Project Details
Description
Nikkomycins are produced by several species of Streptomyces and exhibit fungicidal, insecticidal and acaricidal properties due to their strong inhibition of chitin synthase. Nikkomycins are promising compounds in the cure of the immunosuppressed, such as AIDS patients and organ transplant recipients as well as cancer patients undergoing chemotherapy.
Although the chemical structures of nikkomycins have been known since the 1970s, only a few biosynthetic steps have been investigated in detail. The steps leading to the aminohexuronic acid intermediate are unclear. Originally, it was hypothesized that the aminohexuronic acid moiety is generated by addition of an enolpyruvyl moiety from phosphoenolpyruvate (PEP) to either the uridine or the 4-formyl-4-imidazolin-2-one analog to the 5 -position of ribose. This step is then followed by rather speculative modifications to yield the aminohexuronic acid precursor. In contrast to this hypothesis, we could recently demonstrate that UMP rather than uridine serves as the acceptor for the enolpyruvyl moiety, a reaction catalyzed by an enzyme encoded by a gene of the nikkomycin operon termed nikO. Furthermore, we could demonstrate that it is attached to the 3 - rather than the 5 -position of UMP (Ginj et al., 2005). These results are very intriguing since none of the nikkomycins synthesized possess an enolpyruvyl group in this position of the sugar moiety. Hence, it must be concluded that the resulting 3 -enolpyruvyl-UMP is subject to rearrangement reactions where the enolpyruvyl is detached from its 3 -position and transferred to the 5-position of the ensuing aminohexuronic acid moiety. Currently, nothing is known about the enzymes involved in these putative chemical steps. However, the genes that are co-transcribed with nikO have been reported and are designated nikI, nikJ, nikK, nikL, nikM and nikN. In order to investigate the role of the encoded proteins in the biosynthesis of the aminohexuronic acid moiety, these genes will be cloned, expressed and the proteins purified for biochemical characterization
Although the chemical structures of nikkomycins have been known since the 1970s, only a few biosynthetic steps have been investigated in detail. The steps leading to the aminohexuronic acid intermediate are unclear. Originally, it was hypothesized that the aminohexuronic acid moiety is generated by addition of an enolpyruvyl moiety from phosphoenolpyruvate (PEP) to either the uridine or the 4-formyl-4-imidazolin-2-one analog to the 5 -position of ribose. This step is then followed by rather speculative modifications to yield the aminohexuronic acid precursor. In contrast to this hypothesis, we could recently demonstrate that UMP rather than uridine serves as the acceptor for the enolpyruvyl moiety, a reaction catalyzed by an enzyme encoded by a gene of the nikkomycin operon termed nikO. Furthermore, we could demonstrate that it is attached to the 3 - rather than the 5 -position of UMP (Ginj et al., 2005). These results are very intriguing since none of the nikkomycins synthesized possess an enolpyruvyl group in this position of the sugar moiety. Hence, it must be concluded that the resulting 3 -enolpyruvyl-UMP is subject to rearrangement reactions where the enolpyruvyl is detached from its 3 -position and transferred to the 5-position of the ensuing aminohexuronic acid moiety. Currently, nothing is known about the enzymes involved in these putative chemical steps. However, the genes that are co-transcribed with nikO have been reported and are designated nikI, nikJ, nikK, nikL, nikM and nikN. In order to investigate the role of the encoded proteins in the biosynthesis of the aminohexuronic acid moiety, these genes will be cloned, expressed and the proteins purified for biochemical characterization
| Status | Finished |
|---|---|
| Effective start/end date | 1/07/07 → 30/09/10 |
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