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First Molecular-Level Enzyme Images Could Improve Breast-Cancer Therapy

Press Release Number: 
PR-ROSWELL-09-1-9I
Date: 
Monday, January 12, 2009

(BUFFALO, NY) Like watchmakers prying open a complicated timepiece, researchers at Roswell Park Cancer Institute (RPCI) and Hauptman-Woodward Institute (HWI) are peering into the molecular works of an enzyme that has long defied investigation. And what they’re discovering may one day make it possible to design safer, more effective cancer-fighting drugs.

The enzyme in question is called aromatase. Understanding aromatase is critical to breast-cancer research because it produces estrogen, the hormone responsible for the development and function of female sexual characteristics.

Unfortunately, estrogen also encourages the growth of “hormone-dependent” breast cancers. Drugs that stop aromatase from producing estrogen — aromatase inhibitors, or AIs — have been frontline therapies against hormone-dependent cancers for decades. Commercial AIs include Femara, Aromidex and Aromasin.

But although aromatase has been studied for almost 40 years, its estrogen-producing process has remained poorly understood.

Now, in the current issue of the journal Nature, Debashis Ghosh of RPCI and HWI, and Jennifer Griswold, Mary Erman and Walter Pangborn of HWI report that, for the first time, they have been able to examine the mechanism of aromatase action at the molecular level.

Among the team’s key innovations was a method for crystallizing a pure form of the enzyme, which is derived from donated human placentas. Aromatase is the only protein of its type – a natural microsomal cytochrome P450 enzyme – ever to be crystallized by this approach.

Extracting, purifying and stabilizing pure aromatase was a long-sought goal. “We perfected our method over the past 12 years,” Dr. Ghosh says. “Ordinarily, recombinant DNA technology enables us to make human enzymes and proteins in bacteria and other cells. We can make unlimited quantities of easily purified material. But that approach has proved to be extremely difficult for aromatase, which degrades very rapidly. Researchers all over the world have spent decades trying to crystallize aromatase from bacteria, without success. But fresh human placenta is a rich source of pristine, fully functional aromatase.”

After homing in on the placental approach, Dr. Ghosh’s team had to develop a battery of new techniques for enzyme capture and purification. He calls the search for the right “small-molecule detergent” — used to process aromatase while retaining its functional properties — “especially tedious.”

Securing the purified enzyme was only step one. In the paper “Structural Basis for Androgen Specificity and Oestrogen Synthesis in Human Aromatase,” the team reports gathering data for a high-resolution atomic model of aromatase by examining crystals with X-rays at Cornell University and the Argonne National Laboratory. The completed digital model depicts an intricate, exquisitely tuned molecular machine for manufacturing estrogen.

According to Dr. Ghosh, “The technology we’ve developed will help us to understand how aromatase inhibitors prevent the enzyme from making estrogens, and then to design, synthesize and test a next generation of AIs — highly specific for aromatase, but with minimal side effects.”

Roswell Park Cancer Institute, founded in 1898, is the nation’s first cancer research, treatment and education center. The Institute was one of the first cancer centers in the country to be named a National Cancer Institute-designated comprehensive cancer center and remains the only facility with this designation in Upstate New York. RPCI is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation’s leading cancer centers; maintains affiliate sites; and is a partner in national and international collaborative programs. For more information, visit RPCI’s website at www.roswellpark.org, call 1-877-ASK-RPCI (1-877-275-7724) or e-mail askrpci@roswellpark.org.

The original news release can be found at: http://www.roswellpark.org/Home/MMNR/Press/first-molecular-level-enzyme-images

Also: Scientist First in World to Unravel the Molecular Structure of the Key Breast Cancer Target Enzyme That Makes All Estrogens

Note: Published in Nature, 457, 219-223 (8 January 2009) | doi:10.1038/nature07614; Received 21 June 2008; Accepted 6 November 2008; Debashis Ghosh, Jennifer Griswold, Mary Erman & Walter Pangborn; "Structural basis for androgen specificity and oestrogen synthesis in human aromatase".

Diffraction data were collected at the Cornell High Energy Synchrotron Source (CHESS), beamlines A-1 and F-2. A further data set was gathered at the Advanced Photon Source (Argonne National Laboratory), beamline 19-ID-D. Argonne National Laboratory is funded by the U.S. Department of Energy's Office of Science.

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