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Bikaverin

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Bikaverin
Names
IUPAC name
6,11-Dihydroxy-3,8-dimethoxy-1-methyl-7H-benzo[b]xanthene-7,10,12-trione
Other names
Lycopersin
Identifiers
3D model (JSmol)
ChEBI
ECHA InfoCard 100.230.205 Edit this at Wikidata
UNII
  • Key: QXNACSREWQXWCV-UHFFFAOYSA-N
  • CC1=CC(=CC2=C1C(=O)C3=C(O2)C(=O)C4=C(C3=O)C(=CC(=C4O)OC)O)OC
Properties
C20H14O8
Molar mass 382.324 g·mol−1
Appearance Red solid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Bikaverin is a red polyketide pigment made by several fungi, most of them species of Fusarium. It is a tetracyclic benzoxanthone and was first characterised in 1971 from Gibberella fujikuroi, the fungus better known as the industrial source of gibberellins.[1][2] Bikaverin kills some protozoa and oomycetes, is toxic to a range of tumour cell lines, and has been studied as a natural colourant. Its six-gene biosynthetic cluster is one of the better-understood fungal polyketide pathways.[3][4]

History

[edit]

A red antibiotic named bikaverin was reported in 1970 by Balan and co-workers, who isolated it from Gibberella fujikuroi and found it active against Leishmania braziliensis.[5] Its structure was settled the following year in three back-to-back papers in the Journal of the Chemical Society: John Cornforth's group at Shell described it as a "fungal vacuolation factor", a substance that made hyphae of other fungi form large vacuoles;[1] de Boer and colleagues determined the crystal structure of its chloroform solvate;[6] and Kjær, Bu'Lock and co-workers described bikaverin together with its demethyl analogue norbikaverin.[2] In 1973 a pigment called lycopersin, isolated earlier from Fusarium oxysporum, was shown to be the same compound.[7]

Structure and properties

[edit]

Bikaverin has the formula C20H14O8 and a linear four-ring benzo[b]xanthene skeleton bearing two hydroxyl groups, two methoxy groups, a methyl group and three carbonyls.[2][6] The molecule is a tautomeric hydroxyquinone, and databases list it under two equivalent names, the 6,11-dihydroxy-7,10,12-trione and the 7,10-dihydroxy-6,11,12-trione.[8] Bikaverin is red in the fungal mycelium and in solution; heating biomass that contains it turns the material blue by a mechanism that has not been explained.[9]

Occurrence and biosynthesis

[edit]

Bikaverin has been isolated from Fusarium fujikuroi, F. oxysporum, F. verticillioides and other Fusarium species, and from the unrelated fungus Mycogone jaapii.[3][10] Rare strains of the grey mould Botrytis cinerea carry a complete, functional bikaverin gene cluster that they acquired from Fusarium by horizontal gene transfer.[11] In maize, bikaverin accumulates in kernels rotted by F. verticillioides and has been proposed as a chemical marker of ear rot.[12]

The pigment is a product of a non-reducing polyketide synthase. The synthase gene, first identified as pks4 in F. fujikuroi in 2002,[13] lies in a cluster of six genes, bik1 to bik6, that encode the synthase, an oxidase, a methyltransferase, a transporter, a transcription factor and a regulatory protein. Bikaverin production is switched on by nitrogen starvation and acidic pH and repressed by ammonium.[4] Later work identified the pathway intermediates, including a previously unknown metabolite, oxo-pre-bikaverin.[14] In 2020 the whole pathway was rebuilt in baker's yeast, Saccharomyces cerevisiae, reaching about 200 mg per litre in shake flasks.[15]

Biological activity

[edit]

Bikaverin's earliest reported property was antiprotozoal activity against Leishmania.[5] In the 1970s it was shown to uncouple oxidative phosphorylation in tumour cells and isolated rat-liver mitochondria and to be strongly haemolytic,[16] and to interfere with purine nucleotide metabolism in Ehrlich ascites tumour cells.[17] It is cytotoxic to a range of cancer cell lines,[3] and in 2019 it was identified as an inhibitor of the human protein kinase CK2 with an IC50 of about 1.2 μM.[18] Other reported effects include protection of cultured neurons against oxidative damage[19] and activity against multidrug-resistant bacteria.[20]

Against plant pathogens, bikaverin and fusaric acid from F. oxysporum inhibit the late-blight oomycete Phytophthora infestans, and bikaverin reduced tomato late blight by about 70 per cent in a greenhouse test.[21] In the banana wilt pathogen F. oxysporum f. sp. cubense tropical race 4, bikaverin suppresses beneficial Bacillus bacteria in the root zone and so helps the fungus establish itself; a bikaverin-resistant Bacillus strain has been proposed as a biocontrol agent.[22]

Synthesis

[edit]

The first total synthesis was reported by Derek Barton's group in 1975.[23][24] Kato and co-workers published a second route in 1977, built around the rearrangement of an ortho-quinone to a para-quinone,[25] and further syntheses followed from Hauser (1988), Bekaert (1992) and Anufriev (2018).[26][27][28]

References

[edit]
  1. 1 2 Cornforth, J. W.; Ryback, G.; Robinson, P. M.; Park, D. (1971). "Isolation and characterization of a fungal vacuolation factor (bikaverin)". Journal of the Chemical Society C: Organic. 16: 2786–2788. doi:10.1039/J39710002786. PMID 5168483.
  2. 1 2 3 Kjær, D.; Kjær, A.; Pedersen, C.; Bu'Lock, J. D.; Smith, J. R. (1971). "Bikaverin and norbikaverin, benzoxanthentrione pigments of Gibberella fujikuroi". Journal of the Chemical Society C: Organic. 16: 2792–2797. doi:10.1039/J39710002792. PMID 5168485.
  3. 1 2 3 Limón, M. C.; Rodríguez-Ortiz, R.; Avalos, J. (2010). "Bikaverin production and applications". Applied Microbiology and Biotechnology. 87 (1): 21–29. doi:10.1007/s00253-010-2551-1. PMID 20376635.
  4. 1 2 Wiemann, P.; Willmann, A.; Straeten, M.; Kleigrewe, K.; Beyer, M.; Humpf, H.-U.; Tudzynski, B. (2009). "Biosynthesis of the red pigment bikaverin in Fusarium fujikuroi: genes, their function and regulation". Molecular Microbiology. 72 (4): 931–946. doi:10.1111/j.1365-2958.2009.06695.x. PMID 19400779.
  5. 1 2 Balan, J.; Fuska, J.; Kuhr, I.; Kuhrová, V. (1970). "Bikaverin, an antibiotic from Gibberella fujikuroi, effective against Leishmania brasiliensis". Folia Microbiologica. 15 (6): 479–484. doi:10.1007/BF02880192. PMID 5497222.
  6. 1 2 de Boer, J. J.; Bright, D.; Dallinga, G.; Hewitt, T. G. (1971). "Crystal and molecular structure of the chloroform solvate of bikaverin". Journal of the Chemical Society C: Organic. 16: 2788–2791. doi:10.1039/J39710002788. PMID 5168484.
  7. ↑ Brewer, D.; Arsenault, G. P.; Wright, J. L. C.; Vining, L. C. (1973). "Production of bikaverin by Fusarium oxysporum and its identity with lycopersin". The Journal of Antibiotics. 26 (12): 778–781. doi:10.7164/antibiotics.26.778.
  8. ↑ "Bikaverin (CID 36433)". PubChem. National Center for Biotechnology Information. Retrieved 5 September 2026.
  9. ↑ Santos, M. C. D.; Bicas, J. L. (2021). "Natural blue pigments and bikaverin". Microbiological Research. 244 126653. doi:10.1016/j.micres.2020.126653. PMID 33302226.
  10. ↑ Terashima, N.; Ishida, M.; Hamasaki, T.; Hatsuda, Y. (1972). "Isolation of bikaverin from Mycogone jaapii". Phytochemistry. 11 (9): 2880. Bibcode:1972PChem..11.2880T. doi:10.1016/S0031-9422(00)86530-9.
  11. ↑ Schumacher, J.; Gautier, A.; Morgant, G.; Studt, L.; Ducrot, P.-H.; Le Pêcheur, P.; Azeddine, S.; Fillinger, S.; Leroux, P.; Tudzynski, B.; Viaud, M. (2013). "A functional bikaverin biosynthesis gene cluster in rare strains of Botrytis cinerea is positively controlled by VELVET". PLOS ONE. 8 (1) e53729. Bibcode:2013PLoSO...853729S. doi:10.1371/journal.pone.0053729. PMC 3538735. PMID 23308280.
  12. ↑ Busman, M.; Butchko, R. A. E.; Proctor, R. H. (2012). "LC-MS/MS method for the determination of the fungal pigment bikaverin in maize kernels as an indicator of ear rot". Food Additives & Contaminants: Part A. 29 (11): 1736–1742. doi:10.1080/19440049.2012.704528. PMID 22845490.
  13. ↑ Linnemannstöns, P.; Schulte, J.; del Mar Prado, M.; Proctor, R. H.; Avalos, J.; Tudzynski, B. (2002). "The polyketide synthase gene pks4 from Gibberella fujikuroi encodes a key enzyme in the biosynthesis of the red pigment bikaverin". Fungal Genetics and Biology. 37 (2): 134–148. Bibcode:2002FuGB...37..134L. doi:10.1016/S1087-1845(02)00501-7. PMID 12409099.
  14. ↑ Arndt, B.; Studt, L.; Wiemann, P.; Osmanov, H.; Kleigrewe, K.; Köhler, J.; Krug, I.; Tudzynski, B.; Humpf, H.-U. (2015). "Genetic engineering, high resolution mass spectrometry and nuclear magnetic resonance spectroscopy elucidate the bikaverin biosynthetic pathway in Fusarium fujikuroi". Fungal Genetics and Biology. 84: 26–36. doi:10.1016/j.fgb.2015.09.006. PMID 26382642.
  15. ↑ Zhao, M.; Zhao, Y.; Yao, M.; Iqbal, H.; Hu, Q.; Liu, H.; Qiao, B.; Li, C.; Skovbjerg, C. A. S.; Nielsen, J. C.; Nielsen, J.; Frandsen, R. J. N.; Yuan, Y.; Boeke, J. D. (2020). "Pathway engineering in yeast for synthesizing the complex polyketide bikaverin". Nature Communications. 11 (1) 6197. Bibcode:2020NatCo..11.6197Z. doi:10.1038/s41467-020-19984-3. PMC 7713123. PMID 33273470.
  16. ↑ Kováč, L.; Böhmerová, E.; Fuska, J. (1978). "Inhibition of mitochondrial functions by the antibiotics, bikaverin and duclauxine". The Journal of Antibiotics. 31 (6): 616–620. doi:10.7164/antibiotics.31.616. PMID 681242.
  17. ↑ Henderson, J. F.; Battell, M. L.; Zombor, G.; Fuska, J.; Nemec, P. (1977). "Effects of bikaverin on purine nucleotide synthesis and catabolism in Ehrlich ascites tumor cells in vitro". Biochemical Pharmacology. 26 (21): 1973–1977. doi:10.1016/0006-2952(77)90004-1. PMID 562668.
  18. ↑ Haidar, S.; Aichele, D.; Birus, R.; Hielscher, J.; Laitinen, T.; Poso, A.; Jose, J. (2019). "In vitro and in silico evaluation of bikaverin as a potent inhibitor of human protein kinase CK2". Molecules. 24 (7): 1380. doi:10.3390/molecules24071380. PMC 6479664. PMID 30965682.
  19. ↑ Nirmaladevi, D.; Venkataramana, M.; Chandranayaka, S.; Ramesha, A.; Jameel, N. M.; Srinivas, C. (2014). "Neuroprotective effects of bikaverin on H2O2-induced oxidative stress mediated neuronal damage in SH-SY5Y cell line". Cellular and Molecular Neurobiology. 34 (7): 973–985. doi:10.1007/s10571-014-0073-6. PMC 11488908. PMID 24848007.
  20. ↑ Deshmukh, R.; Mathew, A.; Purohit, H. J. (2014). "Characterization of antibacterial activity of bikaverin from Fusarium sp. HKF15". Journal of Bioscience and Bioengineering. 117 (4): 443–448. doi:10.1016/j.jbiosc.2013.09.017. PMID 24183988.
  21. ↑ Son, S. W.; Kim, H. Y.; Choi, G. J.; Lim, H. K.; Jang, K. S.; Lee, S. O.; Lee, S.; Sung, N. D.; Kim, J. C. (2008). "Bikaverin and fusaric acid from Fusarium oxysporum show antioomycete activity against Phytophthora infestans". Journal of Applied Microbiology. 104 (3): 692–698. Bibcode:2008JApMb.104..692S. doi:10.1111/j.1365-2672.2007.03581.x. PMID 17927749.
  22. ↑ Lu, H.; Guo, S.; Yang, Y.; Zhao, Z.; Xie, Q.; Wu, Q.; Sun, C.; Luo, H.; An, B.; Wang, Q. (2025). "Bikaverin as a molecular weapon: enhancing Fusarium oxysporum pathogenicity in bananas via rhizosphere microbiome manipulation". Microbiome. 13 (1) 107. doi:10.1186/s40168-025-02109-7. PMC 12042607. PMID 40301992.
  23. ↑ Barton, D. H. R.; Cottier, L.; Freund, K.; Luini, F.; Magnus, P. D.; Salazar, I. (1975). "Synthesis of bikaverin". Journal of the Chemical Society, Chemical Communications (15): 646. doi:10.1039/C3975000646A.
  24. ↑ Barton, D. H. R.; Cottier, L.; Freund, K.; Luini, F.; Magnus, P. D.; Salazar, I. (1976). "Total synthesis of bikaverin (6,11-dihydroxy-3,8-dimethoxy-1-methylbenzo[b]xanthen-7,10,12-trione)". Journal of the Chemical Society, Perkin Transactions 1 (5): 499–503. doi:10.1039/P19760000499. PMID 943408.
  25. ↑ Kato, T.; Katagiri, N.; Nakano, J.; Kawamura, H. (1977). "Total synthesis of bikaverin involving the novel rearrangement of an ortho-quinone to a para-quinone". Journal of the Chemical Society, Chemical Communications (18): 645. doi:10.1039/C39770000645.
  26. ↑ Hauser, F. M.; Hewawasam, P.; Baghdanov, V. M. (1988). "Regiospecific preparation of the benz[b]xanthen-12-one ring system". The Journal of Organic Chemistry. 53 (1): 223–224. doi:10.1021/jo00236a055.
  27. ↑ Bekaert, A.; Andrieux, J.; Plat, M. (1992). "New total synthesis of bikaverin". Tetrahedron Letters. 33 (20): 2805–2806. doi:10.1016/S0040-4039(00)78863-0.
  28. ↑ Anufriev, V.; Pelageev, D.; Borisova, K. (2018). "A simple route to benzo[b]xanthene-6,11,12-triones: synthesis of bikaverin". Synthesis. 50 (19): 3931–3935. doi:10.1055/s-0036-1591587.
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