Structural plasticity in the human cytosolic sulfotransferase dimer and its role in substrate selectivity and catalysis

Abstract

The cytosolic sulfotransferases (SULTs) are dimeric enzymes that help maintain homeostasis through the modulation of hormone and drug activity by catalyzing their transformation into hydrophilic sulfate esters and increasing their excretion. Each of the thirteen active human SULT isoforms displays a unique substrate specificity pattern that underlies its individual role in our bodies. These specificities have proven to be complex, in some cases masking the biological role of specific isoforms. The first part of this review offers a short summary of historical underpinnings of human SULTs, primarily centered on the characterization of each isoform's kinetic and structural properties. Recent structural investigations have revealed each SULT has an active site “lid” that undergoes restructuring once the cofactor/sulfonate donor, 3′-phosphoadenosine-5′-phosphosulfate (PAPS), binds to the enzyme. This structural rearrangement can alter substrate-binding profiles, therefore complicating enzyme/substrate interactions and making substrate/cosubstrate concentrations and binding order important considerations in enzyme functionality. Molecular dynamic simulations have recently been employed to describe this restructuring in an attempt to offer insight to its effects on substrate selectivity. In addition to reviewing new data on SULT molecular dynamics, we will discuss the contribution of PAPS concentrations and SULT dimerization in the regulation of SULT activity within the human body.

Introduction

The human body relies on sulfonation as an important metabolic route for regulating the activity and toxicity of small hydrophobic compounds such as steroids, pharmaceutics, and environmental toxicants. This chemical modification is energetically unfavorable, necessitating a family of enzymes, the cytosolic sulfotransferases (SULTs), to catalyze the reaction efficiently. The basic sulfonation reaction involves the transfer of a sulfonate moiety from the universal sulfonate donor, 3′-phosphoadenosine 5′-phosphosulfate (PAPS), to a hydroxyl or primary amine group of a small molecule. Generally, the presence of the highly charged sulfate substituent on the small molecule's scaffold increases the recipient compound's water solubility and alters its target affinity [1], [2]. Thus, sulfation provides an excellent avenue for the homeostatic control of a number of hydrophobic signaling molecules such as oxysterols and steroids like dehydroepiandrosterone (DHEA), which may be preserved as relatively inactive sulfates in the plasma for use by parallel pathways, or until sulfatase activity restores the original compound as illustrated in Fig. 1 [2], [3], [4], [5].

Steroids are not the only compounds regulated by sulfation, as sulfation is also important for the regulation of peptides, vitamins, thyroid hormones, dopamine, and other important biological components [6], [7], [8], [9]. Further, SULTs perform a defensive function in the liver by physically transforming a myriad of dietary chemicals into less harmful chemical species [10], [11]. Together, SULTs and UDP-glucuronosyltransferases catalyze the conjugation of approximately 40% of drugs and carry out a majority of the Phase II conjugation reactions in the body [12]. After conjugation, these metabolites can be rapidly excreted from the body in the urine or feces. This dogmatic route is not always obeyed as sulfation of certain chemicals results in their bioactivation. In the case of minoxidil, the sulfate ester is the bioactive metabolite, which exerts beneficial effects, whereas certain sulfates of hydroxylated heterocyclic amines can form reactive mutagens, which impart deleterious effects [13], [14], [15]. Hundreds, if not thousands, of compounds are sulfated within the human body by the SULTs despite the existence of only 14 identified isoforms. The promiscuity of the SULTs, while having been under investigation for decades, remains difficult to predict even with the aid of quality crystal structures of the individual isoforms. Recent evidence suggests structural dynamics, a property for which crystal structures provide no description, play a key role in the substrate selection mechanism of each SULT [2], [16], [17]. The intention of this review is to summarize our current understanding of the structural plasticity of the SULT dimer as it relates to the substrate specificity and physiological role of each individual isoform. Before discussing the primary topic, we will provide the unfamiliar reader with an abbreviated history of the human SULT isoforms and their enzymatic properties, as this subject matter has been extensively discussed in previous reviews and books [18], [19], [20].