ABSTRACT
Methylation of an exogenous compound was first described by Wilhelm His over one hundred years ago when he observed the excretion of Nmethylpyridine in the urine of dogs after the oral administration of pyridine (His, 1887). Methyl conjugation was subsequently shown to be an important pathway in the biotransformation of many drugs and other xenobiotics, as well as endogenous compounds such as neurotransmitters (Weinshilboum, 1989b; Weinshilboum and Raftogianis, 2000). Today we know that methyltransferase enzymes can catalyze the methyl conjugation not only of small molecules such as drugs, hormones and neurotrans mitters, but also macromolecules such as proteins, RNA and DNA (Tollervey, 1996; Klein and Costa, 1997; Aletta et al., 1998). Over 100 methyltransferase enzymes have already been identified (Enzyme Nomen clature, 1992), and many more will be identified after completion of ongoing “genome projects” for humans and other organisms. The methyl conjugating enzymes described in this chapter are all “small molecule” methyltransferases that participate in the biotransformation of drugs, xenobiotics and endogenous compounds. Although a great deal is known about the biochemistry, molecular biology and regulation of methyl transferase enzymes in experimental animals, this chapter will focus on human enzymes selected from each major methyltransferase functional class. The biochemical and molecular properties of selected members of each of these groups of enzymes will be outlined briefly, followed by a description of their variation in humans - with a focus on pharmaco genetics. Although variations in methyltransferase activities related to age, gender and exposure to drugs or other chemicals have been described, the quantitatively most important and best-studied examples of variation for this family of drug-metabolising enzymes are pharmacogenetic in nature. The clinical implications of those variations in activity will also be discussed. However, before turning to the properties and regulation of methyl transferase enzymes, it might be helpful to briefly discuss the synthesis of
S-adenosyl-L-methionine (AdoMet), the high energy methyl donor cosub strate for the majority of methyltransferase enzymes.
