{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T12:46:28Z","timestamp":1791377188833,"version":"4.3.2"},"reference-count":27,"publisher":"National Academy of Sciences","issue":"9","license":[{"start":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T00:00:00Z","timestamp":1708387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK104998"],"award-info":[{"award-number":["DK104998"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008097","name":"Edward N. and Della L. Thome Memorial Foundation","doi-asserted-by":"publisher","award":["1"],"award-info":[{"award-number":["1"]}],"id":[{"id":"10.13039\/100008097","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","award":["1"],"award-info":[{"award-number":["1"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,2,27]]},"abstract":"<jats:p>The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson\u2019s disease (PD) in which decreased neuronal energy metabolism is a hallmark feature. TZ was neuroprotective in cell-based and animal PD models and in large epidemiological studies of humans. However, how TZ might increase PGK1 activity has remained a perplexing question because structural data revealed that the site of TZ binding to PGK1 overlaps with the site of substrate binding, predicting that TZ would competitively inhibit activity. Functional data also indicate that TZ is a competitive inhibitor. To explore the paradoxical observation of a competitive inhibitor increasing enzyme activity under some conditions, we developed a mass action model of TZ and PGK1 interactions using published data on PGK1 kinetics and the effect of varying TZ concentrations. The model indicated that TZ-binding introduces a bypass pathway that accelerates product release. At low concentrations, TZ binding circumvents slow product release and increases the rate of enzymatic phosphotransfer. However, at high concentrations, TZ inhibits PGK1 activity. The model explains stimulation of enzyme activity by a competitive inhibitor and the biphasic dose\u2013response relationship for TZ and PGK1 activity. By providing a plausible mechanism for interactions between TZ and PGK1, these findings may aid development of TZ or other agents as potential therapeutics for neurodegenerative diseases. The results may also have implications for agents that interact with the active site of other enzymes.<\/jats:p>","DOI":"10.1073\/pnas.2318956121","type":"journal-article","created":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T13:55:21Z","timestamp":1708437321000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":20,"title":["A model for stimulation of enzyme activity by a competitive inhibitor based on the interaction of terazosin and phosphoglycerate kinase 1"],"prefix":"10.1073","volume":"121","author":[{"given":"Mitchell J.","family":"Riley","sequence":"first","affiliation":[{"name":"Department of Mathematics, University of Iowa, Iowa City, IA 52242"},{"name":"Department of Internal Medicine, Pappajohn Biomedical Institute, Roy J. and Lucille A. 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