Heterologous biosynthesis of the sterol O-acyltransferase inhibitor helvamide unveils an α-ketoglutarate-dependent cross-linking oxygenase

Rui Wang; Jia Jing Liang; Wencong Yang; Daniel Vuong; John A. Kalaitzis; Alastair E. Lacey; Ernest Lacey; Andrew M. Piggott; Yit Heng Chooi; Hang Li

doi:10.1021/acs.orglett.3c04310

Heterologous biosynthesis of the sterol O-acyltransferase inhibitor helvamide unveils an α-ketoglutarate-dependent cross-linking oxygenase

Rui Wang, Jia Jing Liang, Wencong Yang, Daniel Vuong, John A. Kalaitzis, Alastair E. Lacey, Ernest Lacey, Andrew M. Piggott, Yit Heng Chooi^*, Hang Li^*

^*Corresponding author for this work

School of Natural Sciences

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Abstract

We have identified the biosynthetic gene cluster (hvm) for the sterol O-acyltransferase inhibitor helvamide (1) from the genome of Aspergillus rugulosus MST-FP2007. Heterologous expression of hvm in A. nidulans produced a previously unreported analog helvamide B (5). An α-ketoglutarate-dependent oxygenase Hvm1 was shown to catalyze intramolecular cyclization of 1 to yield 5. The biosynthetic branch to the related hancockiamides and helvamides was found to be controlled by the substrate selectivity of monomodular nonribosomal peptide synthetases.

Original language	English
Pages (from-to)	1807-1812
Number of pages	6
Journal	Organic Letters
Volume	26
Issue number	9
Early online date	23 Feb 2024
DOIs	https://doi.org/10.1021/acs.orglett.3c04310
Publication status	Published - 8 Mar 2024

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title = "Heterologous biosynthesis of the sterol O-acyltransferase inhibitor helvamide unveils an α-ketoglutarate-dependent cross-linking oxygenase",

abstract = "We have identified the biosynthetic gene cluster (hvm) for the sterol O-acyltransferase inhibitor helvamide (1) from the genome of Aspergillus rugulosus MST-FP2007. Heterologous expression of hvm in A. nidulans produced a previously unreported analog helvamide B (5). An α-ketoglutarate-dependent oxygenase Hvm1 was shown to catalyze intramolecular cyclization of 1 to yield 5. The biosynthetic branch to the related hancockiamides and helvamides was found to be controlled by the substrate selectivity of monomodular nonribosomal peptide synthetases.",

author = "Rui Wang and Liang, {Jia Jing} and Wencong Yang and Daniel Vuong and Kalaitzis, {John A.} and Lacey, {Alastair E.} and Ernest Lacey and Piggott, {Andrew M.} and Chooi, {Yit Heng} and Hang Li",

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T1 - Heterologous biosynthesis of the sterol O-acyltransferase inhibitor helvamide unveils an α-ketoglutarate-dependent cross-linking oxygenase

AU - Wang, Rui

AU - Liang, Jia Jing

AU - Yang, Wencong

AU - Vuong, Daniel

AU - Kalaitzis, John A.

AU - Lacey, Alastair E.

AU - Lacey, Ernest

AU - Piggott, Andrew M.

AU - Chooi, Yit Heng

AU - Li, Hang

PY - 2024/3/8

Y1 - 2024/3/8

N2 - We have identified the biosynthetic gene cluster (hvm) for the sterol O-acyltransferase inhibitor helvamide (1) from the genome of Aspergillus rugulosus MST-FP2007. Heterologous expression of hvm in A. nidulans produced a previously unreported analog helvamide B (5). An α-ketoglutarate-dependent oxygenase Hvm1 was shown to catalyze intramolecular cyclization of 1 to yield 5. The biosynthetic branch to the related hancockiamides and helvamides was found to be controlled by the substrate selectivity of monomodular nonribosomal peptide synthetases.

AB - We have identified the biosynthetic gene cluster (hvm) for the sterol O-acyltransferase inhibitor helvamide (1) from the genome of Aspergillus rugulosus MST-FP2007. Heterologous expression of hvm in A. nidulans produced a previously unreported analog helvamide B (5). An α-ketoglutarate-dependent oxygenase Hvm1 was shown to catalyze intramolecular cyclization of 1 to yield 5. The biosynthetic branch to the related hancockiamides and helvamides was found to be controlled by the substrate selectivity of monomodular nonribosomal peptide synthetases.

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DO - 10.1021/acs.orglett.3c04310

M3 - Article

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AN - SCOPUS:85186217436

SN - 1523-7060

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JO - Organic Letters

JF - Organic Letters

IS - 9

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Heterologous biosynthesis of the sterol O-acyltransferase inhibitor helvamide unveils an α-ketoglutarate-dependent cross-linking oxygenase

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