Biology and function of the reversible sulfation pathway catalysed by human sulfotransferases and sulfatases
Introduction
Sulfation1 has evolved as a key step in xenobiotic metabolism, but also plays a critical role in steroid biosynthesis and in modulating the biological activity and facilitating the inactivation and elimination of potent endogenous chemicals including thyroid hormones, steroids and catechols 1, 2, 3. The sulfation pathway can be thought of as reversible, comprising two enzyme systems: the sulfotransferases (SULTs) which catalyse the sulfation reaction and the sulfatases which catalyse the hydrolysis of sulfate esters formed by the action of SULTs. These two enzyme systems are both the products of multigene families, with the SULTs located in the cytoplasm and the arylsulfatases (ARS) present in either the lysosomes or the endoplasmic reticulum. Although much is now known of the molecular biology of these enzyme systems, less is understood about their detailed biological function, and in particular about how the interplay between various members of the SULT and ARS enzyme families regulates the availability and biological activity of xenobiotics and endogenous chemicals which constitute their substrate profiles. Of particular interest and relevance is how genetic, hormonal and environmental factors control the relative isoenzyme complements in different tissues and at different stages of development and ageing.
This review will focus on the various essential components of the sulfation systems and on some of the studies underway to try and understand the function of these fascinating and important enzymes.
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Components of the sulfation system
When considering the biological function of sulfation, it is important to recognise the various components which constitute the whole sulfation system, not just the enzymes themselves, since the individual components will contribute collectively to the overall capacity and ability for sulfation in any given in vitro or in vivo system. Key features of the system are the supply of substrate, the supply of the activated sulfate donor molecule (or co-substrate) PAPS, and the balance between
Supply of substrate
The supply of substrate for the enzymes of sulfation is obviously of central importance to the overall sulfation system. Absorption of xenobiotics through the skin, lungs or gastrointestinal tract, transport in the circulation, import or export to and from target cells and intracellular movement of small molecules will collectively determine the availability of compounds for the reversible sulfation pathway. Sulfate conjugates are, in general, polar and water soluble molecules, which should not
Supply of PAPS
3′-phosphoadenosine 5′-phosphosulfate or 3′-phosphoadenylylsulfate (PAPS) is the sulfate donor molecule for eukaryotic SULTS. PAPS is formed from ATP and inorganic sulfate by two enzyme activities, ATP sulfurylase and APS kinase. In the first step Eq. (1), adenosine 5′-phosphosulfate is formed by the action of ATP sulfurylase and as a result of the kinetically unfavourable nature of this reaction in the forward (physiological) direction, APS kinase Eq. (2)drives the activation pathway for
Sulfotransferase enzymes
The human SULT enzyme family as currently known comprises of five well characterised members, each the product of a distinct gene, with widely differing substrate specificities and amino acid sequences [3]. Based on amino acid sequence identity and substrate preferences, the various human SULTs fully characterised to date can be subdivided into two families, phenol SULTs (P-PST, SULT1A2, M-PST and EST) and hydroxysteroid SULT (HST). The existence of further human SULTs, related to the rat SULTs
Arylsulfatase enzymes
The arylsulfatase family was classically thought to comprise of three members: the lysosomal ARSA and ARSB which hydrolyse sulfates of glycolipids and complex carbohydrates such as dermatan and chondroitin, respectively, and the steroid sulfatase, or arylsulfatase C (ARSC), which is present in the endoplasmic reticulum and which hydrolyses sulfate esters of a wide range of steroids and cholesterol (Table 3). Sulfate conjugates of xenobiotics are also hydrolysed by ARS. These ARS enzymes and
Heterologous expression systems for human SULT and ARS enzymes
The ability to study the kinetic and catalytic properties of individual SULT and ARS enzymes in isolation is extremely valuable for understanding their substrate specificities, and also the physical and chemical properties of enzyme and substrate which determine substrate preference. Heterologous expression allows the synthesis of recombinant enzyme protein from a cDNA clone in, usually, bacterial, yeast, insect or mammalian cells. The properties of the enzyme (e.g. membrane bound, cytosolic,
Biological function of sulfation
Sulfation of small molecules appears ubiquitous to mammalian species, however, we are only beginning to unravel the complexities of its functions. Based on current knowledge, the functions of sulfation may be sub-divided into the broad areas of chemical defence, hormone biosynthesis and bioactivation.
Sulfation and chemical defence
Sulfation is considered an important component of what is called phase II of xenobiotic metabolism, i.e. the conjugation and true detoxication step and is, therefore, a central feature of the body’s chemical defence armoury. The classical view of sulfation is that it protects against the toxic or potentially toxic effects of numerous xenobiotics and their metabolites, as sulfate conjugates are in general more polar, more water soluble and, therefore, more readily excreted in urine or bile, in
Sulfation and steroid biosynthesis
In humans dehydroepiandrosterone sulfate (DHEAS) is the major circulating steroid 60, 61and estrone sulfate is the major estrogen in the circulation [62]. These chemicals are known to act as precursors for the formation of estrogens and androgens. For example, during the second half of pregnancy, the human fetal adrenal gland secretes extremely large quantities of DHEAS which is utilised (following hydroxylation by cytochrome P450 and hydrolysis by steroid sulfatase, ARSC) as the major
Sulfation as a bioactivation reaction
It is increasingly recognised that whilst sulfation is normally a detoxication reaction, with the sulfate conjugate exhibiting reduced biological and/or pharmacological activity compared with the parent compound, there are a number of important examples where sulfate conjugates are more biologically active than the corresponding free compounds.
Drugs such as minoxidil 70, 71and cicletanine [72]are bioactivated upon sulfation, with the sulfate conjugate identified as the pharmacologically active
Dietary compound interaction with sulfation
Most SULTs are expressed (to varying degrees) in the human gastrointestinal tract 52, 86, 87, 88, 89. In light of this fact and of the important role sulfation plays in the bioactivation of dietary procarcinogens, it is reasonable to assume that there is potential for the production of highly reactive, unstable, mutagenic sulfuric acid esters within the gastrointestinal tract. This may be an important mechanism in, for example, colon cancer where dietary aromatic amines known to be activated
Genetic and environmental factors affecting sulfation
The important biological functions of sulfation outlined above may be adversely affected by factors influencing the expression and/or activity of components of the sulfation system. The effect of defective PAPS synthesis is illustrated by the brachymorphic mouse 9, 81, 82. Additional factors known to affect sulfation are described below.
Sulfatases
There are a number of genetic diseases associated with heritable mutations in the genes coding for ARSA, ARSB, ARSC 21, 22, 23and ARSE [24], as well as the multiple sulfatase deficiency which affects all sulfatases 22, 26(Table 3). Of these, X-linked ichthyosis is probably the most pertinent to small molecule sulfation.
X-linked ichthyosis, which results from mutations (usually complete gene deletions) in the STS gene coding for steroid sulfatase or ARSC, is one of the more common genetic
Sulfotransferases
To date, no genetic disease associated with a defect in any cytosolic sulfotransferase is known. However, there is extreme variation in the expression of various SULTs within the human population and there is good evidence for the existence for a genetic polymorphism affecting the P-PST isoform 3, 117, 118. HST expression in human liver also appears to follow a bimodal distribution, with about 25% of individuals belonging to a high activity group [119]. The explosion in the cloning of the cDNAs
Conclusions
Over the last 10 years or so, much progress has been made in our understanding of the sulfation system. The application of recombinant DNA technology has rapidly advanced our ability to identify, catalogue and characterise the members of the SULT and ARS gene families although it is clear that additional members remain to be identified. Heterologous expression in prokaryotic and eukaryotic systems has facilitated our study of their substrate specificities and provides the raw material for
Acknowledgements
Recent work in our laboratory has been supported by Action Research, the Biotechnology and Biological Sciences Research Council, the Commission of the European Communities (BMH1-CT92-0097, EV5V-CT94-0410), Glaxo Wellcome, the Scottish Hospitals Endowment Research Trust and the Wellcome Trust. cDNAs encoding ARSA, ARSB and ARSC were generously provided by Professor Kurt von Figura.
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