Genome-based characterization of two prenylation steps in the assembly of the stephacidin and notoamide anticancer agents in a marine-derived Aspergillus sp.
Stephacidin and notoamide natural products belong to a group of prenylated indole alkaloids containing a core bicyclo[2.2.2]diazaoctane ring system. These bioactive fungal secondary metabolites have a range of unusual structural and stereochemical features but their biosynthesis has remained uncharacterized. Herein, we report the first biosynthetic gene cluster for this class of fungal alkaloids based on whole genome sequencing of a marine-derived Aspergillus sp. Two central pathway enzymes catalyzing both normal and reverse prenyltransfer reactions were characterized in detail. Our results establish the early steps for creation of the prenylated indole alkaloid structure and suggest a scheme for the biosynthesis of stephacidin and notoamide metabolites. The work provides the first genetic and biochemical insights for understanding the structural diversity of this important family of fungal alkaloids.
Ding
Yousong
Y
Life Sciences Institute and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
de Wet
Jeffrey R
JR
Cavalcoli
James
J
Li
Shengying
S
Greshock
Thomas J
TJ
Miller
Kenneth A
KA
Finefield
Jennifer M
JM
Sunderhaus
James D
JD
McAfoos
Timothy J
TJ
Tsukamoto
Sachiko
S
Williams
Robert M
RM
Sherman
David H
DH
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001230:Aspergillus / Q000235:genetics* / Q000378:metabolism; D001685:Biological Factors / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D016678:Genome; D026121:Indole Alkaloids / Q000737:chemistry / Q000378:metabolism*; D008968:Molecular Conformation; D054876:Prenylation; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D001685:Biological Factors; D026121:Indole Alkaloids; C520596:notoamide B; C470895:stephacidin A