Staff Members of the Institute of Biochemistry, TU - Institut für ...

Nikkomycin biosynthesis
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, organ
transplant recipients and cancer patients undergoing chemotherapy. Nikkomycin Z (R 1 = uracil &
R 2 = OH, see below) is currently in clinical trial for its antifungal activity. Structurally,
nikkomycins can be classified as peptidyl nucleosides containing two unusual amino acids, i.e.
hydroxypyridylhomothreonine (HPHT) and aminohexuronic acid with an N-glycosidically linked
base:
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 synthesis of
aminohexuronic acid 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 at 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. 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 as 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
(thesis project of Alexandra Binter).
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