Cis double bond formation in polyketide biosynthesis

Area of Science:

• Biochemistry
• Organic Chemistry
• Metabolomics

Background:

• Polyketides are a diverse class of bioactive secondary metabolites.
• Most polyketides feature trans (E)-configured double bonds.
• However, cis (Z)-configured double bonds are present in some polyketides, necessitating specific formation mechanisms.

Purpose of the Study:

• To review and elucidate the distinct mechanisms responsible for cis double bond formation in polyketide biosynthesis.
• To highlight the stereochemical control exerted by polyketide synthases (PKSs) in double bond configuration.
• To discuss alternative pathways for cis double bond generation, including post-biosynthetic modifications.

Main Methods:

• Literature review of polyketide biosynthesis pathways.
• Analysis of stereochemical outcomes in PKS-catalyzed reactions.
• Examination of known post-PKS modification enzymes and their roles.

Main Results:

• Ketoreduction and dehydration of ACP-tethered intermediates by PKSs are the primary routes for double bond formation, with ketoreduction dictating stereochemistry.
• Rare cis double bonds can arise from specific stereochemical outcomes during ketoreduction.
• Alternative mechanisms include double bond formation during chain release and post-PKS modifications like isomerizations or oxidative installations.

Conclusions:

• The biosynthesis of polyketides involves intricate enzymatic machinery for double bond formation.
• While trans double bonds are predominant, specific mechanisms ensure the generation of cis double bonds.
• Understanding these pathways provides insights into the structural diversity and biological activity of polyketides.