Incorporation of Nonmethyl Branches by Isoprenoid-like Logic: Multiple β-Alkylation Events in the Biosynthesis of Myxovirescin A1

SummarySeveral polyketide secondary metabolites are predicted to undergo isoprenoid-like β-alkylations during biosynthesis. One such secondary metabolite is myxovirescin A1, produced by Myxococcus xanthus. Myxovirescin is of special interest in that it appears to undergo two distinct β-alkylations. Additionally, the myxovirescin biosynthetic gene cluster lacks tandem thiolation domains required in the synthesis of other β-branched secondary metabolites. To probe the origins of the β-branches in myxovirescin, we heterologously overexpressed the proteins predicted to be responsible for myxovirescin β-alkylation and reconstituted their activities in vitro on model substrates. Our results confirm that myxovirescin undergoes two isoprenoid-like β-alkylations during its biosynthesis, including an unprecedented β-ethylation. The study of its biosynthesis should shed light on the scope and requirements for isoprenoid-like biosynthetic logic in a polyketide context