5.12: Phase II Reactions: Methylation Reactions

Methylation is a phase II biotransformation process involving the attachment of a methyl group to a substrate. Enzymes known as methyltransferases orchestrate this reaction.

The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled back to methionine through a process referred to as remethylation.

Methylated products exhibit distinct characteristics. They are generally irreversible, highly polar, and water-soluble metabolites. While often less pharmacologically active than their parent drug due to decreased affinity for target receptors or enzymes, methylation can enhance or retain a drug's activity in some instances.

Several functional groups, including hydroxyl, amino, thiol, and carboxyl, can undergo methylation. A notable example is the drug codeine, which morphs into a more potent analgesic, morphine, via methylation. Similarly, the neurotransmitter dopamine can be methylated to produce epinephrine, a hormone that plays a pivotal role in the body's stress response.

To sum up, methylation is a significant biotransformation reaction integral to drug detoxification and elimination from the body. It transforms lipophilic drugs into polar metabolites that are readily excreted. Catalyzed by methyltransferase enzymes, methylation impacts various functional groups, resulting in altered pharmacological activity of the products.

Phase II methylation reactions involve the attachment of a methyl group to a substrate. This reaction is the reverse of the phase I demethylation. However, it has a phase II-type reaction mechanism.

Methyltransferases, such as catechol-O-methyltransferase (COMT) and thiopurine methyltransferase (TPMT), primarily catalyze these reactions.

Methylation involves a two-step mechanism:  an initial activation of coenzyme SAM, which transfers a methyl group to the substrate, catalyzed by a methyltransferase. SAH is released as a byproduct.

Although the methylated products don't have a higher polarity or  water-solubility than their parent drugs, they exhibit equal or enhanced pharmacological activity.

Functional groups capable of methylation include hydroxyl, amine, thiol, and carboxylic acid groups.

Morphine exemplifies a drug undergoing methylation.

Methylation is also a significant reaction in the biosynthesis and inactivation of endogenous amines.