Analysis of the substrate specificity of human sulfotransferases SULT1A1 and SULT1A3: Site-directed mutagenesis and kinetic studies

Sulfonation is an important metabolic process involved in the excretion and in some cases activation of various endogenous compounds and xenobiotics. This reaction is catalyzed by a family of enzymes named sulfotransferases. The cytosolic human sulfotransferases SULT1A1 and SULT1A3 have overlapping yet distinct substrate specificities. SULT1A1 favors simple phenolic substrates such as p-nitrophenol, whereas SULT1A3 prefers monoamine substrates such as dopamine. In this study we have used a variety of phenolic substrates to functionally characterize the role of the amino acid at position 146 in SULT1A1 and SULT1A3. First, the mutation A146E in SULT1A1 yielded a SULT1A3-like protein with respect to the Michaelis constant for simple phenols. The mutation E146A in SULT1A3 resulted in a SULT1A1-like protein with respect to the Michaelis constant for both simple phenols and monoamine compounds. When comparing the specificity of SULT1A3 toward tyramine with that for p-ethylphenol (which differs from tyramine in having no amine group on the carbon side chain), we saw a 200-fold preference for tyramine. The kinetic data obtained with the E146A mutant of SULT1A3 for these two substrates clearly showed that this protein preferred substrates without an amine group attached. Second, changing the glutamic acid at position 146 of SULT1A3 to a glutamine, thereby neutralizing the negative charge at this position, resulted in a 360-fold decrease in the specificity constant for dopamine. The results provide strong evidence that residue 146 is crucial in determining the substrate specificity of both SULT1A1 and SULT1A3 and suggest that there is a direct interaction between glutamic acid 146 in SULT1A3 and monoamine substrates.

Preface - Special issue on environmental toxicology of metals and metalloids

Following the Ninth International Congress of Toxicology (ICT-IX) and its satellite meeting ‘The International Conference on the Environmental Toxicology of Metals and Metalloids’ held in 2001 in Australia, a special issue on Arsenic was published in July 2002 (Toxicology Letters, 133(1), 1–120, 2002). We felt that it was timely to follow up with a special issue covering a wider range of metals and metalloids. Participants from the above conferences were invited to contribute to this special issue on ‘Environmental Toxicology of Metals and Metalloids’. This special issue consists of 11 manuscripts, representing up to date studies on a number of important harmful elements including aluminium, arsenic, cadmium, selenium, tin (tributyltin) and zinc. It illustrates the multidisciplinary nature of modern research in environmental toxicology involving chemical, biological and molecular technological approaches. It has been our great pleasure to produce this special issue. We would like to thank the authors for their contributions. We greatly appreciate the guidance and assistance provided by Dr J.P. Kehrer (Managing Editor), Dr Lulu Stader (Senior Publishing Editor) and their colleagues at Elsevier Science.