Conjugation: Acetylation, Methylation

The body’s ability to methylate organic compounds was discovered by German physician Wilhelm His in 1887, when he isolated N-methyl pyridinium hydroxide from the urine of dogs dosed with pyridine acetate. He studied metabolism with Schmiedeberg in Strassburg and went on to become director of the first medical clinic in Berlin. A musician and painter, His also pioneered studies in cardiac conduction and campaigned to promote disclosure of the composition of proprietary drugs.

In 1954, MacLagan and Wilkinson first described methylation of oxygen in their studies of potential anti-thyroid compounds. The significance of their discovery in physiology was uncovered three years later when Axelrod, as well as Armstrong and McMillan, described the O-methylation of adrenaline and noradrenaline. The following year Sarcione and Sokal described S-methylation in their study of thiouracil metabolism in the rat.

Acetylation was first described by Jaffe and Cohn when they observed a most unusual urinary product following furfural administration to dogs and rabbits. The product, furfuracrylic acid, presumably arose from condensation of the aldehyde with the methyl carbon of acetic acid.

Cohn’s interest in finding further examples of this type of conjugation led him to administer m-nitrobenzaldehyde to dogs, wherein he found m-nitrohippuric acid as a urinary product. Fortunately for his career, he also tried rabbits—and this urine yielded N-acetyl aminobenzoic acid, the first N-acetylated metabolite.

More than 50 years later, F. Lipmann studied the acetylation of sulfanilamides and unraveled the role of coenzyme A in acetylation reactions. His work led to a Nobel Prize in 1953.