October 25, 1996

Enzyme analysis leads to MERIT award for VUMC researcher

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Michael Waterman, Ph.D.

Enzyme analysis leads to MERIT award for VUMC researcher

Discovering ways that the body produces hormones for healing injuries and reproduction has long been a goal in medical research.

Michael R. Waterman, Ph.D., Natalie Overall Warren Distinguished Chair in Biochemistry at Vanderbilt University Medical Center, has been named to receive a MERIT (Method to Extend Research In Time) award from the National Institutes of Health to help continue his work analyzing the structure and function of enzymes which produce steroid hormones.

MERIT funding is given to selected researchers who have had a grant from the NIH for at least ten years, who have made significant contributions to scientific understanding during that time, and who recieve an outstanding score upon competitive review of their project. Qualifying for a MERIT award means that the research is funded for five years, instead of the NIH's usual four, and that investigators are eligible for funding for an additional three to five years without filing a normal competitive grant proposal.

The goal of the award is to allow the researcher more time to investigate instead of being bogged down by administrative burdens.

"The advantages are quite significant," Waterman said. "It is a great privilege and a wonderful opportunity."

Waterman is studying the roles of proteins found in the endoplasmic reticulum and the mitochondrion of steroidogenic tissues (gonads and adrenal) which participate in steriod hormone biosynthesis. Previously it was difficult to study these enzymes because they are membrane-bound and difficult to purify.

"By over-expressing the enzymes in bacteria, it is possible to obtain large quantities for study," said Waterman.

The mitochondrial enzyme under study (cholesterol side chain cleavage P450) is involved in the conversion of cholesterol to pregnenolone, which is a key intermediate in production of all steriod hormones including: androgens, which stimulate the development of male sex organs, and estrogens, which control female sexual development.

Waterman is also studying the17-hydroxylase cytochrome P450, found in the endoplasmic reticulum, which is important for the development of stress-regulating hormones as well as sex hormones.

"We are interested in characterizing their structure and function both by high and low resolution methods to determine the exact mechanisms leading from cholesterol to the biosynthesis of these active hormones," said Waterman.

X-ray crystallography, a high-resolution snapshot of the protein, and protein-protein interaction by chemical modification are two of the methods that Waterman is using in his research.

Waterman hopes to understand the precise mechanisms of the steps catalyzed by these two enzymes by the end of his MERIT grant.

"This important lipid, cholesterol, is converted in a multi-step process into key steroid hormones by a number of enzymes that require oxygen for their catalytic activity. Thus, we are studying the oxidative metabolism of cholesterol," said Waterman.

This is the second MERIT award in the Biochemistry Department. The other MERIT award was received in 1995 by Conrad Wagner, Ph.D., professor of Biochemistry, for his work on folic acid metabolism.

"This reflects the continuing high quality research going on in VUMC's Biochemistry Department," said Waterman.