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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
These drugs comprise statins, fibrates, niacin, Ezetimibe, and bile acid sequestrants as well as phytosterols and (n − 3) long-chain polyunsaturated fatty acids that can reduce circulating triglycerides and raise HDL-cholesterol (Micallef and Garg, 2008), and Orlistat (Tetrahydrolipstatin) that is derived from Lipstatin (its biosynthesis has been reported by Bai et al., 2014), isolated from Streptomyces toxytricini and acting as a potent and selective inhibitor of human pancreatic lipase. Orlistat is used as drug to treat obesity; as a consequence of inhibiting lipase activity, triglycerides from the diet are not hydrolyzed and therefore excreted unchanged. Phytosterols, omega-3 fatty acids, and Orlistat are not treated here in more detail.
Pharmacological Treatment of Obesity
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Amie A. Ogunsakin, Ayotunde O. Dokun
Orlistat is a lipase inhibitor that reduces fat absorption from intestines. It was FDA approved in 1999. Orlistat, a semisynthetic derivative of lipstatin, is a potent and selective inhibitor of these enzymes, with little or no activity against amylase, trypsin, chymotrypsin, and phospholipases. Orlistat acts by binding covalently to the serine residue of the active site of gastric and pancreatic lipases (Figure 7.1). When administered with fat-containing foods, orlistat partially inhibits hydrolysis of triglycerides, thus reducing the subsequent absorption of monoacylglycerides and free fatty acids [60–62]. Orlistat blocks absorption of 25%–30% of fat calories and is not appreciably absorbed systemically. The drug is available over the counter at a dosage of 60 mg TID. The recommended prescription dosage is 120 mg TID, and this dose should not be exceeded, as there is no evidence from clinical trials that efficacy is greater at higher dosages. Orlistat 120 mg TID has been studied and approved for treatment of adolescents with obesity [23,31,33].
Anti-Obesity Potential of Indian Traditional Medicinal Plants and Their Phytochemicals
Published in Parimelazhagan Thangaraj, Medicinal Plants, 2018
Vellingiri Vadivel, Pichai Venkatalakshmi, Pemaiah Brindha
Since dietary lipids represent the major source of unwanted calories, the inhibition of fat digestion is an interesting approach for reducing fat absorption (Bray and Ryan 2007). Orlistat is the only authorized anti-obese drug in Europe and has been shown to act through the inhibition of pancreatic lipase, which is a key enzyme for the digestion of dietary triglycerides (McClendon et al. 2007). Orlistat is the saturated derivative of lipstatin (Figure 7.3), an inhibitor of pancreatic lipase isolated from the bacterium Streptomyces toxytricini (Weibel et al. 1987). This molecule exerts a modest weight-lowering effect when accompanying a suitable dietary advice. Thus, in a recent meta-analysis (Viner et al. 2010), the mean BMI change with Orlistat (120 mg three times daily) was a reduction of 0.83 kg m−2 (95% CI: 0.47–1.19) compared with placebo. Accompanying this anti-obesity action, Orlistat is also able to modestly reduce blood pressure, improve oral glucose tolerance and prevent the onset of type II diabetes (Heymsfield et al. 2000).
Strong inhibitory activities and action modes of lipopeptides on lipase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Mei-chun Chen, Tian-tian Liu, Jie-ping Wang, Yan-ping Chen, Qing-xi Chen, Yu-jing Zhu, Bo Liu
Dietary and lifestyle modifications such as calorie restriction and physical exercises are the common strategies adopted to control body weight; further, these methods have limited anti-obesity effects4. It has previously been reported that lipase inhibition is a potential strategy for counteracting obesity. Digestive lipase hydrolyses non-absorbable dietary triglycerides to smaller absorbable molecules of monoglycerides and free fatty acids, which are absorbed by the intestine. Inhibiting digestive lipase can reduce intestinal fat absorption5–7. Human pancreatic lipase is the main enzyme in intestinal digestion of dietary fats in the human digestive system. To date, a wide variety of natural products have been used as pancreatic lipase inhibitors, which originate from plants and metabolites of microorganisms. These include lipstatin, panclicins, saponins, polyphenols, flavonoids, caffeine, chitin, chitosan, etc5. The lipase inhibitor orlistat is the only one obesity-treatment drug currently available in the market, which reduces intestinal fat absorption via inhibition of pancreatic lipase; however, it has been reported to cause certain side effects, e.g. oily stools, oily spotting, and flatulence1,8. Some polyphenol compounds have been reported to have potential adverse effects on microorganisms and animal at high concentrations9,10. Thus, there is still a need to explore safe and effective anti-obesity drugs.
Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2018
Alejandro Schcolnik-Cabrera, Alma Chávez-Blanco, Guadalupe Domínguez-Gómez, Lucia Taja-Chayeb, Rocio Morales-Barcenas, Catalina Trejo-Becerril, Enrique Perez-Cardenas, Aurora Gonzalez-Fierro, Alfonso Dueñas-González
Up to date, the first FASN inhibitor has entered into clinical trials [72]. Early in 1972, the antifungal cerulenin was the first FASN inhibitor identified [73] and it was widely evaluated as an anticancer agent in experimental models, showing activity against a variety of tumor cell lines and xenograft models [74]. To avoid the highly reactive nature of the cysteine-reactive epoxide in cerulein, Kuhahda et al. in 2000 reported the synthesis and antitumor activity of the synthetic, chemically stable inhibitor of FASN, C75, which was proven to inhibit purified mammalian FASN as a slow-binding inhibitor and also by blocking fatty acid synthesis in human cancer cells [27]. Orlistat, a reduced form of the natural product lipstatin, was proposed as an antiobesity treatment in 1987 by virtue of its potency and selectivity to inhibit pancreatic lipase [75], but it was not until 1994 that Kridel et al. uncovered that orlistat was an irreversible inhibitor of FASN via the thioesterase (TE) domain of the enzyme. Moreover, orlistat showed potent antitumor effects in vitro and in vivo in the prostate cancer cell line PC-3 [76]. A number of other compounds have been—mainly natural—compounds have been demonstrated to inhibit by diverse mechanism the enzyme FASN, mostly at micromolar concentrations. Among these are epigallocatechin-3-gallate (EGCG), luteolin, quercetin, resveratrol, triclosan, curcumin, alpha-mangostatin, platensimycin, and tannic acid [72]. None of these is being in clinical development.