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Dihydromaltophilin

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Dihydromaltophilin
Names
IUPAC name
(3E,5S,7S,8R,9S,10S,11S,13R,15R,16S,18Z)-11-Ethyl-7,24,28-trihydroxy-10-methyl-21,26-diazapentacyclo[23.2.1.05,16.08,15.09,13]octacosa-1(28),3,18-triene-2,20,27-trione
Systematic IUPAC name
(3E,5S,7S,8R,9S,13R,15R,16S)-11-Ethyl-7,28-dihydroxy-8,10-dimethyl-21,26-diazapentacyclo[23.2.1.05,16.08,15.09,13]octacosa-1(28),3-diene-2,27-dione
Other names
Heat-Stable Anti-fungal Factor (HSAF)
Identifiers
3D model (JSmol)
ChemSpider
  • InChI=1S/C29H40N2O6/c1-3-15-11-17-12-19-18-5-4-6-23(35)30-10-9-21(33)27-28(36)26(29(37)31-27)20(32)8-7-16(18)13-22(34)25(19)24(17)14(15)2/h4,6-8,14-19,21-22,24-25,27,32-34H,3,5,9-13H2,1-2H3,(H,30,35)(H,31,37)/b6-4-,8-7+,26-20?/t14-,15-,16+,17+,18-,19+,21?,22-,24+,25-,27?/m0/s1
    Key: VYCDZNHSSDXACI-SGXRADKASA-N
  • CC[C@H]1C[C@@H]2C[C@@H]3[C@H]4C/C=C\C(=O)NCCC(C5C(=C(C(=O)/C=C/[C@@H]4C[C@@H]([C@H]3[C@@H]2[C@H]1C)O)C(=O)N5)O)O
Properties
C29H40N2O6
Molar mass 512.647 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Dihydromaltophilin, or heat stable anti-fungal factor (HSAF), is a secondary metabolite of Streptomyces sp. and Lysobacter enzymogenes.[1][2][3] HSAF is a polycyclic tetramate lactam containing a single tetramic acid unit and a 5,5,6-tricyclic system. HSAF has been shown to have anti-fungal activity mediated through the disruption of the biosynthesis of Sphingolipid's by targeting a ceramide synthase unique to fungi.[4][5]

Biosynthesis

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The backbone of HSAF is formed through a hybrid PKS-NRPS cluster containing one nonribosomal peptide synthase (NRPS) module and one polyketide synthase (PKS) module.[2][6][7][8] The single PKS module functions in a non-canonical fashion in that it is an iterative type I PKS responsible for the generation of the two unique polyketides needed in the backbone of HSAF using malonyl-CoA as both the starter and extender unit, while the NRPS module is responsible for the linking of the polyketides to an L-ornithine unit and the initial cyclization to create the tetramate back bone.[2][7][8] The coding region related to HSAF production contains a PKS-NRPS with a total of 9 domains, (KS-AT-DH-KR-ACP-C-A-PCP-TE), while a cascade of FAD-dependent redox reactions (OX1-OX4) flank the PKS-NRPS cluster proposed to be responsible for formation of the 5,5,6-tricyclic system, there are additional coding regions for a putative regulator, an arginase for L-ornithine production from Arginine, and a transporter which flank the PKS-NRPS.[2][3][7][8]

Figure 1. Proposed mechanism of HSAF biosynthesis
Figure 2. Schematic of the function of the hybrid PKS-NRPS in the biosynthesis of HSAF

References

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  1. ^ Graupner, P. R.; Thornburgh, S.; Mathieson, J. T.; Chapin, E. L.; Kemmitt, G. M.; Brown, J. M.; Snipes, C. E. (1997). "Dihydromaltophilin; a novel fungicidal tetramic acid containing metabolite from Streptomyces sp". The Journal of Antibiotics. 50 (12): 1014–1019. doi:10.7164/antibiotics.50.1014. ISSN 0021-8820. PMID 9510907.
  2. ^ a b c d Xie, Yunxuan; Wright, Stephen; Shen, Yuemao; Du, Liangcheng (2012). "Bioactive natural products from Lysobacter". Natural Product Reports. 29 (11): 1277–1287. doi:10.1039/c2np20064c. ISSN 1460-4752. PMC 3468324. PMID 22898908.
  3. ^ a b Lou, Lili; Qian, Guoliang; Xie, Yunxuan; Hang, Jiliang; Chen, Haotong; Zaleta-Rivera, Kathia; Li, Yaoyao; Shen, Yuemao; Dussault, Patrick H. (2011-02-02). "Biosynthesis of HSAF, a tetramic acid-containing macrolactam from Lysobacter enzymogenes". Journal of the American Chemical Society. 133 (4): 643–645. doi:10.1021/ja105732c. ISSN 1520-5126. PMC 3078565. PMID 21171605.
  4. ^ Li, Shaojie; Du, Liangcheng; Yuen, Gary; Harris, Steven D. (2006). "Distinct Ceramide Synthases Regulate Polarized Growth in the Filamentous Fungus Aspergillus nidulans". Molecular Biology of the Cell. 17 (3): 1218–1227. doi:10.1091/mbc.E05-06-0533. ISSN 1059-1524. PMC 1382311. PMID 16394102.
  5. ^ Li, Shaojie; Calvo, Ana M.; Yuen, Gary Y.; Du, Liangcheng; Harris, Steven D. (2009). "Induction of cell wall thickening by the antifungal compound dihydromaltophilin disrupts fungal growth and is mediated by sphingolipid biosynthesis". The Journal of Eukaryotic Microbiology. 56 (2): 182–187. doi:10.1111/j.1550-7408.2008.00384.x. ISSN 1550-7408. PMID 21462551. S2CID 33464609.
  6. ^ Yu, Fengan; Zaleta-Rivera, Kathia; Zhu, Xiangcheng; Huffman, Justin; Millet, Jeffrey C.; Harris, Steven D.; Yuen, Gary; Li, Xing-Cong; Du, Liangcheng (2007-01-01). "Structure and Biosynthesis of Heat-Stable Antifungal Factor (HSAF), a Broad-Spectrum Antimycotic with a Novel Mode of Action". Antimicrobial Agents and Chemotherapy. 51 (1): 64–72. doi:10.1128/AAC.00931-06. ISSN 0066-4804. PMC 1797680. PMID 17074795.
  7. ^ a b c Li, Yaoyao; Chen, Haotong; Ding, Yanjiao; Xie, Yunxuan; Wang, Haoxin; Cerny, Ronald L.; Shen, Yuemao; Du, Liangcheng (2014-07-14). "Iterative assembly of two separate polyketide chains by the same single-module bacterial polyketide synthase in the biosynthesis of HSAF". Angewandte Chemie International Edition. 53 (29): 7524–7530. doi:10.1002/anie.201403500. ISSN 1521-3773. PMC 4107061. PMID 24890524.
  8. ^ a b c Chen, Haotong; Du, Liangcheng (2014). "Iterative polyketide biosynthesis by modular polyketide synthases in bacteria". Applied Microbiology and Biotechnology. 100 (2): 541–557. doi:10.1007/s00253-015-7093-0. ISSN 1432-0614. PMC 4706475. PMID 26549236.
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