Small-molecule control of neurotransmitter sulfonation
| العنوان: | Small-molecule control of neurotransmitter sulfonation |
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| المؤلفون: | Alexander Deiters, Thomas S. Leyh, Ting Wang, Kristie Darrah, Ian Cook, Mary Cacace |
| المصدر: | The Journal of Biological Chemistry |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Sulfotransferase, 1-HP, 1-hydroxypyrene, sulfotransferase, MDD, major depressive disorder, Biochemistry, allosteric, chemistry.chemical_compound, Catecholamines, DOPAC, 3,4-dihydroxyphenylacetic acid, MEM, Minimum Essential Media, education.field_of_study, Neurotransmitter Agents, biology, Molecular Structure, SULT1A3, structure activity relationship, MD, molecular dynamics, Arylsulfotransferase, Cell biology, inhibitor, Enzyme inhibitor, catecholamine, Sulfotransferases, DPS, dopamine sulfate, Allosteric Site, Research Article, neurotransmitter, Gene isoform, DP, dopamine, Serotonin, Allosteric regulation, Population, SULT, sulfotransferase, Molecular Dynamics Simulation, GST, glutathione sepharose, Structure-Activity Relationship, PAPS, 3′-phosphoadenosine 5′-phosphosulfate, Extracellular, HVA, homovanillic acid, Humans, education, Molecular Biology, Depressive Disorder, Major, HME, human mammary epithelial, 3-MT, 3-methoxytyramine, Epithelial Cells, Cell Biology, In vitro, molecular dynamics, human mammary epithelial cells, 3'-Phosphoadenosine-5'-phosphosulfate, Tam, 4-hydroxy-tamoxifen, Kinetics, chemistry, DTT, dithiothreitol, biology.protein, PAP, 3′-phosphoadenosine-5′-phosphate |
| الوصف: | Controlling unmodified serotonin levels in brain synapses is a primary objective when treating major depressive disorder - a disease that afflicts ~20% of the world's population. Roughly 60% of patients respond poorly to first-line treatments and thus new therapeutic strategies are sought. Toward this end, we have constructed isoform-specific inhibitors of the human cytosolic sulfotransferase 1A3 (SULT1A3) - the isoform responsible for sulfonating ~80% of the serotonin in extracellular brain fluid. The inhibitor design includes a core ring structure, which anchors the inhibitor into a SULT1A3-specific binding pocket located outside the active site, and a sidechain crafted to act as a latch to inhibit turnover by fastening down the SULT1A3 active-site cap. The inhibitors are allosteric, they bind with nanomolar affinity and are highly specific for the 1A3 isoform. The cap-stabilizing effects of the latch can be accurately calculated and are predicted to extend throughout the cap and into the surrounding protein. A free energy correlation demonstrates that the percent inhibition at saturating inhibitor varies linearly with cap stabilization - the correlation is linear because the rate-limiting step of the catalytic cycle, nucleotide release, scales linearly with the fraction of enzyme in the cap-open form. Inhibitor efficacy in cultured cells was studied using a human mammary epithelial cell line that expresses SULT1A3 at levels comparable to those found in neurons. The inhibitors perform similarly in ex vivo and in vitro studies; consequently, SULT1A3 turnover can now be potently suppressed in an isoform-specific manner in human cells. |
| اللغة: | English |
| تدمد: | 1083-351X 0021-9258 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8cad720d003b48d451231b4b31986a0cTest http://europepmc.org/articles/PMC7948405Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8cad720d003b48d451231b4b31986a0c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1083351X 00219258 |
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