Lienhwalides: Unique Tropolone–Maleidride Hybrids from Hypoxylon lienhwacheense

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Authors

  • Katharina Schmidt
  • Esteban Charria-Girón
  • Tatiana E. Gorelik
  • Christian Kleeberg
  • Eric Kuhnert
  • Jennifer Gerke
  • Russell Cox

External Research Organisations

  • Helmholtz Centre for Infection Research (HZI)
  • Technische Universität Braunschweig
  • Forschungszentrum Jülich
  • Bielefeld University
  • Mae Fah Luang University
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Original languageEnglish
Article numbere202500037
JournalCHEMBIOCHEM
Volume26
Issue number10
Early online date7 Mar 2025
Publication statusPublished - 28 May 2025

Abstract

Hypoxylon lienhwacheense, a fungal species with an unclear taxonomic placement within the Hypoxylaceae, presents a highly rare stromatal secondary metabolite profile. Isolation of its major stromatal constituents leads to the discovery of a novel tropolone–maleidride hybrid molecule, lienhwalide A 5, in addition to the known cordyanhydride B 6, its new derivative 7, and binaphthalenetetraol 8. Unexpectedly, Hypoxylon lienhwacheense produces in liquid cultures various lienhwalide A congeners 9–11. Their structures and relative configurations are elucidated using high-resolution mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, with their absolute configurations determined using X-ray analysis of a semisynthetic brominated derivative of 9 and synthesizing α-methoxy-α-trifluoromethylphenylacetyl esters of 11. Feeding experiments with 13C-labeled precursors (13C-methionine; 1-13C- and U-13C6-glucose) reveal insights into the biogenesis of tropolone and maleidride moieties, according to 13C couplings and incredible natural abundance double quantum transfer NMR data. Genome analysis identifies two separate biosynthetic gene clusters responsible for these moieties, and heterologous expression experiments provide further insights into the interplay of both clusters during the biosynthesis of these hybrid natural products. Remarkably, lienhwalides exhibit reduced toxicity and enhance antibacterial selectivity compared to related fungal tropolones.

Keywords

    antibiotics, biosyntheses, genomics, metabolomics, secondary metabolites, structure elucidations

ASJC Scopus subject areas

Cite this

Lienhwalides: Unique Tropolone–Maleidride Hybrids from Hypoxylon lienhwacheense. / Schmidt, Katharina; Charria-Girón, Esteban; Gorelik, Tatiana E. et al.
In: CHEMBIOCHEM, Vol. 26, No. 10, e202500037, 28.05.2025.

Research output: Contribution to journalArticleResearchpeer review

Schmidt, K, Charria-Girón, E, Gorelik, TE, Kleeberg, C, Muema, JM, Heitkämper, S, Verwaaijen, B, Kuhnert, E, Gerke, J, Kalinowski, J, Hyde, KD, Stadler, M, Cox, R & Surup, F 2025, 'Lienhwalides: Unique Tropolone–Maleidride Hybrids from Hypoxylon lienhwacheense', CHEMBIOCHEM, vol. 26, no. 10, e202500037. https://doi.org/10.1002/cbic.202500037
Schmidt, K., Charria-Girón, E., Gorelik, T. E., Kleeberg, C., Muema, J. M., Heitkämper, S., Verwaaijen, B., Kuhnert, E., Gerke, J., Kalinowski, J., Hyde, K. D., Stadler, M., Cox, R., & Surup, F. (2025). Lienhwalides: Unique Tropolone–Maleidride Hybrids from Hypoxylon lienhwacheense. CHEMBIOCHEM, 26(10), Article e202500037. https://doi.org/10.1002/cbic.202500037
Schmidt K, Charria-Girón E, Gorelik TE, Kleeberg C, Muema JM, Heitkämper S et al. Lienhwalides: Unique Tropolone–Maleidride Hybrids from Hypoxylon lienhwacheense. CHEMBIOCHEM. 2025 May 28;26(10):e202500037. Epub 2025 Mar 7. doi: 10.1002/cbic.202500037
Schmidt, Katharina ; Charria-Girón, Esteban ; Gorelik, Tatiana E. et al. / Lienhwalides : Unique Tropolone–Maleidride Hybrids from Hypoxylon lienhwacheense. In: CHEMBIOCHEM. 2025 ; Vol. 26, No. 10.
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title = "Lienhwalides: Unique Tropolone–Maleidride Hybrids from Hypoxylon lienhwacheense",
abstract = "Hypoxylon lienhwacheense, a fungal species with an unclear taxonomic placement within the Hypoxylaceae, presents a highly rare stromatal secondary metabolite profile. Isolation of its major stromatal constituents leads to the discovery of a novel tropolone–maleidride hybrid molecule, lienhwalide A 5, in addition to the known cordyanhydride B 6, its new derivative 7, and binaphthalenetetraol 8. Unexpectedly, Hypoxylon lienhwacheense produces in liquid cultures various lienhwalide A congeners 9–11. Their structures and relative configurations are elucidated using high-resolution mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, with their absolute configurations determined using X-ray analysis of a semisynthetic brominated derivative of 9 and synthesizing α-methoxy-α-trifluoromethylphenylacetyl esters of 11. Feeding experiments with 13C-labeled precursors (13C-methionine; 1-13C- and U-13C6-glucose) reveal insights into the biogenesis of tropolone and maleidride moieties, according to 13C couplings and incredible natural abundance double quantum transfer NMR data. Genome analysis identifies two separate biosynthetic gene clusters responsible for these moieties, and heterologous expression experiments provide further insights into the interplay of both clusters during the biosynthesis of these hybrid natural products. Remarkably, lienhwalides exhibit reduced toxicity and enhance antibacterial selectivity compared to related fungal tropolones.",
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T1 - Lienhwalides

T2 - Unique Tropolone–Maleidride Hybrids from Hypoxylon lienhwacheense

AU - Schmidt, Katharina

AU - Charria-Girón, Esteban

AU - Gorelik, Tatiana E.

AU - Kleeberg, Christian

AU - Muema, Jackson M.

AU - Heitkämper, Simone

AU - Verwaaijen, Bart

AU - Kuhnert, Eric

AU - Gerke, Jennifer

AU - Kalinowski, Jörn

AU - Hyde, Kevin D.

AU - Stadler, Marc

AU - Cox, Russell

AU - Surup, Frank

N1 - Publisher Copyright: © 2025 The Author(s). ChemBioChem published by Wiley-VCH GmbH.

PY - 2025/5/28

Y1 - 2025/5/28

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KW - antibiotics

KW - biosyntheses

KW - genomics

KW - metabolomics

KW - secondary metabolites

KW - structure elucidations

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VL - 26

JO - CHEMBIOCHEM

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ER -

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