A ketoreductase domain in the PksJ protein of the bacillaene assembly line carries out both alpha- and beta-ketone reduction during chain growth.

Proceedings of the National Academy of Sciences of the United States of America
Christopher T CalderoneNathan A Magarvey

Abstract

The polyketide signaling metabolites bacillaene and dihydrobacillaene are biosynthesized in Bacillus subtilis on an enzymatic assembly line with both nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) modules acting along with catalytic domains servicing the assembly line in trans. These signaling metabolites possess the unusual starter unit alpha-hydroxyisocaproate (alpha-HIC). We show here that it arises from initial activation of alpha-ketoisocaproate (alpha-KIC) by the first adenylation domain of PksJ (a hybrid PKS/NRPS) and installation on the pantetheinyl arm of the adjacent thiolation (T) domain. The alpha-KIC unit is elongated to alpha-KIC-Gly by the second NRPS module in PksJ as demonstrated by mass spectrometric analysis. The third module of PksJ uses PKS logic and contains an embedded ketoreductase (KR) domain along with two adjacent T domains. We show that this KR domain reduces canonical 3-ketobutyryl chains but also the alpha-keto group of alpha-KIC-containing intermediates on the PksJ T-domain doublet. This KR activity accounts for the alpha-HIC moiety found in the dihydrobacillaene/bacillaene pair and represents an example of an assembly-line dual-function alpha- and beta-KR acting on disparate...Continue Reading

References

Jul 28, 1999·Chemistry & Biology·T StachelhausM A Marahiel
Jul 10, 2003·Chembiochem : a European Journal of Chemical Biology·Patrick Caffrey
Sep 16, 2004·Chembiochem : a European Journal of Chemical Biology·Ellen YehChristopher T Walsh
Dec 17, 2004·Nature·Jon Clardy, Christopher Walsh
Jun 8, 2006·Proceedings of the National Academy of Sciences of the United States of America·Christopher T CalderonePieter C Dorrestein
Dec 28, 2006·Proceedings of the National Academy of Sciences of the United States of America·Paul D StraightRoberto Kolter
Jan 20, 2007·Proceedings of the National Academy of Sciences of the United States of America·Rebecca A ButcherJon Clardy
May 8, 2007·Biochemical and Biophysical Research Communications·Jason J ReddickGregory M Raner
Aug 23, 2007·Chembiochem : a European Journal of Chemical Biology·Sven C FeifelRainer Zocher
May 1, 2008·Journal of the American Chemical Society·Hui JiangBen Shen

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Citations

May 15, 1988·Analytical Biochemistry·N TomiyaN Takahashi
Aug 10, 2011·Journal of the American Chemical Society·Yousong DingDavid H Sherman
May 16, 2012·Proceedings of the National Academy of Sciences of the United States of America·Chao PengGong-Li Tang
Jul 16, 2015·Natural Product Reports·Christopher T Walsh
Dec 23, 2015·Natural Product Reports·Eric J N Helfrich, Jörn Piel
Oct 22, 2009·Natural Product Reports·John A KalaitzisBrett A Neilan
May 14, 2010·Natural Product Reports·Jörn Piel
Oct 23, 2019·Nature Chemical Biology·Jia Jia ZhangBradley S Moore
Feb 2, 2017·Beilstein Journal of Organic Chemistry·Daniel BragaMarkus Nett
Nov 18, 2016·Molecular BioSystems·Jennifer A E PayneMax J Cryle
Jun 26, 2012·Chembiochem : a European Journal of Chemical Biology·Barbara WacklerDirk Hoffmeister
Aug 30, 2012·Natural Product Reports·John Crosby, Matthew P Crump
Oct 6, 2020·The Journal of Clinical Endocrinology and Metabolism·Yi GuoMin Xia

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