FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Helliwell Stephen B, Karkare Shantanu, Bergdoll Marc, Rahier Alain, Leighton-Davis Juliet R, Fioretto Celine, Aust Thomas, Filipuzzi Ireos, Frederiksen Mathias, Gounarides John, Hoepfner Dominic, Hofmann Andreas, Imbert Pierre-Eloi, Jeker Rolf, Knochenmuss Richard, Krastel Philipp, Margerit Anais, Memmert Klaus, Miault Charlotte V, Rao Movva N, Muller Alban, Naegeli Hans-Ulrich, Oberer Lukas, Prindle Vivian, Riedl Ralph, Schuierer Sven, Sexton Jessica A, Tao Jianshi, Wagner Trixie, Yin Hong, Zhang Juan, Roggo Silvio, Reinker Stefan, Parker Christian N
Аннотация
FR171456 is a natural product with cholesterol-lowering properties in animal models, but its molecular target is unknown, which hinders further drug development. Here we show that FR171456 specifically targets the sterol-4-alpha-carboxylate-3-dehydrogenase (Saccharomyces cerevisiae--Erg26p, Homo sapiens--NSDHL (NAD(P) dependent steroid dehydrogenase-like)), an essential enzyme in the ergosterol/cholesterol biosynthesis pathway. FR171456 significantly alters the levels of cholesterol pathway intermediates in human and yeast cells. Genome-wide yeast haploinsufficiency profiling experiments highlight the erg26/ERG26 strain, and multiple mutations in ERG26 confer resistance to FR171456 in growth and enzyme assays. Some of these ERG26 mutations likely alter Erg26 binding to FR171456, based on a model of Erg26. Finally, we show that FR171456 inhibits an artificial Hepatitis C viral replicon, and has broad antifungal activity, suggesting potential additional utility as an anti-infective. The discovery of the target and binding site of FR171456 within the target will aid further development of this compound.