Paradigms of Sulfotransferase Catalysis – The Mechanism of SULT2A1 [Metabolism]

July 23rd, 2014 by Wang, T., Cook, I., Falany, C. N., Leyh, T. S.

Human cytosolic sulfotransferases (SULTs) regulate the activities of thousands of signaling small-molecules via transfer of the sulfuryl-moiety (-SO3) from PAPS (3′-phosphoadenosine 5′-phosphosulfate) to the hydroxyls and primary amines of acceptors. Sulfonation controls the affinities of ligands for their targets, and thereby regulates numerous receptors which, in turn, regulate complex cellular responses. Despite their biological and medical relevance, basic SULT mechanism issues remain unresolved. To settle these issues, and to create an in-depth model of SULT catalysis, the complete kinetic mechanism of a representative member of the human SULT family, SULT2A1, was determined. The mechanism is comprised of eight enzyme forms that interconvert via 22 rate constants, each of which was determined independently. The result is a complete quantitative description of the mechanism that accurately predicts complex enzymatic behavior. This is the first description of a SULT mechanism at this resolution and it reveals numerous principles of SULT catalysis and resolves previously ambiguous issues. The structures and catalytic behaviors of numerous SULT isozymes, including SULT2A1, are remarkably similar; hence, the mechanism presented here should provide a paradigm for sulfuryl-transfer mechanisms in the SULT family.