Enzyme structure points to new drugs.

Enzymes work as chemical traffic cops, keeping the body's metabolic pathways flowing. They convert inactive substances into essential ones and render dangerous substances harmless. Now, advances in understanding a bacterial enzyme suggest a new mechanism for controlling human blood pressure.

For the first time, two crystallographers have figured out the three-dimensional structure of a short-chain dehydrogenase, an enzyme belonging to a widespread class of compounds that regulate levels of sugars, prostaglandins, alcohols and other important substances. The bacterial enzyme closely resembles its human counterpart, report William L. Duax and Debashis Ghosh of the Medical Foundation of Buffalo (N.Y.), Inc. They described their findings this week at the annual meeting of the American Crystallographic Association in Toledo, Ohio.

By controlling kidney levels of natural steroids, the human enzyme figures importantly in regulating blood pressure and plays a key role in the established link between licorice and hypertension. "Maybe there is a way to manipulate this enzyme to bring blood pressure down," Duax says.

Licorice contains an ingredient that prevents the human enzyme from converting the steroid hormone cortisol into cortisone. High levels of cortisol affect the body's salt balance and can cause blood pressure to rise, sometimes to dangerously high levels. Babies born without the ability to make enzyme develop life-threatening hypertension.

Licorice also inhibits the bacterial enzyme, the Buffalo researchers found. In addition, the amino acid sequences in the two versions look alike, even though they do not match those of longer, more intensively studied dehydrogenases containing 350 amino acids. Duax says. These similarities suggest that the bacterial enzyme can serve as a useful surrogate for the human version, which is difficult to obtain in large quantities, he says.

"We're hoping that by studying this [bacterial] enzyme we can gain some insight into how our [own] enzyme is working," says Carl Monder, an endocrinologist at the Population Council Cente for Biomedical Research in New York City. That insight, he says, might suggest ways to alter the enzyme's activity to control blood pressure--and in other instances, to prolong the effects of steroidal medications.

The active form of the bacterial enzyme consists of four enzyme subunits that twist together into an asymmetric molecule. Using X-ray diffraction, Ghosh and Duax pinpointed the "handcuffs" used by this chemical cop--the twists and kinks in its molecular structure that temporarily snare steroid molecules and a "cofactor" compound necessary to metabolize them. Each of the four enzyme components contains about 250 amino acid building blocks, but most of these serve only as scaffolding to hold a few key amino acids in the proper position to create the handcuffs, Duax explains.

Its seems that a cortisol molecules nestles into one fold of the bacterial enzyme, and a cofactor molecule fits into another spot nearby. Then one of the amino acids, arginine, deactivates the cortisol by transferring a hydrogen from the steroid to the cofactor. "The enzyme is there to expedite the removal of the hydrogen," says Duax.

These findings may help pharmacologists create new drug compounds. "If you know the topology of the active site, then it should be possible to design chemical agents that fit into the active site and inhibit the enzyme," Monder says. He envisions drugs that could slow the deactivation of steroid drugs, prolonging their anti-inflammatory effects. As for hypertension, Monder says, "by knowing the [enzyme's] three-dimensional structure, we possibly gain some insight on how to enhance [its] activity."