important first step in making better antiestrogens
now they need to study how best to target tissue specific aromatase, 17HSD, estrone sulfatase
ie, the enzyme(s) in fat, liver, breast, placenta are different
HWI scientist unravels structure of key breast cancer target enzyme [Eureka News Service]
The molecular details of Aromatase, the key enzyme required for the body to make estrogen, are no longer a mystery thanks to the structural biology work done by the Ghosh lab at the Hauptman-Woodward Medical Research Institute (HWI) in Buffalo, New York. Dr. Debashis Ghosh's solution of the three-dimensional structure of aromatase is the first time that scientists have been able to visualize the mechanism of synthesizing estrogen.
In fact, the Ghosh lab has determined the structures of all three of the enzymes involved in controlling estrogen levels that can serve as drug targets for estrogen-dependent tumors in breast cancer. This work is so significant, the world-renowned journal Nature will be publishing the structure of aromatase at 2.90 angstrom resolution in an upcoming issue. The other two enzyme structures determined by the Ghosh lab as part of this project were estrone sulfatase (2003) and 17β-hydroxysteroid dehydrogenase type 1 (1996). All three enzymes control the levels of estradiol in different tissues.
"This is a dream come true," Dr. Debashis Ghosh, an HWI senior research scientist and a principal investigator who also holds a joint faculty appointment at the Roswell Park Cancer Institute (RPCI), said. "Scientists worldwide have been trying for 35 years to crystallize this membrane-bound enzyme and we are the first to succeed. Now that we know the structures of all three key enzymes implicated in estrogen-dependant breast cancers, our goal is to have a personalized cocktail of inhibitors customized to the specific treatment needs of each patient. Our knowledge about these three enzymes will enable us to develop three mutually exclusive inhibitors customized to each patient's needs which will work in harmony together with minimal side effects."
Why Is This Important?
Most people know that breast cancer is the most common cancer among women in the United States and the second leading cause of cancer death in women, after lung cancer. Many people also may be aware that the chance of a woman having invasive breast cancer some time during her life is about 1 in 8 and the chance of dying from breast cancer is about 1 in 35. But many may not be aware that 75-80 percent of all breast cancer tumors are estrogen-fed. Estrogen is a female sex hormone and androgens are the male sex hormones. Regardless of gender, everyone has some percentage of both estrogens and androgens in their bodies. Each of the enzymes discussed above can individually promote the growth of estrogen-dependent breast cancers, but knowing all three structures opens the door to customized, comprehensive medical treatment.
Aromatase is the only enzyme in the vertebrate world that makes estrogens from androgens. All estrogens in the human body are made by aromatase. Drugs, such as Tamoxifen, that prevent aromatase from making estrogens constitute one of the foremost therapies for estrogen-dependent breast cancer. These drugs do not discriminate in what they target in the body, which results in significant side effects. Aromatase inhibitor drugs (AIs) have only been on the market a few years and are targeted to inhibit aromatase specifically. But because the structure was not known, nor the mechanism of androgen to estrogen conversion, the AIs currently in use have been developed using trial and error methods resulting in greater vulnerability to contraindications and side effects.
"Now that the Ghosh Lab has unraveled the molecular details of aromatase, drugs can be designed to specifically target aromoatase," Dr. Walter A. Pangborn, Executive Vice President at HWI, said. "This means that results from this research will form the basis for novel breast cancer drugs that are highly specific for aromatase but cause minimal side effects."
ABSTRACT: Structural basis for androgen specificity and oestrogen synthesis in human aromatase [Nature]
Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. Aromatase inhibitors therefore constitute a frontline therapy for oestrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O2, 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16α-hydroxytestosterone to oestrone, 17β-oestradiol and 17β,16α-oestriol, respectively1, 2, 3. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme's androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.