Journal of the American Chemical Society
Article
(20) Del Vecchio, F.; Petkovic, H.; Kendrew, S. G.; Low, L.;
Wilkinson, B.; Lill, R.; Cortes, J.; Rudd, B. A. M.; Staunton, J.;
Leadlay, P. F. Active-site residue, domain and module swaps in
modular polyketide synthases. J. Ind. Microbiol. Biotechnol. 2003, 30
(8), 489−494.
(21) Koryakina, I.; McArthur, J. B.; Draelos, M. M.; Williams, G. J.
Promiscuity of a modular polyketide synthase towards natural and
non-natural extender units. Org. Biomol. Chem. 2013, 11, 4449−4458.
(22) Xue, Y.; Zhao, L.; Liu, H. W.; Sherman, D. H. A gene cluster for
macrolide antibiotic biosynthesis in Streptomyces venezuelae: archi-
tecture of metabolic diversity. Proc. Natl. Acad. Sci. U. S. A. 1998, 95
(21), 12111−6.
(23) Jung, W. S.; Kim, E.; Yoo, Y. J.; Ban, Y. H.; Kim, E. J.; Yoon, Y.
J. Characterization and engineering of the ethylmalonyl-CoA pathway
towards the improved heterologous production of polyketides in
Streptomyces venezuelae. Appl. Microbiol. Biotechnol. 2014, 98 (8),
3701−13.
(24) Bonnett, S. A.; Rath, C. M.; Shareef, A. R.; Joels, J. R.; Chemler,
J. A.; Hakansson, K.; Reynolds, K.; Sherman, D. H. Acyl-CoA subunit
selectivity in the pikromycin polyketide synthase PikAIV: steady-state
kinetics and active-site occupancy analysis by FTICR-MS. Chem. Biol.
2011, 18 (9), 1075−81.
(25) Kim, B. S.; Cropp, T. A.; Beck, B. J.; Sherman, D. H.; Reynolds,
K. A. Biochemical evidence for an editing role of thioesterase II in the
biosynthesis of the polyketide pikromycin. J. Biol. Chem. 2002, 277
(50), 48028−34.
(26) Kalkreuter, E.; Williams, G. J. Engineering enzymatic assembly
lines for the production of new antimicrobials. Curr. Opin. Microbiol.
2018, 45, 140−148.
(27) Hansen, D. A.; Koch, A. A.; Sherman, D. H. Identification of a
thioesterase bottleneck in the pikromycin pathway through full-
module processing of unnatural pentaketides. J. Am. Chem. Soc. 2017,
139 (38), 13450−13455.
(28) Chemler, J. A.; Tripathi, A.; Hansen, D. A.; O’Neil-Johnson,
M.; Williams, R. B.; Starks, C.; Park, S. R.; Sherman, D. H. Evolution
of efficient modular polyketide synthases by homologous recombina-
tion. J. Am. Chem. Soc. 2015, 137 (33), 10603−9.
(29) Pieper, R.; Gokhale, R. S.; Luo, G.; Cane, D. E.; Khosla, C.
Purification and characterization of bimodular and trimodular
derivatives of the erythromycin polyketide synthase. Biochemistry
1997, 36 (7), 1846−51.
(30) Bycroft, M.; Weissman, K. J.; Staunton, J.; Leadlay, P. F.
Efficient purification and kinetic characterization of a bimodular
derivative of the erythromycin polyketide synthase. Eur. J. Biochem.
2000, 267 (2), 520−6.
(31) Aldrich, C. C.; Beck, B. J.; Fecik, R. A.; Sherman, D. H.
Biochemical investigation of pikromycin biosynthesis employing
native penta- and hexaketide chain elongation intermediates. J. Am.
Chem. Soc. 2005, 127 (23), 8441−52.
(32) Mortison, J. D.; Kittendorf, J. D.; Sherman, D. H. Synthesis and
biochemical analysis of complex chain-elongation intermediates for
interrogation of molecular specificity in the erythromycin and
pikromycin polyketide synthases. J. Am. Chem. Soc. 2009, 131 (43),
15784−93.
(33) Yuzawa, S.; Deng, K.; Wang, G.; Baidoo, E. E.; Northen, T. R.;
Adams, P. D.; Katz, L.; Keasling, J. D. Comprehensive in vitro analysis
of acyltransferase domain exchanges in modular polyketide synthases
and its application for short-chain ketone production. ACS Synth. Biol.
2017, 6 (1), 139−147.
(34) Holzbaur, I. E.; Ranganathan, A.; Thomas, I. P.; Kearney, D. J.;
Reather, J. A.; Rudd, B. A.; Staunton, J.; Leadlay, P. F. Molecular basis
of Celmer’s rules: role of the ketosynthase domain in epimerisation
and demonstration that ketoreductase domains can have altered
product specificity with unnatural substrates. Chem. Biol. 2001, 8 (4),
329−340.
(36) Smith, L.; Hong, H.; Spencer, J. B.; Leadlay, P. F. Analysis of
specific mutants in the lasalocid gene cluster: evidence for enzymatic
catalysis of a disfavoured polyether ring closure. ChemBioChem 2008,
9 (18), 2967−2975.
(37) Menzella, H. G.; Reid, R.; Carney, J. R.; Chandran, S. S.;
Reisinger, S. J.; Patel, K. G.; Hopwood, D. A.; Santi, D. V.
Combinatorial polyketide biosynthesis by de novo design and
rearrangement of modular polyketide synthase genes. Nat. Biotechnol.
2005, 23 (9), 1171−1176.
(38) Lowry, B.; Li, X.; Robbins, T.; Cane, D. E.; Khosla, C. A
Turnstile Mechanism for the Controlled Growth of Biosynthetic
Intermediates on Assembly Line Polyketide Synthases. ACS Cent. Sci.
2016, 2 (1), 14−20.
(39) Klaus, M.; Ostrowski, M. P.; Austerjost, J.; Robbins, T.; Lowry,
B.; Cane, D. E.; Khosla, C. Protein-protein interactions, not substrate
recognition, dominate the turnover of chimeric assembly line
polyketide synthases. J. Biol. Chem. 2016, 291 (31), 16404−15.
(40) Ruan, X.; Pereda, A.; Stassi, D. L.; Zeidner, D.; Summers, R. G.;
Jackson, M.; Shivakumar, A.; Kakavas, S.; Staver, M. J.; Donadio, S.;
Katz, L. Acyltransferase domain substitutions in erythromycin
polyketide synthase yield novel erythromycin derivatives. J. Bacteriol.
1997, 179 (20), 6416−25.
(41) Hans, M.; Hornung, A.; Dziarnowski, A.; Cane, D. E.; Khosla,
C. Mechanistic analysis of acyl transferase domain exchange in
polyketide synthase modules. J. Am. Chem. Soc. 2003, 125 (18),
5366−5374.
(42) Patel, K.; Piagentini, M.; Rascher, A.; Tian, Z. Q.; Buchanan, G.
O.; Regentin, R.; Hu, Z.; Hutchinson, C. R.; McDaniel, R. Engineered
biosynthesis of geldanamycin analogs for Hsp90 inhibition. Chem.
Biol. 2004, 11 (12), 1625−33.
(43) Pfeifer, B. A.; Admiraal, S. J.; Gramajo, H.; Cane, D. E.; Khosla,
C. Biosynthesis of complex polyketides in a metabolically engineered
strain of E. coli. Science 2001, 291 (5509), 1790−2.
(44) Zhang, Y. I-TASSER server for protein 3D structure prediction.
BMC Bioinf. 2008, 9, 40.
(45) Roy, A.; Kucukural, A.; Zhang, Y. I-TASSER: a unified platform
for automated protein structure and function prediction. Nat. Protoc.
2010, 5 (4), 725−38.
(46) Yang, J.; Yan, R.; Roy, A.; Xu, D.; Poisson, J.; Zhang, Y. The I-
TASSER Suite: protein structure and function prediction. Nat.
Methods 2015, 12 (1), 7−8.
(47) Humphrey, W.; Schulten, K.; Dalke, A. VMD - Visual
Molecular Dynamics. J. Mol. Graphics 1996, 14, 33−38.
(48) Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.;
Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. UCSF Chimera–a
visualization system for exploratory research and analysis. J. Comput.
Chem. 2004, 25 (13), 1605−1612.
(49) Sanner, M. F.; Olson, A. J.; Spehner, J. C. Reduced surface: an
efficient way to compute molecular surfaces. Biopolymers 1996, 38
(3), 305−320.
(50) Roe, D. R.; Cheatham, T. E., 3rd PTRAJ and CPPTRAJ:
Software for processing and analysis of molecular dynamics trajectory
data. J. Chem. Theory Comput. 2013, 9 (7), 3084−95.
(51) Persistence of Vision Pty Ltd. Persistence of Vision Raytracer
(Version 3.6); 2004.
(52) Case, D. A.; J, T. B., Betz, R. M.; Cerutti, D. S.; Cheatham, T.
E., III; Darden, T. A.; Duke, R. E.; Giese, T. J.; Gohlke, H.; Goetz, A.
W.; Homeyer, N.; Izadi, S.; Janowski, P.; Kaus, J.; Kovalenko, A.; Lee,
T. S.; LeGrand, S.; Li, P.; Luchko, T.; Luo, R.; Madej, B.; Merz, K.
M.; Monard, G.; Needham, P.; Nguyen, H.; Nguyen, H. T.; Omelyan,
I.; Onufriev, A.; Roe, D. R.; Roitberg, A.; Salomon-Ferrer, R.;
Simmerling, C. L.; Smith, W.; Swails, J.; Walker, R. C.; Wang, J.; Wolf,
R. M.; Wu, X.; York, D. M.; Kollman, P. A. AMBER 2015; University
of California: San Francisco, 2015.
(35) Koch, A. A.; Hansen, D. A.; Shende, V. V.; Furan, L. R.; Houk,
K. N.; Jimenez-Oses, G.; Sherman, D. H. A single active site mutation
in the pikromycin thioesterase generates a more effective macro-
cyclization catalyst. J. Am. Chem. Soc. 2017, 139 (38), 13456−13465.
I
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX