# Effects of Chemical Modulators on Enzyme Specificity

## TL;DR

The paper explores how different types of chemical inhibitors affect enzyme specificity and provides theoretical insights into their mechanisms.

## Contribution

The study introduces a theoretical framework showing how noncompetitive and mixed inhibitors can alter enzyme specificity.

## Key findings

- Competitive and uncompetitive inhibitors do not affect substrate specificity.
- Noncompetitive and mixed inhibitors can alter enzyme specificity and cause nonmonotonic responses.
- The suicide inhibitor TM cannot influence SIRT2 substrate specificity without specific biochemical conditions.

## Abstract

Chemical inhibitors bind to enzymes, thereby inhibiting
their catalytic
activity. While many enzymes catalyze reactions with a single substrate,
others, like DNA polymerase, can act on multiple related substrates.
Substrate-selective inhibitors (SSIs) target these multisubstrate
enzymes to modulate their specificity. Although SSIs hold promise
as therapeutics, our theoretical understanding of how different inhibitors
influence enzyme specificity remains limited. In this study, we examine
enzyme selectivity within kinetic networks corresponding to known
inhibition mechanisms. We demonstrate that competitive and uncompetitive
inhibitors do not affect substrate specificity, regardless of rate
constants. In contrast, noncompetitive and mixed inhibition can alter
specificity and can lead to nonmonotonic responses to the inhibitor.
We show that mixed and noncompetitive inhibitors achieve substrate-selective
inhibition by altering the effective free-energy barriers of product
formation pathways that are enabled by the inhibitor’s presence.
We then apply this framework to the Sirtuin-family deacylase SIRT2,
showing that the suicide inhibitor thiomyristoyl lysine (TM) cannot
influence substrate specificity unless there is a direct substrate
exchange reaction or biochemical constraints are relaxed. These findings
provide insights into engineering systems where cofactor binding modulates
metabolic flux ratios.