Function and organization of the human cytosolic sulfotransferase (SULT) family

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Highlights

  • The organization of the human cytosolic sulfotransferase family is described.

  • The role of sulfation in chemical defence, hormone homeostasis and bioactivation of carcinogens is outlined.

  • Some important interspecies differences in sulfation are highlighted.

Abstract

The sulfuryl transfer reaction is of fundamental biological importance. One of the most important manifestations of this process are the reactions catalyzed by members of the cytosolic sulfotransferase (SULT) superfamily. These enzymes transfer the sulfuryl moiety from the universal donor PAPS (3′-phosphoadenosine 5′-phosphosulfate) to a wide variety of substrates with hydroxyl- or amino-groups. Normally a detoxification reaction this facilitates the elimination of a multitude of xenobiotics, although for some molecules sulfation is a bioactivation step. In addition, sulfation plays a key role in endocrine and other signalling pathways since many steroids, sterols, thyroid hormones and catecholamines exist primarily as sulfate conjugates in humans. This article summarizes much of our current knowledge of the organization and function of the human cytosolic sulfotransferases and highlights some of the important interspecies differences that have implications for, among other things, drug development and chemical safety analysis.

Introduction

Sulfation is one of the major conjugating pathways responsible for the detoxification and subsequent elimination from the body of a host of xenobiotics and endogenous small molecules [1], [2], [3]. Sulfation is also important in the biosynthesis of steroid hormones and in modulating signalling pathways mediated by thyroid hormones, catecholamines, steroids and sterols [4], [5], [6], [7]. These biotransformation reactions are catalyzed by members of the cytosolic sulfotransferase (SULT) superfamily [3], [8], all of which utilize the universal sulfuryl donor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) [9] in the transfer of SO3 to acceptor substrates through hydroxyl or amino functions. These are soluble, cytosolic proteins that exist as homodimers (and potentially heterodimers [10]) of between 61 and 82 kDa, although the mouse Sult1e1 is known to exist as a monomer [11] and SULT6 family members are predicted to exist as monomers due to disruption of the dimerization sequence ([12], Fig. 1). The sulfated products of the sulfotransferase reaction usually exhibit reduced biological activity compared to the parent compounds – they are generally water-soluble and are substrates for one or more of the many transporters involved in uptake into cells, elimination from organs, traverse of the blood-brain barrier, etc. This is true for the vast majority of xenobiotics and endogenous compounds that are sulfated, however there are many molecules which, when sulfated, either retain some pharmacological, toxic or other biological activity or acquire it in the biotransformation process. Examples include: steroid sulfates, which are important intermediates in the biosynthesis of estrogens and androgens, such as dehydroepiandrosterone sulfate (DHEAS) [4]; neurosteroids including pregnenolone sulfate and DHEAS that influence the function of neurotransmitter receptors [13]; and many dietary and environmental chemicals and their metabolites such as N-hydroxyarylamines, N-arylhydroxamic acids, benzylic alcohols of polycyclic aromatic hydrocarbons, and hydroxylated alkenylbenzenes [14], [15].

PAPS is synthesized in a two-step reaction from inorganic sulfate and ATP by enzymes called PAPS synthetases (PAPSS). These are bifunctional enzymes in vertebrates with the two domains catalyzing the sequential ATP sulfurylase and APS kinase reactions required for the synthesis of PAPS [9], [16]. In prokaryotes these functions are encoded in separate enzymes, and lower animals have a single PAPS synthetase. However, vertebrates have two PAPSS enzymes, PAPSS1 and PAPSS2, and it has long been debated what is the requirement for both enzymes. Mutations in PAPSS2 are associated with rare musculoskeletal disorders in humans [17] and also with murine brachymorphism [18], [19], and more recently with endocrine disorders (e.g. Refs. [20], [21]). There are differences in tissue distribution and in vitro enzyme kinetics, however more recently it has been demonstrated that there are marked differences in protein stability between the two human PAPSS enzymes that are directly influenced by the intermediate APS [16]. The authors of this work suggest, therefore, that PAPSS enzymes function as “biochemical sensors” for cellular sulfation capacity [16].

Section snippets

The human sulfotransferase family

The human genome contains 13 expressed SULT genes that encode the 13 known SULT enzymes, although each gene does not produce a single protein. For example, SULT1A3 and SULT1A4 arose from a gene duplication event however, despite slight sequence variation, they encode identical proteins (termed SULT1A3/4). Second, the SULT2B1 gene uses alternate transcription start sites and differential incorporation of first exons to produce two functionally distinct enzymes that differ in size and in

Interspecies and sex differences in sulfation and sulfotransferases

Given the importance of sulfotransferases in the metabolism and detoxification of many drugs and other xenobiotics, the biosynthesis and homeostasis of hormones and the bioactivation of environmental mutagens and carcinogens, it is of particular importance to identify and understand major interspecies differences in sulfotransferases and sulfation. Some of these interspecies differences are further confounded by sex differences that do not occur in humans. The following examples illustrate some

Conclusion

Sulfation plays an important role in protecting the body following exposure to xenobiotics. In addition, many potent endogenous chemicals exist in the body as their sulfate conjugates, performing a variety of roles including as reservoirs of precursor for further biosynthetic reactions, inactivated products and biologically active molecules. Some dietary and environmental chemicals rely on sulfation as the final step in their bioactivation to mutagens and carcinogens. Capacity for sulfation

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