Details
Original language | English |
---|---|
Article number | e202500037 |
Journal | CHEMBIOCHEM |
Volume | 26 |
Issue number | 10 |
Early online date | 7 Mar 2025 |
Publication status | Published - 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
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
- Chemistry(all)
- Organic Chemistry
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In: CHEMBIOCHEM, Vol. 26, No. 10, e202500037, 28.05.2025.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
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
N2 - 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.
AB - 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.
KW - antibiotics
KW - biosyntheses
KW - genomics
KW - metabolomics
KW - secondary metabolites
KW - structure elucidations
UR - http://www.scopus.com/inward/record.url?scp=105001980158&partnerID=8YFLogxK
U2 - 10.1002/cbic.202500037
DO - 10.1002/cbic.202500037
M3 - Article
C2 - 40052702
AN - SCOPUS:105001980158
VL - 26
JO - CHEMBIOCHEM
JF - CHEMBIOCHEM
SN - 1439-4227
IS - 10
M1 - e202500037
ER -