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Adenosine-5′-phosphosulfate - a multifaceted modulator of bifunctional 3′-phospho-adenosine-5′-phosphosulfate synthases and related enzymes

Mueller, Jonathan W. and Shafqat, Naeem (2013) Adenosine-5′-phosphosulfate - a multifaceted modulator of bifunctional 3′-phospho-adenosine-5′-phosphosulfate synthases and related enzymes. FEBS Journal. pp. 1-8. ISSN 1742464X

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URL of Published Version: http://dx.doi.org/10.1111/febs.12252

Identification Number/DOI: doi:10.1111/febs.12252

All sulfation reactions rely on active sulfate in the form of 3′-phosphoadenosine-5′-phosphosulfate (PAPS). In fungi, bacteria, and plants, the enzymes responsible for PAPS synthesis, ATP sulfurylase and adenosine-5′-phosphosulfate (APS) kinase, reside on separate polypeptide chains. In metazoans, however, bifunctional PAPS synthases catalyze the consecutive steps of sulfate activation by converting sulfate to PAPS via the intermediate APS. This intricate molecule and the related nucleotides PAPS and 3′-phospho-adenosine-5′-phosphate modulate the function of various enzymes from sulfation pathways, and these effects are summarized in this review. On the ATP sulfurylase domain that initially produces APS from sulfate and ATP, APS acts as a potent product inhibitor, being competitive with both ATP and sulfate. For the APS kinase domain that phosphorylates APS to PAPS, APS is an uncompetitive substrate inhibitor that can bind both at the ATP/ADP binding site and the PAPS/APS-binding site. For human PAPS synthase 1, the steady-state concentration of APS has been modelled to be 1.6 lM, but this may increase up to 60 lM under conditions of sulfate excess. It is noteworthy that the APS concentration for maximal APS kinase activity is 15 lM. Finally, we recognized APS as a highly specific stabilizer of bifunctional PAPS synthases. APS most likely stabilizes the APS kinase part of these proteins by forming a dead-end enzyme–ADP–APS complex at APS concentrations between 0.5 and 5 lM; at higher concentrations, APS may bind to the catalytic centers of ATP sulfurylase. Based on the assumption that cellular concentrations of APS fluctuate within this range, APS can therefore be regarded as a key modulator of PAPS synthase functions.

Type of Work:Article
Date:2013 (Publication)
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Clinical and Experimental Medicine
Subjects:RC Internal medicine
Institution:University of Birmingham
Copyright Holders:Wiley-Blackwell
ID Code:1362
Refereed:YES
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