Effects of Chemical Modulators on Enzyme Specificity.

Area of Science:

• Biochemistry
• Enzyme kinetics
• Chemical biology

Background:

• Enzymes can process multiple substrates, presenting opportunities for substrate-selective inhibitors (SSIs).
• Understanding how inhibitors affect enzyme specificity is crucial for therapeutic development.
• Current theoretical models for SSIs are limited.

Purpose of the Study:

• To investigate how different chemical inhibition mechanisms influence enzyme substrate specificity.
• To develop a theoretical framework for predicting SSI effects.
• To apply the framework to specific enzyme systems like SIRT2.

Main Methods:

• Analysis of kinetic networks for various enzyme inhibition mechanisms.
• Modeling of substrate specificity changes under different inhibition types.
• Application of the developed framework to the deacylase SIRT2.

Main Results:

• Competitive and uncompetitive inhibitors do not alter substrate specificity.
• Noncompetitive and mixed inhibition mechanisms can change enzyme specificity.
• These specific inhibitors alter free-energy barriers, affecting product formation pathways.
• The suicide inhibitor thiomyristoyl lysine (TM) does not affect SIRT2 specificity without relaxed constraints.

Conclusions:

• Noncompetitive and mixed inhibition are key mechanisms for achieving substrate selectivity.
• The findings provide a framework for understanding and engineering enzyme specificity.
• Insights are relevant for systems where cofactor binding impacts metabolic flux.