Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 IC(50) values of 52 microM and 42 microM mainly by reacting on the beta-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 IC(50) values ranging from 2 to 112 microM. 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 IC(50) values range from 5 microM to 40 microM. From these results, a common model for polyphenol inhibitor of FAS is conceived.
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PMID:Inhibition of fatty acid synthase by polyphenols. 1661 Oct 78

In metabolic disorders like obesity, NAFLD and T2DM, adipocytes are dysfunctional. Hence, pharmacological interventions have importance in preventing differentiation of adipocytes and stimulating lipid uptake. We, therefore, investigated the effects of arbutin (ARB), purpurin (PUR), quercetin (QR), and pterostilbene (PTS) on adipocyte differentiation and lipid uptake using 3T3-L1 adipocytes. Further, in silico docking studies were achieved to investigate interactions of ARB, PUR, QR, and PTS with beta-ketoacyl reductase (KR) and thioesterase (TE) domains of fatty acid synthase (FAS) enzyme. Mature 3T3-L1 adipocytes were used to investigate the anti-adipogenic effect of selected pharmacological agents by Oil Red O staining and in vitro fatty acid uptake analysis. Molecular docking studies were performed to predict the binding interactions of selected compounds with KR and TE domains of FAS enzyme. All these agents significantly decrease the adipocyte differentiation and showed the stimulatory effect on fatty acid uptake in 3T3-L1 adipocytes. However, PTS and PUR proved to be anti-adipogenic, whereas ARB and QR showed significant effect on fatty acid uptake, compared to others. Similarly, all the compounds displayed significant binding interactions with KR and TE domains of FAS enzyme, supporting the results of in vitro studies. Graphical abstract.
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PMID:In vitro targeted screening and molecular docking of stilbene, quinones, and flavonoid on 3T3-L1 pre-adipocytes for anti-adipogenic actions. 3258 69