Human health is enhanced by physical exercise (see previous post) and an appropriate diet. The ideal contemporary diet includes adequate intake of low-calorie foods full of essential vitamins and minerals. These essential vitamins and minerals perform an important role in specific biochemical reactions and pathways. Moreover, a low calorie regimen enhances wellbeing by lowering blood sugar, triglycerides, and cholesterol levels as well as reducing body fat. Unfortunately, the modern human diet is calorically dense contributing to numerous ailments. However, a diet supplemented with novel compounds that reverse the harmful effects of high-caloric diets could help alleviate this emerging epidemic. The recent discovery of the molecule resveratrol supports this proposal (Fig. 1 is the chemical structure of the polyphenol resveratrol). Resveratrol is found in the skin of red grapes and red wine and promotes wellbeing by mimicking caloric restriction. Some of reseveratrol’s health benefits include anti-cancer and anti-diabetic effects in humans in addition to life span extension in budding yeast. Resveratrol mimics caloric restriction by binding and activating the protein deacetylase SIRT1. SIRT1 is an energy-sensing molecule normally activated by an increase in NAD+ concentration which can be brought about by low caloric intake. NAD+ is the required cofactor in the SIRT1 catalyzed deacetylation reaction (Fig. 2 shows the proposed SIRT1 reaction scheme). Upon activation by resveratrol or caloric restriction, SIRT1 deacetylates many targets including DNA packaging histones. SIRT1 deacetylates lysine residues at the N-terminus of histone molecules. Histone deacetylation reinstates the positive charge on these lysine residues strengthening histone interaction with the negatively charged phosphate backbone of DNA. This interaction encourages high-affinity binding between histones and DNA (Fig. 3a illustrates lysines positive charge and Fig. 3b reveals the proximity of two lysine residues from the histone tail to the phosphate groups from DNA). The increased DNA binding condenses the DNA structure and prevents transcription (Fig. 4 depicts how deacetylation produces histone conformational changes consequently silencing gene transcription). For example, SIRT1 activation turns off genes that inhibit gluconeogenesis leading to the production of glucose for energy production during prolonged periods of caloric restriction. In addition, SIRT1 also indirectly activates the AMP-activated protein kinase (see previous post) by deacetylating and turning on LKB1, which phosphorylates and activates AMPK. Triggering AMPK produces energy (ATP) by stimulating glycolysis, fatty acid oxidation, and inhibiting ATP consuming pathways. This energy production is vital during times of depleted food intake and contributes to the healthier metabolic profile characteristically obtained from caloric limitation. Interestingly, AMPK activation has also been shown to activate SIRT1 in a positive-feedback loop. This intimate relationship intensifies SIRT1 and AMPK function creating a synergistic effect and a more robust response to metabolic stress. This partnership explains why low caloric diets rich in beneficial compounds, like resveratrol, combined with plenty of exercise are so advantageous to human health.
SIRT1 represents an attractive pharmaceutical target. Still, the molecular details regarding SIRT1-resveratrol interaction have not been uncovered despite several years of work by many groups including work done by my colleagues and I at Columbia University. Interestingly residues 183-225 of SIRT1 are essential for resveratrol interaction. Due to the dearth of structural data and for some fun, I generated a molecular model of the resveratrol-binding region by threading SIRT1 residues 183-225 onto an acceptable protein fold. Then I performed resveratrol docking experiments with this newly generated SIRT1 molecular model. Intriguingly, resveratrol docks nicely into a large hydrophobic pocket within the molecular model of SIRT1 possibly representing the resveratrol-SIRT1 binary complex (Fig. 5 depicting the putative resveratrol binding pocket on the SIRT1 molecular model surface colored in grey). Structural information like this could be a starting point for rational drug design (see post from 7-26-10) to enhance resveratrol’s beneficial properties and potentially generate treatment for a number of metabolic disorders. Finally, I believe further investigation will provide greater insight into the intricate biology of energy balance and impart a deeper understanding of how a molecular-based diet and rigorous exercise can mitigate human disease.
