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.
|Buzz killer. CE1 can break down cocaine, heroin, and similar drugs.
CREDIT: MATTHEW R. REDINBO
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.
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.
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.
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
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