10/07/10

Bioactivity associated with fumonisins

Fumonisins have been associated with the development of liver and kidney cancer in humans (Howard et al., 2001). Fumonisins typically only exerts low levels of acute toxicity, however horses and pigs are more susceptible than other production animals and ingestion can cause equine leukoencephalomalacia (liquirifaction of the brain matter in horses) and porcine pulmonary oedema syndrome in pigs (Marasas et al., 1988). Diseases that might be a result of Fumonisin B1’s inhibitory effects on ceramide synthesis (Wang et al., 1991).
The fumonisin biosynthesis has been described in G. fujikuroi (anamorph F. moniliforme), but the biosynthetic pathway in F. graminearum is believed to be similar. Elucidation of the genetic basis for fumonisin biosynthesis was initiated with a classical linkage analysis in 1996, followed by studies in 1999 and 2001 which identified a cluster of five genes required for synthesis (Desjardins et al., 1996;Proctor et al., 1999;Seo et al., 2001). Subsequent mapping and characterization of the surrounding genes resulted in the identification of 16 co-expressed genes (Figure 13), responsible for a highly complex biosynthetic pathway, which included a iPKS, two fatty acid synthases and numerous different classes of modifying enzymes, including monooxygeases, dehydrogenases, an aminotransferase and a dioxygenase (Proctor et al., 2003).

Identification of this gene cluster allowed for the formulation of a biosynthetic model (Figure 14) which also offered an explanation for the different types of reported fumonisins (B1, B2, B3 and B4). Presently only FUM1 has been linked to the formation of the polyketide backbone and FUM9 to hydroxylation of the C5 position, meaning the the majority of the suggested steps remain to be experimentally proven (Butchko et al., 2003).

The involved PKS (FUM1) in addition to the core domains also include KR, DH, ER and CMeT domains. Fumonisins are nitrogen containing polyketides and could in theory as is the case of fusarin C, be expected to include NRPS related domains. However, here the amino group must be added by an external factor such as FUM8, an aminotransfearase, also encoded by the gene cluster (Brown et al., 2007). Further analysis of the FUM gene cluster has resulted in the identification of a cluster specific transcription factor (FUM21), located adjacent to the iPKS. FUM21 belongs to the binuclear zinc cluster class of transcription factors, and is the prime candidate for a FUM gene cluster specific transcription factor (Brown et al., 2007).

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