Drugs to control metabolic switches
|
Disease control and cure have become more subtle enterprises
|
photo: afp
FIGHTING OBESITY: The regulator molecule Adenosine Monophosphate-activated Kinase fights obesity.
CHEMISTRY BECAME an organized science but two hundred years ago. A major breakthrough already at that time was to have shown that living beings are full of chemicals.
Friedrich Wohler showed in 1828 that these come not through any supernatural or `vital' forces but through mundane chemical reactions. His conversion of inorganic ammonium cyanate into the organic animal product urea, in the laboratory, ushered in the field of biochemistry (though I wish it had a classier start).
By the 1940s, biochemists had worked out much of the chemical pathways seen in biological cells and tissues. The extensive maps of intermediary metabolism that they drew up show how we digest food and get energy out of it, how we build our bodies and grow, how we live and die.
The field of nutrition connected biochemistry with aspects of human health. We came to know the molecular basis of several diseases — beriberi, rickets, kwashiorkor, anaemia, to cite a few. The body came to be appreciated as a living chemical laboratory, with chemical pathways involved in its maintenance and performance, its input and output.
A short while later, we came to understand how a subtle change in one part of a molecule involved in one metabolic step can affect a host of seemingly unconnected, independent reactions.
Systems approach
It was not enough to think of metabolism in a simple reductionist way, but more in a `systems approach' — the way control systems engineers do. We now think of metabolic control circuits, genetic and biochemical switches and regulators, and even `action at a distance' across molecules (the term used is allostery).
The same molecule might `up-regulate' one pathway in one circumstance and `down-regulate' it in another circumstance. Disease control and cure have thus become more subtle enterprises than before.
An outstanding recent example of such a regulator molecule is Adenosine Monophosphate-activated Kinase or AMPK for short. This enzyme has now come to be known variously as a metabolic master switch, a fuel gauge that monitors the energy status of the body, an exercise product and so forth.
AMPK has direct bearing on the biochemical paths leading to two important pandemics plaguing the world — Type 2 diabetes and obesity. Little wonder then that several drug companies around the world have marshalled their research looking for candidate molecules that would tweak AMPK into action against diabetes and obesity.
AMPK is an enzyme that is made up of three separate parts or subunits called alpha, beta and gamma. Each of these has a function of its own, but each modulates the function of the others.
The gamma subunit binds the key metabolite AMP and, upon doing so, opens up the jaws of the alpha subunit allowing it to do its catalytic action.
The basic function of AMPK is to help attach a phosphate group to several other proteins. It is this phosphorylation that acts as a trigger for many metabolic reactions in the body, including energy production through the `burning up' of foodstuff (It is with this in mind that a whimsical biochemist has named phosphorylating enzymes as kinases, from the Greek word kinesis meaning vigour, action or motion).
Indeed, even the action of AMPK itself is switched on only when the alpha subunit is phosphorylated first by the enzyme AMPKK. AMPK phosphorylates numerous target proteins in the metabolic labyrinth. To be able to do so, it recognises specific structural shapes or motifs in the target molecule that fits into them, just as two pieces in a jigsaw puzzle.
This results in increase in the rates of some pathways and a decrease in those of certain others. In a lucid review (American Journal of Physiology 1999), Drs. Winder and Hardie point out that in the liver, AMPK increases the rates of fatty acid oxidation as well as decreases the rate of production of cholesterol and several other lipids.
In the skeletal muscles, it increases fat burning and also the uptake of glucose. These results are good news for keeping the body trim and the heart healthy.
In the pancreas, AMPK controls insulin secretion, which is helpful in controlling diabetes. As these reviewers say: "We consider a defect in the AMPK signalling cascade to be a feasible primary cause of the insulin resistance, dyslipidemia, and possibly other metabolic derangements of some Type 2 diabetes patients."
Also a fuel gauge
There is more. Exercising activates AMPK. Muscle AMPK increases in response to moderate intense exercise for 30 minutes; smaller periods of exercise done in repeated bouts seem helpful as well. One would like other modes of activating AMPK for people who cannot, or would not, exercise. More recently, Barbara Kahn and co-workers (Nature 2004) have shown that AMPK regulates food intake by responding to hormonal and nutritional signals in the brain.
In other words, besides being a metabolic switch, AMPK is also a fuel gauge, controlling the appetite and thus the amount of food intake.
What do all these results mean? That AMPK activation is good against Type 2 diabetes on one hand and obesity or overeating on the other. Given the staggering statistics that every third American (and apparently every public school going student in Delhi) is obese, and that 3 crore Indians are diabetic today (and close to 6 crore will be by 2025), a drug that activates AMPK will surely be a double-whammy blockbuster.
Happily enough, a molecule called Perlecan-DRL 16356 seems to be such a possible candidate. When tried on animals, it lowers blood glucose, lowers lipid levels in disease models and has the additional potential for weight loss.
Molecule from India
Based on these, it is currently undergoing phase 1 human trials (one dose a day) in the Netherlands. Once the safety of the molecules is established, phases 2 and 3 will proceed. Happily enough again, this molecule came about from the laboratories of Indian researchers in India!
AMPK is but one example of metabolic switches. The era of correcting a single condition is fast giving way to attempts to find ways to regulate the regulators. Focusing on the systems biology of the body is of value in controlling dysfunctions.
Some of these conditions can be corrected through diet control, regular exercise and lifestyle alterations. Others may require chemical intervention.
These efforts would need extensive collaboration between basic scientists and drug hunters. Gratifyingly, as the above example shows, such engagement is already taking place in India. Let us hope for more...
D. BALASUBRAMANIAN
dbala@lvpei.org
Printer friendly
page
Send this article to Friends by
E-Mail
Sci Tech
