Bikaverin

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. 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.

History

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. 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; de Boer and colleagues determined the crystal structure of its chloroform solvate; and Kjær, Bu'Lock and co-workers described bikaverin together with its demethyl analogue norbikaverin. In 1973 a pigment called lycopersin, isolated earlier from Fusarium oxysporum, was shown to be the same compound.

Structure and properties

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. 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. 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.

Occurrence and biosynthesis

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

The pigment is a product of a non-reducing polyketide synthase. The synthase gene, first identified as pks4 in F. fujikuroi in 2002, 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. Later work identified the pathway intermediates, including a previously unknown metabolite, oxo-pre-bikaverin. In 2020 the whole pathway was rebuilt in baker's yeast, Saccharomyces cerevisiae, reaching about 200 mg per litre in shake flasks.

Biological activity

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

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. 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.

Synthesis

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

References

  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.