The red mycelium pigmentation of members of the Fusarium section Liseola is due to their production of the monomeric naphthoquinone bikaverin (Leslie et al., 2004). Production of this metabolite has in F. fujikuroi been linked to a 18 kb a gene cluster (Figure 8). The cluster is regulated by a positive acting pathway specific transcription factor (bik5) and positive acting NmrA-like regulator (Wiemann et al., 2009).

The cluster encodes three catalytic enzymes: an O-methyltransferase (bik3), a flavin dependent monooxygenase (bik2) and a non-reducing iPKS (bik1 or FfPKS4). Targeted replacement of bik1 resulted in a down regulation of the gene cluster, suggesting the existence of a feedback mechanism whereby the modifying enzymes only are expressed if their substrates are present in the cell. A theory that has gained further support as ectopic overexpression of bik1 (FfPKS4) in a Dbik1 strain restored cluster expression, ruling out that the observed regulation was due to alterations in the local chromatin structure in the Dbik1 strain (Wiemann et al., 2009). Similar down regulation effects have also been reported for the cercosporin gene cluster in Cercospora nicotianae (Chen et al., 2007). Down regulation of cluster expression was also observed upon targeted replacement of bik2 and bik3, a situation that unfortunately has hindered direct characterization of the intermediates in the biosynthetic pathway that leads to bikaverin formation. However, heterologous expression of bik1 (FfPKS4) in E. coli has shown that the unmodified product of the iPKS is the compound SMA76a (Ma et al., 2007), later confirmed by overexpression of the PKS in F. fujikuroi (Wiemann et al., 2009).

Though the bikaverin gene cluster has been subjected to extensive analysis, a biosynthetic model for the formation of the compound has not been presented. However, based on the available data and theoretical biochemical considerations, I have formulated one that fits with the reported chemical information as described in Figure 9. The order of step 2, 4, 5 and 6 are interchangeable and determination of the correct order will require additional experimental data, generated by heterologous expression of the entire biosynthetic pathway.