Allosteres to regulate neurotransmitter sulfonation

Journal of Biological Chemistry(2019)

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摘要
Catecholamine neurotransmitter levels in the synapses of the brain shape human disposition-cognitive flexibility, aggression, depression, and reward seeking-and manipulating these levels is a major objective of the pharmaceutical industry. Certain neurotransmitters are extensively sulfonated and inactivated by human sulfotransferase 1A3 (SULT1A3). To our knowledge, sulfonation as a therapeutic means of regulating transmitter activity has not been explored. Here, we describe the discovery of a SULT1A3 allosteric site that can be used to inhibit the enzyme. The structure of the new site is determined using spin-label-triangulation NMR. The site forms a cleft at the edge of a conserved similar to 30-residue active-site cap that must open and close during the catalytic cycle. Allosteres anchor into the site via pi-stacking interactions with two residues that sandwich the planar core of the allostere and inhibit the enzyme through cap-stabilizing interactions with substituents attached to the core. Changes in cap free energy were calculated ab initio as a function of core substituents and used to design and synthesize a series of inhibitors intended to progressively stabilize the cap and slow turnover. The inhibitors bound tightly (34 nm to 7.4 mu m) and exhibited progressive inhibition. The cap-stabilizing effects of the inhibitors were experimentally determined and agreed remarkably well with the theoretical predictions. These studies establish a reliable heuristic for the design of SULT1A3 allosteric inhibitors and demonstrate that the free-energy changes of a small, dynamic loop that is critical for SULT substrate selection and turnover can be calculated accurately.
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关键词
sulfotransferase,allosteric regulation,enzyme inhibitor,enzyme structure,neurotransmitter,catecholamine,dopamine,nuclear magnetic resonance (NMR),enzyme mechanism,enzyme kinetics,epinephrine,norepinephrine,serotonin,spin label,SULT1A3,allostery,mechanism,inhibition
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