Structural insights into the novel inhibition mechanism of Trypanosoma cruzi spermidine synthase

Acta Crystallographica. Section D, Biological Crystallography
Yasushi AmanoHitoshi Sakashita

Abstract

Trypanosoma cruzi causes Chagas disease, a severe disease affecting 8-10 million people in Latin America. While nifurtimox and benznidazole are used to treat this disease, their efficacy is limited and adverse effects are observed. New therapeutic targets and novel drugs are therefore urgently required. Enzymes in the polyamine-trypanothione pathway are promising targets for the treatment of Chagas disease. Spermidine synthase is a key enzyme in this pathway that catalyzes the transfer of an aminopropyl group from decarboxylated S-adenosylmethionine (dcSAM) to putrescine. Fragment-based drug discovery was therefore conducted to identify novel, potent inhibitors of spermidine synthase from T. cruzi (TcSpdSyn). Here, crystal structures of TcSpdSyn in complex with dcSAM, trans-4-methylcyclohexylamine and hit compounds from fragment screening are reported. The structure of dcSAM complexed with TcSpdSyn indicates that dcSAM stabilizes the conformation of the `gatekeeping' loop to form the putrescine-binding pocket. The structures of fragments bound to TcSpdSyn revealed two fragment-binding sites: the putrescine-binding pocket and the dimer interface. The putrescine-binding pocket was extended by an induced-fit mechanism. The crystal...Continue Reading

References

Aug 1, 1988·Chemical & Pharmaceutical Bulletin·A ShirahataK Samejima
May 1, 1995·The International Journal of Biochemistry & Cell Biology·A E PeggJ K Coward
Mar 24, 1999·Archives of Biochemistry and Biophysics·J M TrevillyanS W Djurić
Nov 24, 1999·Free Radical Biology & Medicine·L FlohéP Steinert
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Jan 24, 2006·Journal of Biochemistry·Yoshihiko IkeguchiAnthony E Pegg
Jun 26, 2007·Biochemistry·Hong WuAlexander N Plotnikov
Nov 15, 2007·JAMA : the Journal of the American Medical Association·Caryn BernAnne C Moore
Apr 9, 2008·Biochimica Et Biophysica Acta·R Luise Krauth-Siegel, Marcelo A Comini
Apr 19, 2008·Journal of Synchrotron Radiation·Masahiko HirakiSoichi Wakatsuki
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Mar 5, 2011·Methods in Enzymology·Christopher A Lepre
Mar 5, 2011·Methods in Enzymology·James K Kranz, Celine Schalk-Hihi
Mar 5, 2011·Methods in Enzymology·John C Spurlino
Mar 5, 2011·Methods in Enzymology·Masaya OritaTatsuya Niimi
Mar 5, 2011·Methods in Enzymology·Marta C AbadXuqing Zhang
Mar 5, 2011·Methods in Enzymology·Roderick E Hubbard, James B Murray
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Garib N MurshudovAlexei A Vagin
Mar 31, 2012·Trends in Pharmacological Sciences·Christopher W MurrayDavid C Rees
Jan 1, 2013·Nature Reviews. Drug Discovery·Monya Baker
Feb 12, 2013·Biochimica Et Biophysica Acta·Bruno MantaRafael Radi
Oct 15, 2013·Journal of Synchrotron Radiation·Masahiko HirakiNaohiro Matsugaki
Oct 23, 2013·Future Medicinal Chemistry·Gianni ColottiAndrea Ilari
Nov 21, 2013·Current Medicinal Chemistry·J D MayaR López-Muñoz
Mar 12, 2015·Acta Crystallographica. Section D, Biological Crystallography·Janina SprengerSalam Al-Karadaghi

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Citations

Feb 3, 2016·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Ichiji Namatame
Jan 1, 2016·Proceedings of the National Academy of Sciences of the United States of America·Khaled ElokelyVincenzo Carnevale
Dec 14, 2016·Future Medicinal Chemistry·Andrea IlariGianni Colotti
Mar 17, 2019·The Biochemical Journal·Gabriela GuédezTiina A Salminen
Sep 28, 2018·Current Medicinal Chemistry·Alan TaleviMarcelo Comini
Mar 17, 2017·World Journal of Microbiology & Biotechnology·Apiradee PothipongsaAran Incharoensakdi
Nov 26, 2020·International Journal of Molecular Sciences·Melissa F AdasmeMichael Schroeder
Apr 30, 2021·Parasitology International·Nobuaki YasuoMasakazu Sekijima
Feb 28, 2019·Journal of Chemical Information and Modeling·Nobuaki Yasuo, Masakazu Sekijima

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