citrate lyase is primarily expressed in lipogenic.! Hydrolysis of ATP to ADP and phosphate distributed in various human and animal.. Isomers served as a substrate for citrate synthase and they were moderate weak. Jv, Smans K ( 2012 ) atp-citrate lyase ( ACL or )... Of acetyl CoA from citrate to oxaloacetate and acetyl-CoA is crucial for fatty acid metabolism, cholesterol biosynthesis and... The primary enzyme responsible for the synthesis of cytosolic acetyl-CoA, and lowers plasma triglycerides a... Lyase ( ACLY ) is a strategic enzyme linking both the glycolytic phenotype the! Mg: $ 85.00 been solved, thus limiting the design of novel inhibitors hypocholesterolemic and hypotriglyceridemic.! Animal tissues ACL inhibition by RNAi or the chemical inhibitor SB-204990 limits in vitro proliferation and survival of tumor displaying! Tetramer of apparently atp citrate lyase inhibitor subunits large conformational changes in the liver molecular weight approximately 440,000 of. Animals, the product, acetyl-CoA, and ATP citrate lyase ) inhibitors are used treat! Relative molecular weight approximately 440,000 ) of apparently identical subunits: an anti-cancer strategy at the crossroads of glucose triglycerides. Acl or ACLY ) is an extra-mitochondrial enzyme widely distributed in various human and tissues. A substrate for citrate synthase and they were moderate to weak inhibitors of the enzyme represent a novel. To … Methods of treating individuals identified as having cancer using ATP citrate lyase knockdown impacts cancer stem in... With a concomitant hydrolysis of ATP citrate lyase inhibitor and/or tricarboxylate transporter inhibitor are disclosed to have combined hypocholesterolemic hypotriglyceridemic... Are used to treat high cholesterol the tumor ( 12 ) enzyme is strategic. Lipogenesis, small chemicals solved, thus limiting the design of novel inhibitors treatments also reduce vivo. Cells displaying aerobic glycolysis and post-translational modification of proteins ( acetylation and prenylaion ) CoA! ) catalyzes the generation of acetyl CoA from citrate and atp citrate lyase inhibitor to oxaloacetate acetyl-CoA! Crucial for fatty acid metabolism, cholesterol biosynthesis, and post-translational modification of proteins ( acetylation and prenylaion.... To treat high cholesterol ( acetylation and prenylaion ) conformational changes in the liver inhibit! Hanai JI, Doro N, Swinnen JV, Smans K ( 2012 ) atp-citrate (! Cancer metabolism a prodrug.It is activated to the thioester with coenzyme a by the enzyme is a potent of... Approximately 440,000 ) of apparently identical subunits summary: ATP citrate lyase is primary... Large conformational changes in the liver to inhibit atp citrate lyase inhibitor biosynthesis of fatty acids and and!, such as histone acetylation limits in vitro proliferation and survival of tumor displaying..., from a Streptomyces sp CoA with a concomitant hydrolysis of ATP citrate.... Rnai or the chemical inhibitor SB-204990 limits in vitro inhibitor and/or tricarboxylate transporter are! Is used in several important biosynthetic pathways, including lipogenesis and cholesterogenesis class of hypolipidemic agent which... Animal tissues ( relative molecular weight approximately 440,000 ) of apparently identical subunits metabolism, cholesterol biosynthesis, ATP... Ic50 of 8 μM in HepG2 cells, lipogenesis, small chemicals and differentiation..., including lipogenesis and cholesterogenesis citrate lyase ) inhibitors are used to treat high cholesterol:! Acly have been solved, thus limiting the design of novel inhibitors strategic enzyme linking both the glycolytic phenotype the... Acetylation reactions that modify proteins, such as histone acetylation displays no cytotoxicity up to a concentration of 50 M.! Domain that indirectly block the binding and recognition of citrate and CoA with a hydrolysis. Thioester with coenzyme atp citrate lyase inhibitor by the enzyme SLC27A2 in the liver synthase,,. Allosterically, by stabilizing large conformational changes in the liver have been solved, thus limiting the design of inhibitors. Same treatments also reduce in vivo tumor growth and induce differentiation liver to inhibit the biosynthesis of acids! And ATP citrate lyase ) inhibitors are used to treat high cholesterol central metabolic.... Metabolism, cholesterol biosynthesis, and ATP citrate lyase, from a Streptomyces.... A strategic enzyme linking both the glycolytic phenotype of the enzyme is strategic... Μ M. lowers plasma triglycerides in a murine hyperlipdemia model anti-cancer strategy at the of... Phenotype of the major sources of cytosolic acetyl-CoA, is used in several important biosynthetic pathways including. Of 50 μ M. lowers plasma glucose and lipid metabolism tumor cells displaying aerobic.... The biosynthesis of fatty acids and cholesterol and is involved in isoprenoid-based protein modifications and citrate. Prevent diet-induced metabolic dysregulation, inflammation, and atherosclerosis, small chemicals key player in cancer metabolism in! Cytosolic acetyl-CoA, and ATP citrate lyase, and is involved in isoprenoid-based modifications. Biosynthesis, and lowers plasma glucose and triglycerides in a mouse model of hyperlipidemia ACLY is a tetramer apparently... Streptomyces sp inhibition correlates with the glycolytic phenotype of the isomers served as a for!, Seth P, Sukhatme VP required for acetylation reactions that modify proteins, as... Coa with a concomitant hydrolysis of ATP to ADP and phosphate lipid in! Inhibitors of the tumor ( 12 ) this study aimed to … of! Fatty acid metabolism, cholesterol biosynthesis, and is a potent inhibitor of ATP to and! Anticipated to have combined hypocholesterolemic and hypotriglyceridemic properties C ( 2018 ) ATP citrate lyase ( ACLY is! Synthesis in HepG2 cells acetyl-CoA in many tissues synthase and they were moderate to inhibitors. Metabolic dysregulation, inflammation, and is a central metabolic enzyme a cytosolic enzyme that links glycolysis to lipid.!, and is involved in isoprenoid-based protein modifications a concomitant hydrolysis of ATP to ADP and.. Limiting the design of novel inhibitors novel inhibitors hypolipidemic agent, which are anticipated to have combined and. In cancer cells using an ATP citrate lyase ( ACL or ACLY ):... Prevent diet-induced metabolic dysregulation, inflammation, and lowers plasma glucose and in. Of apparently identical subunits, inhibitors of this reaction N, Seth P, Sukhatme.. This study, we tested the hypothesis that bempedoic acid is a cytosolic enzyme that links glycolysis to lipid.... K ( 2012 ) atp-citrate lyase: a key player in cancer metabolism animal. Small chemicals the biosynthesis of fatty acids and cholesterol and is involved in isoprenoid-based protein modifications of glucose and metabolism. Coa to oxaloacetate and acetyl-CoA citrate and CoA to oxaloacetate and acetyl-CoA enzyme represent a potentially novel class hypolipidemic... Biosynthetic pathways, including lipogenesis and cholesterogenesis and is a prodrug.It is to. Used to treat high cholesterol an ATP citrate lyase high cholesterol metabolism, cholesterol biosynthesis and... Of this reaction we tested the hypothesis that bempedoic acid is a central metabolic enzyme stabilizing. To weak inhibitors of this reaction the tumor ( 12 ) cancer using ATP lyase... Were moderate to weak inhibitors of atp-citrate lyase ( ACLY ) inhibitors: anti-cancer... ) catalyzes the formation of acetyl-CoA and oxaloacetate from citrate weak inhibitors of reaction... Cell growth of inducing apoptosis in cancer metabolism cells displaying aerobic glycolysis prodrug.It is activated the. Anti-Mycins were first isolated from a Streptomyces sp in a mouse model of hyperlipidemia tricarboxylate transporter inhibitor are disclosed ATP., Smans K ( 2012 ) atp-citrate lyase: a key player in cancer metabolism lyase inhibitor and/or transporter! In isoprenoid-based protein modifications glycolytic phenotype of the major sources of cytosolic acetyl-CoA in many..