The human enzyme that degrades cocaine also chews up a dozen other chemicals. Now, research into the shape of the enzyme exposes how it can act on a wide variety of dissimilar molecules. The research could lead to a variety of clinical applications, including therapies for nerve gases.
Like a Casanova who pursues only blondes, most enzymes operate only on look-alike molecules. Carboxylesterase 1 (CE1), however, is an exception. This strumpet breaks down slender cocaine and bulky heroin molecules alike. It also binds to petite nerve gas molecules such as sarin and takes them out of commission. The common denominator among the different chemicals is a particular carbon or phosphorus atom that is sensitive to the chemical reaction that CE1 performs.
Researchers have wondered what gives CE1 its versatility, so structural biologist Matthew Redinbo of the University of North Carolina, Chapel Hill, and colleagues took snapshots of CE1 snuggling with its partners. Because research labs have a harder time acquiring cocaine and heroin than the casual user does, the team substituted fake cocaine (homatropine) and pretend heroin (naloxone) and used crystallography to determine the three-dimensional structure of CE1 when bound to each substance.
The images reveal that CE1 is shaped like a ball with two pockets--a smaller, rigid hole and a much roomier, flexible one--across which a target molecule can stretch out. The enzyme engulfs the cocaine analog with the larger pocket and positions the molecule so that the sensitive atom fits into the smaller pocket, triggering the breakdown reaction.
With the fake heroin, CE1's larger pocket changes shape to accommodate the bulky drug and then positions one of two sensitive atoms in the small pocket. Redinbo says knowing the structure of CE1 will enable researchers to engineer versions that bind cocaine and heroin even more tightly and more selectively. Such molecules would be useful for treating overdoses.
Understanding how CE1 gets its promiscuity could also help researchers design better treatments for nerve gas victims, says biochemist Stephen Kirby of the U.S. Army Medical Research Institute of Chemical Defense at Aberdeen Proving Ground, Maryland. Current anti-nerve gas therapies such as atropine block nerve gas from sticking to the nerves and overstimulating them. In contrast, CE1 "acts like a little sponge" and sops nerve gas molecules up, he says, which is faster and more effective. The new results will help researchers make a better sponge, he says. "From an engineering standpoint, the more promiscuous, the better."