Enzymes are essential to human life, mediating biochemical processes including signal transduction, cell differentiation and proliferation, metabolic processes, DNA damage repair, apoptosis, and response to stress. The dysfunction, overexpression, or hyperactivation of enzymes has been considered one of the first causes of several diseases, including cancers. An enzyme inhibitor is a substance that binds to the enzyme reversibly or irreversibly and decreases its activity. Therefore, some enzyme inhibitors are used as important drugs since they are related to specific diseases.
Metabolites have always been the target of new drug discovery, and likewise, metabolites are also considered a source of enzyme inhibitors for medicine and pharmaceutical applications. In the last several years, enzyme inhibitors derived from metabolites have received an increasing attention for their potential value in medicine and pharmaceutical fields. Many chronic diseases have been successfully treated or controlled by metabolites-derived enzyme inhibitors.
Applications
Metabolites chemistry is a major contributor to the drug discovery program. Recent studies have indicated that 50% of the prescribed pharmaceuticals are derived from natural products. Of these, some specialized metabolites have been reported as enzyme inhibitors to treat diseases. Several examples of metabolites used as enzyme inhibitors are as follows.
AchE inhibitors
Alzheimer's disease (AD) is a neurodegenerative disorder, and one of the main causes of memory loss in AD patients is due to the overexpression of acetylcholinesterase (AchE) in the brain. Accordingly, reducing the activity of AChE in the brain is one of the most effective approaches to treat AD. This task can be accomplished by using potent AchE inhibitors. Metabolites, as natural products, provide great potential for the AchE inhibitors discovery. For example, galantamine, a plant metabolite, is a well-known AchE inhibitor that has been used in the treatment of AD.
α-Glucosidase inhibitors
α-Glucosidase is a membrane-bound enzyme and lies at intestinal cells. This enzyme catalyzes the final step of carbohydrate digestion by hydrolyzing the glycosidic bonds in carbohydrates to liberate free glucose that causes postprandial hyperglycemia. High levels of α-glucosidase will lead to type 2 diabetes, which affects approximately 300 million people worldwide. α-Glucosidase inhibitors are important drugs for the treatment of type 2 diabetes, because they can delay the uptake of dietary carbohydrates and reduce postprandial hyperglycemia. Research has demonstrated that a metabolite called Rhanteriol extracted from Rhanterium suaveolens Desf can be used as α-glucosidase inhibitors[1].
XO inhibitors
Hypercholesterolemia has posed a serious threat to heart disease worldwide. Xanthine oxidase (XO), a rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generate hypercholesterolemia. Therefore, finding suitable XO inhibitors is the best way to reduce the prevalence of heart disease indirectly. Secondary metabolites such as amentoflavone, 6-paradol, and selgina are candidates for XO inhibitors, which fit well in the binding site of XO and can lower the catalytic activity of XO by changing its conformation[2].
What Can We Do?
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References
- Belaabed, S.; et al. Rhanteriol, a new Rhanterium suaveolens Desf. lignan with pharmacological potential as an inhibitor of enzymes involved in neurodegeneration and type 2 diabetes. Plants. 2023, 12(2): 301.
- Marahatha, R.; et al. Potential natural inhibitors of xanthine oxidase and HMG-CoA reductase in cholesterol regulation: in silico analysis. BMC Complementary Medicine and Therapies. 2021, 21: 1.
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