5.9: Phase II Reactions: Sulfation and Conjugation with α-Amino Acids

Sulfation and α-amino acid conjugation are two critical biotransformation reactions in drug metabolism. Sulfation, a phase II biotransformation reaction, involves adding a polar sulfate group to a drug, enhancing its water solubility and promoting excretion. This process can either co-occur with or occur independently of glucuronidation. Nonmicrosomal sulfotransferase enzymes catalyze the process. The reaction involves 3'-phosphoadenosine-5'-phosphosulfate or PAPS coenzyme activation, sulfur group transfer to the substrate, and sulfated metabolite creation. Various drugs, including those containing phenols, alcohols, arylamines, N-hydroxylamines, and N-hydroxyamides (such as acetaminophen, minoxidil, and morphine), undergo sulfation. The resulting sulfoconjugates are pharmacologically active and may cause tissue damage or carcinogenesis.

α-amino acid conjugation, another phase II reaction, involves linking a drug to an α-amino acid like glycine or glutamine. This reaction is catalyzed by acyltransferases. The reaction mechanism involves activating the α-amino acid, its transfer to the drug substrate, and the formation of the conjugated metabolite. Drugs with aliphatic, alicyclic, aryl, or heterocyclic aryl acids, such as salicylic and valproic acids, undergo α-amino acid conjugation.

Sulfation, a phase II biotransformation reaction, involves the addition of a polar sulfate group to a drug.

The process is catalyzed by nonmicrosomal sulfotransferases and involves PAPS coenzyme activation, sulfate group transfer to the substrate, and sulfated metabolite generation.

Drugs containing phenols, alcohols, aromatic amines, and amides like acetaminophen, minoxidil, and morphine undergo sulfation.

Sulfate conjugates can be pharmacologically active, potentially causing tissue damage or carcinogenesis.

α-amino acid conjugation involves a drug linking to an α-amino acid like glycine or glutamine.

Acyltransferases catalyze this reaction by transferring the α-amino acid to the drug substrate.

The process comprises activating the carboxylic acid substrate, followed by acylation of the α-amino acid by the acyl CoA, catalyzed by N-acyltransferase, forming the conjugated metabolite.

Drugs with aliphatic or aromatic carboxylic acids, such as valproic and salicylic acids, undergo this conjugation.