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sure and the actions of reproductive hormones. This progress has come from several directions. First, the
cloning and sequencing the dehydrogenases that regulate the actions of aldosterone, cortisol, estradiol,
and testosterone. Second, determination of the 3D structure of 17β-HSD-1 and several homologs.
Analyses of their 3D structures confirm a general principle that structural similarity is much higher than
sequence similarity. This supports proposed molecular models of medically important steroid
dehydrogenases using the alignment of their sequences onto the templates of 3D structural homologs.
Models of 11β-HSD-1 and -2 are beginning to reveal important properties about these enzymes. We
now have a good picture of the structural basis for specificity for NADPH and NADH in 11β-HSD-1
and -2. With this information, we can now turn our attention to modeling cortisol in these two enzymes.
This information will open up the possibility for developing analogs to regulate the actions of these two
enzymes for use in regulating blood pressure and other physiological processes. The development of
carbenoxolone, a water-soluble synthetic analog of glycyrrhetinic acid, shows that chemists can create
compounds that have high affinity for 11β-HSD. The next task is to synthesize compounds that are
specific for 11β-HSD-1 or 11β-HSD-2. Molecular modeling can contribute important information to
solving this kind of problem.
Similarly important information will come from the 3D models of 17β-HSD-1, -2, -3 and -4. These
models will be useful in developing compounds to regulate estrogen and androgen action, which have
important application in reproductive medicine and in treating estrogen-dependent breast tumors and
androgen-dependent prostatic tumors. Many compounds in plants have estrogenic and androgenic
activity; some of these compounds are likely to work via inhibition of one of the 17β-HSD enzymes
[27]. Analogous to the development of carbenoxolone to regulate 11β-HSD, we can seek synthetic
compounds that regulate specific types of 17β-HSD, which may be useful in reproductive medicine and
in treating cancers.
Considering the explosive pace of biomedical research and the new developments in computers for
sophisticated structural analyses, the next few years promise to yield important advances in design of
new hormone therapies based on the knowledge of the structure of steroid dehydrogenases.
Acknowledgments
We thank Drs. Tanaka, Nonaka, Nakanishi, Deyashiki, Hara, and Mitsui for providing us with the x-ray
crystallographic coordinates of carbonyl reductase and 7α-hydroxysteroid dehydrogenase. The support
of the Supercomputer Center of the University of California, San Diego is gratefully acknowledged.
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