Structure, Function, and Inhibition of O6-Alkylguanine-DNA Alkyltransferase

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This chapter focuses on the structure and function of alkyltransferase protein. O6-alkylguanine-DNA alkyltransferase is a remarkable protein that alone can, in a single step, remove adducts from DNA that are formed at the O6-position of guanine and the O4-position of thymine and can, thus, restore the original DNA. Production of such adducts is a major contributor to the toxic, mutagenic, and carcinogenic effects of alkylating agents. Alkyltransferase activity has been detected in many species, including microorganisms, insects, fish, and mammals. The unique activity of alkyltransferase suggests that it is an ideal target for biochemical modulation. The efficient repair of toxic lesions formed at the O6-position of guanine without additional enzymes or cofactors provides a less complex target to modulate than other DNA repair proteins. Furthermore, the high degree of correlation that exists between alkyltransferase activity and sensitivity to nitrosoureas indicates that elimination of this protein may reverse resistance in many cases. Two methods have been used to overcome alkylnitrosourea resistance by inactivation of alkyltransferase. One uses methylating agents that indirectly decrease alkyltransferase levels by introducing O6-methylguanine residues in DNA that are then repaired by the alkyltransferase. The second method uses direct alkyltransferase inactivators such as O6-methylguanine.

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