Abstract
Recently, animal fatty acid synthase (FAS) is reported as a potential therapeutic target for obesity and cancer. Considerable interest has been developed in identifying novel inhibitors of the enzyme. It is found that tea polyphenols inhibit FAS in both reversible and irreversible manners. Epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) inhibit FAS with IC50 values of 52 μM and 42 μM mainly by reacting on the β-ketoacyl reductase (KR) domain of FAS. The inhibitory ability of catechin gallate (CG) is 15 and 12 folds higher than that of EGCG and ECG. Its major reacting site on FAS is not KR. All of these irreversibly inactivate FAS on the KR domain with similar rates. Mulliken population analysis suggests that the positive charge is distributed on the carbon atom of galloyl ester, and this carbon becomes more susceptible for a nucleophilic attack. 12 flavonoids inhibit FAS with IC50 values ranging from 2 to 112 μM. SAR analysis shows that the flavonoids containing two hydroxyl groups in B ring and 5, 7-hydroxyl groups in A ring with C-2, 3 double bond are the most potent inhibitors. The inhibition kinetics shows that they inhibit FAS competitively with acetyl CoA and most likely react mainly on acyl transferase domain. Further studies show that C ring of flavonoids is not necessary for the inhibition. Resveratrol, phlorizin and NDGA contain two phenyl rings connected by 2 to 4 atom chains instead of C ring. Their IC50 values range from 5 μM to 40μM. From these results, a common model for polyphenol inhibitor of FAS is conceived.
Keywords: Fatty acid synthase, inhibition, polyphenols, catechins, theaflavins, flavonoids, obesity, cancer
Current Medicinal Chemistry
Title: Inhibition of Fatty Acid Synthase by Polyphenols
Volume: 13 Issue: 8
Author(s): Wei-Xi Tian
Affiliation:
Keywords: Fatty acid synthase, inhibition, polyphenols, catechins, theaflavins, flavonoids, obesity, cancer
Abstract: Recently, animal fatty acid synthase (FAS) is reported as a potential therapeutic target for obesity and cancer. Considerable interest has been developed in identifying novel inhibitors of the enzyme. It is found that tea polyphenols inhibit FAS in both reversible and irreversible manners. Epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) inhibit FAS with IC50 values of 52 μM and 42 μM mainly by reacting on the β-ketoacyl reductase (KR) domain of FAS. The inhibitory ability of catechin gallate (CG) is 15 and 12 folds higher than that of EGCG and ECG. Its major reacting site on FAS is not KR. All of these irreversibly inactivate FAS on the KR domain with similar rates. Mulliken population analysis suggests that the positive charge is distributed on the carbon atom of galloyl ester, and this carbon becomes more susceptible for a nucleophilic attack. 12 flavonoids inhibit FAS with IC50 values ranging from 2 to 112 μM. SAR analysis shows that the flavonoids containing two hydroxyl groups in B ring and 5, 7-hydroxyl groups in A ring with C-2, 3 double bond are the most potent inhibitors. The inhibition kinetics shows that they inhibit FAS competitively with acetyl CoA and most likely react mainly on acyl transferase domain. Further studies show that C ring of flavonoids is not necessary for the inhibition. Resveratrol, phlorizin and NDGA contain two phenyl rings connected by 2 to 4 atom chains instead of C ring. Their IC50 values range from 5 μM to 40μM. From these results, a common model for polyphenol inhibitor of FAS is conceived.
Export Options
About this article
Cite this article as:
Tian Wei-Xi, Inhibition of Fatty Acid Synthase by Polyphenols, Current Medicinal Chemistry 2006; 13 (8) . https://dx.doi.org/10.2174/092986706776361012
DOI https://dx.doi.org/10.2174/092986706776361012 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Current Status and Future Directions of Nanoparticulate Strategy for Cancer Immunotherapy
Current Drug Metabolism Calcimimetic Drugs and Biomarkers
Recent Patents on Biomarkers Treatment of HCV-Related Mixed Cryoglobulinemia
Current Drug Targets Zebrafish As a Genetic Model in Pre-Clinical Drug Testing and Screening
Current Medicinal Chemistry The Role of HLA Promoters in Autoimmunity
Current Pharmaceutical Design Emerging Therapeutic Approaches Based on Nanotechnology for the Treatment of Diseases Associated with Telomere Dysfunction
Mini-Reviews in Medicinal Chemistry Angiogenic and Antiangiogenic Factors in Proliferative Diabetic Retinopathy
Current Diabetes Reviews Review of the Contribution of Radiolabelled Tracers for Tumour Cell Status Imaging
Current Medical Imaging The Antidepressant-like Effects of Estrogen-mediated Ghrelin
Current Neuropharmacology Do Not Say Ever Never More: The Ins and Outs of Antiangiogenic Therapies
Current Pharmaceutical Design Natural Compounds as Anticancer Agents Targeting DNA Topoisomerases
Current Genomics The Ca2+-Activated K+ Channel of Intermediate Conductance:A Molecular Target for Novel Treatments?
Current Drug Targets Relationship between CNS and Immunology: Correlation with Psychology
Current Drug Metabolism The Close Interplay of Nitro-Oxidative Stress, Advanced Glycation end Products and Inflammation in Inflammatory Bowel Diseases
Current Medicinal Chemistry QSAR and Complex Network Recognition of miRNAs in Stem Cells
Current Bioinformatics A Systems Biology Road Map for the Discovery of Drugs Targeting Cancer Cell Metabolism
Current Pharmaceutical Design CRM1-Mediated Nuclear Export of Proteins and Drug Resistance in Cancer
Current Medicinal Chemistry Modulation of k-Ras Signaling by Natural Products
Current Medicinal Chemistry Multiple Functions of Mammalian Germinal Center Kinases
Current Chemical Biology Procathepsin D as a Tumor Marker, Anti-Cancer Drug or Screening Agent
Anti-Cancer Agents in Medicinal Chemistry