Androgen Receptor Complexes

While Bowers et al. center their attention on the structural requirements of ring A, the more difficult question still remains, What are the steric requirements of androgen-receptor complex interactions The contradiction still exists between Ringold s a-sided and Bush s j8-sided attachment of androgens to their receptors. 

Tsai Y-H and Steinberger A (1982) Effect of sodium molybdate on the binding of androgen-receptor complexes to germ cell and Sertoli cell chromatin. 

Inhibition of androgen receptor complexes in vitro Endemic gout in Armenia High uric acid level in serum and tissue xanthine oxidase activity, gout ... 

Pyridoxal phosphate is a coenzyme for many enzymes involved in amino acid metabolism, especially in transamination and decarboxylation. It is also the cofactor of glycogen phosphorylase, where the phosphate group is catalytically important. In addition, vitamin Bg is important in steroid hormone action where it removes the hormone-receptor complex from DNA binding, terminating the action of the hormones. In vitamin Bg deficiency, this results in increased sensitivity to the actions of low concentrations of estrogens, androgens, cortisol, and vitamin D. 

Antiandrogens inhibit the formation of the DHT-receptor complex and thereby interfere with androgen-mediated action at the cellular level.22 Megestrol acetate, a progestational agent, also is available and has antiandrogen actions.21 Finally, the conversion of testosterone to DHT may be inhibited by 5-a-reductase inhibitors.6... 

PRMTl, a nuclear receptor coactivator, exists as in a 330 kDa complex and is a H4 Arg-3 methyltransferase [133,215]. The enzyme appears to be a chromatin bound, and evidence from immunodepletion and knockout studies suggest that it is the principle, if not sole, H4 Arg-3 methyltransferase [133,215]. Mutation of the S-adenosyl methionine binding site in PRMTl annihilated its nuclear receptor coactivator activity with the androgen receptor, providing evidence for the importance of the methylation event in gene expression [215]. Yeast Rmtl, which is homologous to human PRMTl, methylates Arg-3 only in free H4 [208]. 

All classes of steroid hormones bind to specific cytoplasmic receptors in their respective target tissues, and are then translocated to the nucleus. For example, testosterone, a lipid-soluble substance, enters the cell and is enzymatically reduced to dihydrotestosterone by 5-a reductase. Dihydrotestosterone then becomes bound to a specific androgen receptor site located in the cytoplasm. This complex becomes activated and is then translocated to the nucleus, where it binds to the chromatin acceptor site consisting of DNA and nonhistone chromosomal proteins. This interaction results in the transcription of a specific messenger RNA that is then relocated to the cytoplasm and translated on the cytoplasmic ribosomes, resulting in the synthesis of a new protein that sponsors the androgenic functions (Figure 61.6). 

The mechanisms of action of steroid hormones on lymphoid, mammary, and prostatic cancer have been partially clarified. Specific cell surface receptors have been identified for estrogen, progesterone, corticosteroids, and androgens in neoplastic cells in these tissues. As in normal cells, steroid hormones also form an intracellular steroid-receptor complex that ultimately binds directly to nuclear proteins associated with DNA to activate transcription of a broad range of cellular genes involved in cell growth and proliferation (see Chapter 39 Adrenocorticosteroids Adrenocortical Antagonists). 

Huang W, Shostak Y, Tarr P, Sawyers C, Carey M. Cooperative assembly of androgen receptor into a nucleoprotein complex that regulates the prostate-specific antigen enhancer. J Biol Chem 1999 274 25756-25768. 

Soderholm, A.A., Lehtovuori, P.T., Nyro-nen, T. H. Three-dimensional Structure-Activity Relationships of Nonsteroidal Ligands in Complex with Androgen Receptor Ligand-binding Domain. J. Med. Chem. 2005, 48, 917-925. 

---