A kinetic rationale for functional redundancy in fatty acid biosynthesis

Area of Science:

• Biochemistry
• Systems Biology
• Metabolic Engineering

Background:

• Fatty acid synthesis (FAS) pathways utilize enzymatic assembly lines.
• Enzymes within FAS pathways often exhibit overlapping catalytic activities.
• The functional significance of this catalytic redundancy is not well understood.

Purpose of the Study:

• To investigate the capabilities and importance of functional redundancy in fatty acid synthesis.
• To examine the control afforded by partially redundant enzymes in FAS.
• To provide a kinetic and control-theoretic rationale for enzyme redundancy in metabolic pathways.

Main Methods:

• Development of a detailed kinetic model of the fatty acid synthase (FAS) from *Escherichia coli*.
• Reconstitution of a functional in vitro FAS system.
• In silico and in vitro compositional analyses of FAS systems.

Main Results:

• Kinetic modeling accurately captures and explains experimental perturbations in FAS systems.
• FAS systems with partially redundant enzymes offer tighter control over total production, unsaturated fraction, and fatty acid chain length compared to systems with single multifunctional enzymes.
• Maximal production of unsaturated fatty acids requires a non-essential secondary dehydratase, highlighting the role of redundancy.

Conclusions:

• Partially redundant enzymes in fatty acid pathways provide a kinetic and control-theoretic advantage.
• Enzyme redundancy enables more independent and broader control of distinct biochemical objectives in fatty acid synthesis.
• This study offers a framework for detailed kinetic investigations of FAS and other metabolic pathways.