Methylation of demethylavermectins

Area of Science:

• * Biochemistry
• * Molecular Biology
• * Microbial Biosynthesis

Background:

• * Avermectins are complex polyketide natural products with significant biological activity.
• * The biosynthesis of avermectins involves multiple enzymatic steps, including glycosylation and methylation.
• * The precise timing and order of these modifications are crucial for understanding the pathway.

Purpose of the Study:

• * To investigate the timing of methylation events in the biosynthesis of avermectins.
• * To determine if methylation of the oleandrose sugar moiety occurs before or after its attachment to the macrolide ring.
• * To compare avermectin biosynthesis with that of other macrolide antibiotics like tylosin and erythromycin.

Main Methods:

• * Feeding experiments using demethylavermectins (lacking methyl groups on the oleandrose) to wild-type *Streptomyces avermitilis*.
• * Identification and analysis of bioconversion products using analytical techniques.
• * Comparative analysis of methylation patterns in avermectin and other macrolide biosynthesis.

Main Results:

• * Wild-type *Streptomyces avermitilis* did not methylate the oleandrose units of demethylavermectins.
• * The C-5 position of the macrolide ring was methylated in the bioconversion products.
• * These results indicate that methylation of the oleandrose occurs prior to its attachment to the macrolide ring.

Conclusions:

• * Methylation of the oleandrose moiety is not a terminal step in avermectin biosynthesis.
• * Sugar methylation precedes glycosylation in avermectin production.
• * Avermectin biosynthesis pathway differs from tylosin and erythromycin, where hexose methylation is a terminal reaction.