From Steroid and Drug Metabolism to Glycobiology, Using Sulfotransferase Structures to Understand and Tailor Function

Abstract

Sulfotransferases are ubiquitous enzymes that transfer a sulfo group (SO 3 ) from the universal cofactor donor PAPS to a broad range of acceptor substrates. In humans, the cytosolic sulfotransferases (SULTs) are involved in the sulfation of endogenous compounds such as steroids, neurotransmitters, hormones and bile acids as well as xenobiotics including drugs, toxins and environmental chemicals. The Golgi associated membrane-bound sulfotransferases are involved in post-translational modification of macromolecules from glycosaminoglycans to proteins. The sulfation of small molecules can have profound biological effects on the functionality of the acceptor, including activation, deactivation or enhanced metabolism and elimination. Sulfation of macromolecules has been shown to regulate a number of physiological and pathophysiological pathways by enhancing binding affinity to regulatory proteins or binding partners. Over the last 25 years, crystal structures of these enzymes have provided a wealth of information on the mechanisms of this process and the specificity of these enzymes. This review will focus on the general commonalities of the sulfotransferases, from enzyme structure to catalytic mechanism as well as providing examples into how structural information is being utilized to either design drugs that inhibit sulfotransferases or to modify the enzymes to improve drug synthesis.

O-Sulfation disposition of curcumin and quercetin in SULT1A3 overexpressing HEK293 cells: the role of arylsulfatase B in cellular O-sulfation regulated by transporters

“…Sulfotransferases are divided into two classes according to their subcellular localization, cytosolic sulfotransferases, and Golgi-associated membrane-bound sulfotransferases. 1 Cytosolic sulfotransferases catalyze the sulfation of various xenobiotic agents (e.g., drugs, toxins, and environmental chemicals) and endogenous compounds (e.g., steroid hor-mones, neurotransmitters, and bile acids), which are thought to be involved in detoxification. 1,2 The membrane-associated sulfotransferases are involved in the sulfation of biomacromolecules (e.g., proteins and carbohydrates), with the potential to participate in the regulation of many critical biological processes.…”

“…1 Cytosolic sulfotransferases catalyze the sulfation of various xenobiotic agents (e.g., drugs, toxins, and environmental chemicals) and endogenous compounds (e.g., steroid hor-mones, neurotransmitters, and bile acids), which are thought to be involved in detoxification. 1,2 The membrane-associated sulfotransferases are involved in the sulfation of biomacromolecules (e.g., proteins and carbohydrates), with the potential to participate in the regulation of many critical biological processes. 1 The sulfation mediated by cytosolic sulfotransferases is related to activation, deactivation, or enhanced metabolism and elimination of small molecules, which can have profound effects on the function and disposition of aglycones in vivo.…”

“…1,2 The membrane-associated sulfotransferases are involved in the sulfation of biomacromolecules (e.g., proteins and carbohydrates), with the potential to participate in the regulation of many critical biological processes. 1 The sulfation mediated by cytosolic sulfotransferases is related to activation, deactivation, or enhanced metabolism and elimination of small molecules, which can have profound effects on the function and disposition of aglycones in vivo. 3 Furthermore, dysregulation of the expression or activity of sulfotransferases could lead to perturbed levels of bioactive endogenous compounds, thereby driving the occurrence and progression of diseases.…”

“…Sulfotransferases are divided into two classes according to their subcellular localization, cytosolic sulfotransferases, and Golgi-associated membrane-bound sulfotransferases. 1 Cytosolic sulfotransferases catalyze the sulfation of various xenobiotic agents ( e.g. , drugs, toxins, and environmental chemicals) and endogenous compounds ( e.g.…”

Special Section on Drug Metabolism and Regulation—Editorial

“…To honor Dr. Negishi's contributions to the sulfotransferase field, particularly with respect to mechanism, specificity, and roles in biology, Pedersen et al reviewed the literature over the last 25 years to highlight Dr. Negishi's contributions and how they have impacted our understanding of the sulfotransferase field (Pedersen et al, 2022).…”