Inhibition of the fungal fatty acid synthase type I multienzyme complex.

Proceedings of the National Academy of Sciences of the United States of America
Patrik JohanssonMartin Grininger

Abstract

Fatty acids are among the major building blocks of living cells, making lipid biosynthesis a potent target for compounds with antibiotic or antineoplastic properties. We present the crystal structure of the 2.6-MDa Saccharomyces cerevisiae fatty acid synthase (FAS) multienzyme in complex with the antibiotic cerulenin, representing, to our knowledge, the first structure of an inhibited fatty acid megasynthase. Cerulenin attacks the FAS ketoacyl synthase (KS) domain, forming a covalent bond to the active site cysteine C1305. The inhibitor binding causes two significant conformational changes of the enzyme. First, phenylalanine F1646, shielding the active site, flips and allows access to the nucleophilic cysteine. Second, methionine M1251, placed in the center of the acyl-binding tunnel, rotates and unlocks the inner part of the fatty acid binding cavity. The importance of the rotational movement of the gatekeeping M1251 side chain is reflected by the cerulenin resistance and the changed product spectrum reported for S. cerevisiae strains mutated in the adjacent glycine G1250. Platensimycin and thiolactomycin are two other potent inhibitors of KSs. However, in contrast to cerulenin, they show selectivity toward the prokaryotic FAS...Continue Reading

References

Jan 1, 1983·Annual Review of Biochemistry·S J WakilV C Joshi
Sep 30, 1983·Biochemical and Biophysical Research Communications·T HayashiH Okazaki
Jul 5, 1994·Proceedings of the National Academy of Sciences of the United States of America·F P KuhajdaG R Pasternack
Jul 8, 1994·Molecular & General Genetics : MGG·J InokoshiS Omura
Jan 15, 1993·European Journal of Biochemistry·N MorisakiS Iwasaki
Aug 26, 1998·Nature·L M McMurryS B Levy
Mar 15, 2000·Proceedings of the National Academy of Sciences of the United States of America·F P KuhajdaC A Townsend
Sep 7, 2001·Annual Review of Microbiology·J W Campbell, J E Cronan
May 22, 2002·Applied Microbiology and Biotechnology·R J HeathC O Rock
Nov 15, 2002·Natural Product Reports·Richard J Heath, Charles O Rock
Jan 28, 2004·Bioscience, Biotechnology, and Biochemistry·Kazuo AritomiRinji Akada
Sep 9, 2004·Microbiology and Molecular Biology Reviews : MMBR·Eckhart Schweizer, Jörg Hofmann
Oct 28, 2004·Proceedings of the National Academy of Sciences of the United States of America·Bornali ChakravartyFlorante A Quiocho
Jun 15, 2005·Annual Review of Biochemistry·Stephen W White Rock
Mar 4, 2006·Science·Simon JenniNenad Ban
May 2, 2006·The Journal of Biological Chemistry·Yong-Mei ZhangCharles O Rock
Aug 23, 2006·Cell·Soo Hee LeePaul T Englund
Jan 24, 2007·Protein Science : a Publication of the Protein Society·Caspar Elo ChristensenAnette Henriksen
Aug 21, 2007·Current Opinion in Microbiology·H Tonie Wright, Kevin A Reynolds

❮ Previous
Next ❯

Citations

Aug 25, 2010·Quarterly Reviews of Biophysics·Timm MaierNenad Ban
Aug 14, 2010·Journal of the American Chemical Society·Claudio AnselmiJosé D Faraldo-Gómez
Jul 6, 2011·Journal of Medicinal Chemistry·Hanley N Abramson
Jun 22, 2011·Organic Letters·Takehiko YoshimitsuTetsuaki Tanaka
Oct 11, 2012·Nature Communications·Zhiwei ZhuZongbao K Zhao
Mar 17, 2010·Proceedings of the National Academy of Sciences of the United States of America·Preeti GipsonWerner Kühlbrandt
Jan 28, 2009·Acta Crystallographica. Section D, Biological Crystallography·Simon Jenni, Nenad Ban
Mar 13, 2015·Protein Science : a Publication of the Protein Society·Manuel FischerMartin Grininger
Jul 29, 2010·The Biochemical Journal·David I Chan, Hans J Vogel
Jan 8, 2013·Journal of Molecular Biology·Daniel BoehringerMarc Leibundgut
May 26, 2015·European Journal of Medicinal Chemistry·Craig A AveryColin W G Fishwick
Feb 6, 2010·Journal of Molecular Biology·Günter PappenbergerMarkus G Rudolph
Oct 6, 2016·Expert Opinion on Drug Discovery·Thelma S Angeles, Robert L Hudkins
Dec 14, 2016·Medicinal Research Reviews·Sergio M MarquesJiri Damborsky
Feb 22, 2017·Nature Chemical Biology·Zhiwei ZhuJens Nielsen
Feb 22, 2017·Nature Chemical Biology·Jan GajewskiMartin Grininger
Mar 11, 2017·Nature Communications·Jan GajewskiMartin Grininger
Aug 24, 2018·Natural Product Reports·Dominik A HerbstTimm Maier
Sep 29, 2018·Chemical Communications : Chem Comm·Emanuele RossiniMartin Grininger
Apr 9, 2009·Angewandte Chemie·Georgy N Varseev, Martin E Maier
Apr 2, 2019·ELife·Edoardo D'ImprimaWerner Kühlbrandt
Jun 19, 2019·The Journal of Biological Chemistry·Angelina S GrossTobias Eisenberg
Jul 12, 2017·Beilstein Journal of Organic Chemistry·Manuel Fischer, Martin Grininger
Jan 23, 2020·Scientific Reports·Manuel FischerMartin Grininger
Jan 8, 2017·Medical Science Monitor : International Medical Journal of Experimental and Clinical Research·George B StefanoRichard M Kream
Aug 30, 2012·Natural Product Reports·John Crosby, Matthew P Crump
Mar 26, 2019·Chembiochem : a European Journal of Chemical Biology·Christina S HeilMartin Grininger
Dec 8, 2019·Protein Science : a Publication of the Protein Society·Alexander RittnerMartin Grininger
May 31, 2020·Communications Biology·Jennifer W Lou, Mohammad T Mazhab-Jafari
Nov 4, 2015·Acta Crystallographica. Section F, Structural Biology Communications·Mathias EnderleMartin Grininger
Mar 12, 2020·Cell·Kashish SinghAshwin Chari

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.