para-Nitrophenyl sulfate activation of human sulfotransferase 1A1 is consistent with intercepting the E[middle dot]PAP complex and reformation of E[middle dot]PAPS.
Cytosolic sulfotransferase (SULT)-catalyzed sulfation regulates biological activities of various biosignaling molecules and metabolizes hydroxyl-containing drugs and xenobiotics. The universal sulfuryl group donor for SULT-catalyzed sulfation is adenosine 3'-phosphate 5'-phosphosulfate (PAPS), whereas the reaction products are a sulfated product and adenosine 3',5'-diphosphate (PAP). Although SULT-catalyzed kinetic mechanisms have been studied since the 1980s, they remain unclear. Human SULT1A1 is an important phase II drug-metabolizing enzyme. Previously, isotope exchange at equilibrium indicated steady-state ordered mechanism with PAPS and PAP binding to the free SULT1A1 (Tyapochkin, E., Cook, P. F., and Chen, G. (2008) Biochemistry 47, 11894-11899). On the basis of activation of SULT1A1 by para-nitrophenyl sulfate (pNPS), an ordered bypass mechanism has been proposed where pNPS sulfates PAP prior to its release from the E.PAP complex regenerating E.PAPS. Data are consistent with uncompetitive substrate inhibition by naphthol as a result of formation of the E.PAP.naphthol dead-end complex; formation of the complex is corroborated by naphthol/PAP double inhibition experiments. pNPS activation data demonstrate an apparent ping-pong behavior with pNPS adding to E.PAP, and competitive inhibition by naphthol consistent with formation of the E.PAP.naphthol complex. Exchange against forward reaction flux (PAPS plus naphthol) beginning with [35S]PAPS and generating [35S]naphthyl sulfate is also consistent with pNPS intercepting the E.PAP complex. Overall, data are consistent with the proposed ordered bypass mechanism.
Tyapochkin
Eduard
E
Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma 74078, USA.
Cook
Paul F
PF
Chen
Guangping
G
D000244:Adenosine Diphosphate / Q000737:chemistry*; D015239:Arylsulfotransferase / Q000737:chemistry*; D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D009578:Nitrobenzenes / Q000737:chemistry*; D010724:Phosphoadenosine Phosphosulfate / Q000737:chemistry*
D009578:Nitrobenzenes; C023379:4-nitrophenyl sulfate; D010724:Phosphoadenosine Phosphosulfate; D000244:Adenosine Diphosphate; C010840:adenosine 3'-phosphate-5'-phosphate; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human
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