Mighty Meprin

David Pacchioli
March 01, 1994

One day in the summer of 1981, biochemist Judy Bond discovered an enzyme.

Bond, now head of the department of biological chemistry in Penn State's College of Medicine, was then at Virginia Commonwealth University. She and a visiting colleague from England, Rob Beynon, were studying diabetic mice, trying to determine the role of proteases (enzymes that specialize in protein breakdown) in the wasting processes of the disease.

Looking at tissue samples, she remembers, "We were surprised to find very high levels of protealytic activity in the kidneys" of the mice: 10 times more activity than in any other tissue.

"We couldn't explain it."

There were a number of different proteases present in the kidneys. The enzyme most active in breaking down proteins, however, appeared distinct from its peers: larger and more complex. Bond and Beynon couldn't identify it. Finding no reference to it in the literature, they proceeded to purify the enzyme, characterize it -- as a metallo-protease, one requiring the presence of zinc to do its work -- and at last to name it: meprin (again, for metallo-protease).

Meprin has kept Bond busy ever since.

First, she detailed the enzyme's structure, finding that it contained a number of distinct molecular domains, or sub-units, each with a different function. Then came another surprise.

"We had been working with a certain strain of mice," Bond remembers. "So we started testing other strains." Strangely, in some of the new mice, the kidneys showed very little meprin activity, or none at all. Meprin, it became apparent, exists in more than one form.

"This led us into looking at gene regulation," Bond says. "What was different about these two strains of mice?"

Cloning and sequencing DNA samples, i.e., mapping the relevant stretches of DNA base pairs, she found that the genes for the different forms of meprin were identical: The difference was that in some mice, a crucial subunit -- the part of the gene that causes meprin to be active -- is not expressed in the cell. The blueprint exists, but the plan isn't executed.

The switching off of protease activity is evidently determined at some point during the translation of the genetic code from DNA into RNA, from which the protein is actually made. In mice without the active subunit, however, Bond later found, meprin could be activated by the presence of other proteases. "So the inactive form is actually latent," she says. "Possibly there's another level of regulation."

A prestigious MERIT (Method to Extend Research in Time) award from the National Institutes of Health, granted in 1989, has allowed Bond and a team of four graduate students -- Petra Marchand, Jie Tang, Jill Erlinger, and Bruce Doll -- to broaden their study. Currently, they are looking at two related metallo-proteases, including insulinase, which is important in the regulation of insulin. Simultaneously, they have begun to examine meprin's function in human cells.

They suspect the enzyme may be involved in activating some cell growth factors, in immune system functions, even in blood pressure control. Understanding meprin could shed light on the degradative processes that destroy tissue in diabetes and kidney disease, and on the regulation of normal cell growth. In mice, Bond and her team have discovered that some forms of meprin are secreted from the kidneys, and are present at high levels in the urine, raising at least the possibility of a role in the release of pheromones, scented hormones that direct mating behavior.

"We are just starting to identify all the places where meprin is expressed" in human tissue, Bond says. High levels of the enzyme show up not just in the kidneys, they find, but in the intestines, and in mammary and salivary glands as well. "Once we've found out where it shows up, then we can look more closely at specific functions."

The enzyme's very structure, she argues, suggests physiological roles that are not yet understood. "There are many other proteases in the kidney," Bond notes, "but they're small, simple. They do one job -- chew everything up. Meprin is more complex.

"The cell wouldn't spend so much energy creating different forms of the enzyme if it were only for digestion."

Judith S. Bond, Ph.D., is professor and chair of the department of biological chemistry in the College of Medicine, The Milton S. Hershey Medical Center, Pennsylvania State University, 500 University Drive, Hershey, PA 17033; 717-531-8585. Petra Marchand, Jie Tang, Jill Erlinger, and Bruce Doll are Ph.D. students working in Bond's laboratory. Bond's work is funded by a MERIT award from the National Institutes of Health.

Last Updated March 01, 1994