TY - JOUR

T1 - Early Oxidative Transformations During the Biosynthesis of Terrein and Related Natural Products

AU - Kahlert, Lukas

AU - Bernardi, Darlon

AU - Hauser, Maurice

AU - Ióca, Laura P.

AU - Berlinck, Roberto G. S.

AU - Skellam, Elizabeth J.

AU - Cox, Russell J.

N1 - Funding Information: Matthias Brock is thanked for the gift of Aspergillus terreus SBUG844. LK was funded by DFG (CO 1328/5-1). MH is funded by DFG (CO 1328 / 9?1). DFG is thanked for the provision of LCMS (DFG, INST 187/621-1,) and NMR (INST 187/686-1) instrumentation. RGSB, DIB and LPI were funded by FAPESP (2013/50228-8, 2019/17721-9, 2016/21341-9, 2020/11691-8, 2018/10742-8, 2016/05133-7). Open access funding enabled and organized by Projekt DEAL. Funding Information: Matthias Brock is thanked for the gift of SBUG844. LK was funded by DFG (CO 1328/5‐1). MH is funded by DFG (CO 1328 / 9–1). DFG is thanked for the provision of LCMS (DFG, INST 187/621‐1,) and NMR (INST 187/686‐1) instrumentation. RGSB, DIB and LPI were funded by FAPESP (2013/50228‐8, 2019/17721‐9, 2016/21341‐9, 2020/11691‐8, 2018/10742‐8, 2016/05133‐7). Open access funding enabled and organized by Projekt DEAL. Aspergillus terreus

PY - 2021/8/16

Y1 - 2021/8/16

N2 - The mycotoxin terrein is derived from the C 10-precursor 6-hydroxymellein (6-HM) via an oxidative ring contraction. Although the corresponding biosynthetic gene cluster (BGC) has been identified, details of the enzymatic oxidative transformations are lacking. Combining heterologous expression and in vitro studies we show that the flavin-dependent monooxygenase (FMO) TerC catalyzes the initial oxidative decarboxylation of 6-HM. The reactive intermediate is further hydroxylated by the second FMO TerD to yield a highly oxygenated aromatic species, but further reconstitution of the pathway was hampered. A related BGC was identified in the marine-derived Roussoella sp. DLM33 and confirmed by heterologous expression. These studies demonstrate that the biosynthetic pathways of terrein and related (polychlorinated) congeners diverge after oxidative decarboxylation of the lactone precursor that is catalyzed by a conserved FMO and further indicate that early dehydration of the side chain is an essential step.

AB - The mycotoxin terrein is derived from the C 10-precursor 6-hydroxymellein (6-HM) via an oxidative ring contraction. Although the corresponding biosynthetic gene cluster (BGC) has been identified, details of the enzymatic oxidative transformations are lacking. Combining heterologous expression and in vitro studies we show that the flavin-dependent monooxygenase (FMO) TerC catalyzes the initial oxidative decarboxylation of 6-HM. The reactive intermediate is further hydroxylated by the second FMO TerD to yield a highly oxygenated aromatic species, but further reconstitution of the pathway was hampered. A related BGC was identified in the marine-derived Roussoella sp. DLM33 and confirmed by heterologous expression. These studies demonstrate that the biosynthetic pathways of terrein and related (polychlorinated) congeners diverge after oxidative decarboxylation of the lactone precursor that is catalyzed by a conserved FMO and further indicate that early dehydration of the side chain is an essential step.

KW - 6-hydroxymellein

KW - cryptosporiopsin

KW - flavin-dependent monooxygenase

KW - oxidative decarboxylation

KW - terrein

UR - http://www.scopus.com/inward/record.url?scp=85108360649&partnerID=8YFLogxK

U2 - 10.1002/chem.202101447

DO - 10.1002/chem.202101447

M3 - Article

VL - 27

SP - 11895

EP - 11903

JO - Chemistry – A European Journal

JF - Chemistry – A European Journal

SN - 1521-3765

IS - 46

ER -