Tuesday, March 13, 2012

New drug therapy targets 'shape-shifting' enzymes

Enzymes are catalysts for chemical reactions that take place in the body. Its shape determines its catalytic features, and every enzyme has an 'active site' which is responsible for enabling the chemical reaction it is responsible for. However, scientists have discovered that enzymes can change their appearance for an almost immeasurably short period of time, in which they perform their catalytic duties. Such behaviour is problematic for researchers that wish to develop drugs based on enzyme inhibition: science has mostly focused on unravelling molecular shapes present during their non-catalytic phase, which is their normal state. Because enzyme shape-shifting takes place in a timespan of femtoseconds, it is hard to study their catalytic forms. However, scientists from the Yeshiva University in New York succeeded in using computer models to calculate these structures, which can be used to make a large variety of new and highly efficacious drugs.

It was long thought that enzymes simply sit in their active form and catalyse a chemical reaction when they bump into the required 'ingredients'. The hypothesis arguing enzymes possess a catalytic phase with an incredibly short life span has shifted this paradigm. Even though the idea is not new, it took decades before scientists were able to prove these shapes actually exist. At the Yeshiva University, researchers developed various drugs based on models of catalytic enzyme shapes and proved that inhibiting them has therapeutic potential.

One of their drugs is an enzyme blocker that kills the parasite causing malaria. Another one is used to treat leukaemia and is already being tested on human patients. In the future, we may also be able to harness the shape-shifting hypothesis to develop antibiotics that will not raise resistance in bacterial strains they are supposed to kill. At the Yeshiva University, they aim to develop an inhibitor of a certain catalyst that enables bacterial communication. Microbes need coordination to launch a coordinated attack against our body, as scientists have shown earlier.

Getting to know the shapes in which enzymes are actually doing something enables us to learn more about many biological processes. Without enzymes, nothing would be happening in the body, as we need catalysts for basically everything. If we can make drugs that target the most important catalytic shape, we gain more control over biological processes. Because such targeting is more effective, we can lower drug dose, which would correspond with lower side effects. By building models of more enzymes, we may also be able to develop new drugs that cause inhibition where others have failed.

Time is short
The way enzymes work is nothing short of amazing. There are countless different enzymes which all have a unique function and a unique structure. Enzymes are basically proteins, but the molecular structure consists of an active that is precisely crafted to bind the required compounds for a chemical reaction. An example can be viewed below. The discovery that enzymes also perform insanely fast shape-shifting to speed up biological chemical reactions makes it even more intriguing. As they are able to change shape, catalyse, and transform back in a femtosecond, which is a quadrillionth of a second, it seems that most of life is based on chemical reactions that are triggered within a timespan that we would hardly call existence.
A simple catalytic response: maltose binds to an enzyme's active site, which enables the catalytic response in which maltose splits into two glucose molecules.

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