Structural classification and properties of ketoacyl synthases

Area of Science:

• Biochemistry
• Enzymology
• Structural Biology

Background:

• Ketoacyl synthases (KSs) are crucial enzymes in polyketide and fatty acid synthesis, catalyzing condensation reactions.
• Traditional classification of KSs is based on substrates and reactions, limiting deeper insights into enzyme evolution and function.
• Understanding KS enzyme families is vital for metabolic engineering and drug discovery.

Purpose of the Study:

• To re-classify Ketoacyl synthases (KSs) based on their primary and tertiary structures.
• To enhance understanding of the evolutionary relationships and functional diversity within the KS enzyme superfamily.
• To provide a structured classification system accessible via the ThYme database.

Main Methods:

• Analysis of KS primary and tertiary structures to identify distinct families.
• Comparison of catalytic residues, mechanisms, and tertiary structures across identified families.
• Utilizing the ThYme (Thioester-active enzYme) database for sequence and structure data.

Main Results:

• KSs were classified into five distinct families (KS1-KS5) based on structural characteristics.
• KS1 (bacterial 3-ketoacyl-ACP synthase III), KS2 (plant fatty acid elongases), KS3 (bacterial/eukaryotic 3-ketoacyl-ACP synthases I/II), KS4 (eukaryotic chalcone/stilbene synthases), and KS5 (animal fatty acid elongases).
• KS1-KS4 form a potential enzyme clan, with most families further divided into subfamilies exhibiting significant structural variations.

Conclusions:

• Structural classification provides a more robust framework for understanding KS enzyme evolution and function compared to substrate-based methods.
• The five identified KS families and their subfamilies offer new avenues for investigating polyketide and fatty acid biosynthesis pathways.
• The ThYme database serves as a valuable resource for accessing KS classification data and facilitating future research.