Comparison of 10,11-Dehydrocurvularin Polyketide Synthases from Alternaria cinerariae and Aspergillus terreus Highlights Key Structural Motifs.
Iterative type I polyketide synthases (PKSs) from fungi are multifunctional enzymes that use their active sites repeatedly in a highly ordered sequence to assemble complex natural products. A phytotoxic macrolide with anticancer properties, 10,11-dehydrocurvularin (DHC), is produced by cooperation of a highly reducing (HR) iterative PKS and a non-reducing (NR) iterative PKS. We have identified the DHC gene cluster in Alternaria cinerariae, heterologously expressed the active HR PKS (Dhc3) and NR PKS (Dhc5) in yeast, and compared them to corresponding proteins that make DHC in Aspergillus terreus. Phylogenetic analysis and homology modeling of these enzymes identified variable surfaces and conserved motifs that are implicated in product formation.
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada.
Rachel V K
RV
Cochrane
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada.
Zhizeng
Z
Gao
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada.
Gareth R
GR
Lambkin
Department of Chemical and Biomolecular Engineering and, Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, 90095, USA.
Wei
W
Xu
Department of Medicinal Chemistry, The University of Utah, Salt Lake City, Utah, 84112, USA.
Jaclyn M
JM
Winter
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada.
Sandra L
SL
Marcus
Department of Chemical and Biomolecular Engineering and, Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, 90095, USA.
Yi
Y
Tang
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada. john.vederas@ualberta.ca.
John C
JC
Vederas
D000528:Alternaria / Q000201:enzymology* / Q000235:genetics; D001230:Aspergillus / Q000201:enzymology* / Q000235:genetics; D020134:Catalytic Domain; D005810:Multigene Family; D010802:Phylogeny; D048630:Polyketide Synthases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry
C013914:dehydrocurvularin; D015025:Zearalenone; D048630:Polyketide Synthases
bioinformatics; biosynthesis; dehydrocurvularin; heterologous expression; polyketide