Monday, September 6, 2010

The evolutionary biology of exercise and man


One of the most fascinating wonders in science is how exercise positively affects the human body, from lowering cholesterol levels to increasing lean body mass. Exercise has an extremely advantageous influence on our health principally due to the evolutionary history of man. Early humans (~100,000 years ago) were hunter-gatherers and used a great deal of energy pursuing their food. Finite hunting resources produced extended periods of time between feeding putting selective pressure on early human genomes to become accustomed to a physically active environment with periods of food shortage. This lead to the thrifty regulation of energy use where physical activity for hunting took precedence over many other energy consuming phenomenon. Moreover, the moment energy was consumed it would be used to recharge the energy deficit caused by physical activity with the remainder immediately stored for the imminent food shortage. As a result, naturally selected genes expressed protein molecules that quickly manufactured energy to recharge the expended energy from the hunt and adeptly store the rest of the captured energy for the approaching fasting period.
Unfortunately, due to the slow rate of evolution, modern human has not changed much genetically relative to early humans yet the modern human environment has changed significantly by becoming a lot more inactive. Consequently the modern human genome, which has been profoundly shaped by early human's environment to be energetically frugal, is poorly acclimated for our current sedentary environment laden with copious amounts food. A lack of activity contributes to caloric surplus, yet more importantly, genes triggered by physical exertion are not expressed creating pathological conditions.
The AMP-activated protein kinase (AMPK) is a perfect example of a thrifty gene dysregulated by physical inactivity that contributes to disease. AMPK functions as the central regulator of energy homeostasis. During energy expenditure/exercise a rising AMP:ATP ratio, signifying low energy, activates AMPK, which shuts off less important energy-consuming processes and stimulates essential energy-producing processes (Fig. 1 shows the regulatory functions of AMPK throughout the human body - green arrows indicate stimulated processes and red bars indicate inhibited processes) recharging the energy state and promoting energy storage. Dysregulation of AMPK’s parsimonious function by inactivity can lead to a host of health problems including obesity, diabetes, and cancer. For example, when AMPK is turned on by physical exertion it causes an increase in fatty acid oxidation producing ATP and inhibits the less important ATP consuming fatty acid biosynthetic pathway. Both of these AMPK functions reduce overall fatty acid concentration reducing the propensity for obesity. Moreover, AMPK stimulates glucose transporter translocation to the cell membrane promoting profound glucose influx into the cell. Initially imported glucose is converted to ATP to compensate the energy debt and the rest of the glucose is stored as glycogen preparing for food shortage. Both of these functions reduce the amount of circulating glucose in the blood inhibiting the progression of diabetes. Furthermore, active AMPK inhibits energetically costly cell division by functioning as an energy checkpoint in the cell division cycle. Improved regulation of cell division by AMPK is antithetical to the unrestrained division of cancer cells and proliferation of cancer. All of these AMPK functions highlight the absolute necessity for modern humans to live a physically active lifestyle in order to prevent many of the ailments plaguing us today.
The molecular details regarding AMPK have increased greatly in recent years due to X-ray crystallographic studies of AMPK, including work done by my colleagues and I at Columbia University. Most AMPKs are heterotrimeric enzymes, consisting of one catalytic subunit and two regulatory subunits. The protein kinase domain, the auto-inhibitory domain, and the regulatory sequence (RS) are located in the catalytic alpha subunit. The regulatory gamma subunit binds AMP or ATP controlling AMPK activity. AMPK functions as a molecular switch changing conformation depending on cellular energy status. During low energy AMP concentrations are high therefore AMP predominantly binds the gamma subunit. The gamma subunit interacts with the RS and pulls the auto-inhibitory domain away from the kinase domain turning on the kinase function. After activated AMPK recharges the energy status and ATP concentration increases, ATP predominantly binds the gamma subunit which releases the RS. The proximity of super-positioned ATP to the RS in our AMPK crystal structure (Fig. 2 highlights the distance of ~7 Angstrom from the RS to the gamma-subunit bound ATP) suggests ATP’s greater negative charge triggers release of the RS. Subsequently the RS interacts with the alpha subunit where the auto-inhibitory domain can impede kinase activity (Fig. 3 represents a model of AMPK function dependent on energy status). Our structure reveals that part of the regulatory sequence is sequestered by the gamma subunit indicating that our structure represents AMPK in its activated conformation (Fig. 4 is a ribbon diagram representation of the crystal structure of AMPK in the active conformation bound to AMP).
As their are no pharmaceuticals directly activating AMPK, this structural information could be used to rationally design a drug that activates AMPK and fights diseases such as diabetes. AMPK binds two molecules of ATP where the negatively charged beta and gamma phosphate groups from ATP putatively trigger inhibition. Our crystal structure with two superpositioned ATP molecules reveals the two gamma phosphate groups from each ATP are ~ 5 Å apart (Fig. 5 illustrates the proximity of the two gamma phosphate groups from the two superpositioned ATP molecules, drawn in all-bonds, onto AMPK's molecular surface colored grey). One possibility for a potential lead compound could be two ATP-like molecules ligated together via the gamma phosphate moiety with the beta and gamma phosphates negative charge mitigated to support AMPK activation. The lead compound should have a higher affinity for AMPK than ATP therefore activating AMPK.

No comments:

Post a Comment