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Molecular modelling and biological evaluation of phyto-molecules as potential activators of gluconolactone oxidase
Sneha Sivadas1, Amaresh Kumar Mohanty2, Saranga Rajesh1
1Department of Biotechnology, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, India.
Abstract:
Diabetes, the cause of colossal economic and disease burden, is a key area of research in drug discovery programs. Elevated blood glucose levels in diabetes lead to several adverse consequences due to the formation of advanced glycation end products and free radicals. Vitamin C, a potent antioxidant, protects the body's cells and tissues from oxidative damage and dysfunctions. Glucose is the precursor of Vitamin C synthesis in plants and some mammals. L-gulono lactone oxidase (GULO) is the rate-limiting enzyme in producing Vitamin C. However, it is not synthesized in bats, primates, humans, and guinea pigs because of the pseudogene. Several phytomolecules having antioxidant properties are hypothesized to be promising and selective activators of GULO. Therefore, the present study focused on screening agonists of GULO from phytomolecules as an effective augmentor for Vitamin C synthesis, thereby suppressing the sequela of diabetic events. The 3D structure of GULO was generated by the ab-initio method. Subsequently, molecular docking explored the possible binding patterns of GULO protein with different plant phenolic compounds, followed by supplementation of the potent phytomolecules to diabetic guinea pigs. It is noteworthy that Resveratrol and Hydroxytyrosol showed better binding affinity. The molecular simulation also confirmed that Resveratrol is an activator of the GULO enzyme. Interestingly, it was also established that Vitamin C levels were improved in diabetic guinea pigs supplemented with the phytomolecules and comparatively Resveratrol modulates the concentration of glucose and Vitamin C levels substantially, thereby alleviating hyperglycemia. However, further studies are warranted to study the mechanisms.Communicated by Ramaswamy H. Sarma.
Insights
This study screened plant compounds to activate the L-gulono lactone oxidase (GULO) enzyme, boosting Vitamin C synthesis. Resveratrol significantly improved Vitamin C levels and reduced glucose in diabetic guinea pigs, offering a potential diabetes management strategy.
Area of Science:
- Biochemistry
- Pharmacology
- Nutritional Science
Background:
- Diabetes poses a significant global health and economic burden, linked to oxidative stress from elevated blood glucose.
- Vitamin C (ascorbic acid), a crucial antioxidant, protects against oxidative damage, but its synthesis is impaired in humans due to a non-functional L-gulono lactone oxidase (GULO) gene.
- Phytochemicals with antioxidant properties are being investigated as potential activators of the GULO enzyme to enhance endogenous Vitamin C production.
Purpose of the Study:
- To screen phytomolecules for their ability to activate the L-gulono lactone oxidase (GULO) enzyme.
- To investigate the potential of GULO activation by natural compounds to increase Vitamin C synthesis.
- To evaluate the efficacy of selected phytomolecules in ameliorating diabetic complications in a preclinical model.
Main Methods:
- Generated the 3D structure of the GULO enzyme using ab-initio methods.
- Performed molecular docking to identify plant phenolic compounds with high binding affinity to GULO.
- Supplemented diabetic guinea pigs with potent phytomolecules, including Resveratrol, and measured Vitamin C and glucose levels.
Main Results:
- Resveratrol and Hydroxytyrosol exhibited strong binding affinity to the GULO enzyme.
- Molecular simulations confirmed Resveratrol as a GULO activator.
- Supplementation with phytomolecules, particularly Resveratrol, significantly increased Vitamin C levels and reduced blood glucose in diabetic guinea pigs, alleviating hyperglycemia.
Conclusions:
- Resveratrol acts as an activator of the GULO enzyme, enhancing Vitamin C synthesis.
- This mechanism offers a potential therapeutic strategy for managing hyperglycemia and associated complications in diabetes.
- Further research is necessary to elucidate the precise mechanisms involved in Resveratrol's effects on glucose and Vitamin C metabolism.
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