TY - JOUR

T1 - Multisite Enzymes as a Mechanism for Bistability in Reaction Networks

AU - Hayes, Clarmyra

AU - Feliu, Elisenda

AU - Soyer, Orkun S.

N1 - Publisher Copyright: © 2022 The Authors. Published by American Chemical Society

PY - 2022

Y1 - 2022

N2 - Here, we focus on a common class of enzymes that have multiple substrate binding sites (multisite enzymes) and analyze their capacity to generate bistable dynamics in the reaction networks that they are embedded in. These networks include both substrate-product-substrate cycles and substrate-to-product conversion with subsequent product consumption. Using mathematical techniques, we show that the inherent binding and catalysis reactions arising from multiple substrate-enzyme complexes create a potential for bistable dynamics in such reaction networks. We construct a generic model of an enzyme with n-substrate binding sites and derive an analytical solution for the steady-state concentration of all enzyme-substrate complexes. By studying these expressions, we obtain a mechanistic understanding of bistability, derive parameter combinations that guarantee bistability, and show how changing specific enzyme kinetic parameters and enzyme levels can lead to bistability in reaction networks involving multisite enzymes. Thus, the presented findings provide a biochemical and mathematical basis for predicting and engineering bistability in multisite enzymes.

AB - Here, we focus on a common class of enzymes that have multiple substrate binding sites (multisite enzymes) and analyze their capacity to generate bistable dynamics in the reaction networks that they are embedded in. These networks include both substrate-product-substrate cycles and substrate-to-product conversion with subsequent product consumption. Using mathematical techniques, we show that the inherent binding and catalysis reactions arising from multiple substrate-enzyme complexes create a potential for bistable dynamics in such reaction networks. We construct a generic model of an enzyme with n-substrate binding sites and derive an analytical solution for the steady-state concentration of all enzyme-substrate complexes. By studying these expressions, we obtain a mechanistic understanding of bistability, derive parameter combinations that guarantee bistability, and show how changing specific enzyme kinetic parameters and enzyme levels can lead to bistability in reaction networks involving multisite enzymes. Thus, the presented findings provide a biochemical and mathematical basis for predicting and engineering bistability in multisite enzymes.

KW - enzyme kinetics

KW - multistability

KW - phenotypic heterogeneity

KW - protein engineering

KW - reaction system dynamics

KW - substrate inhibition

KW - synthetic biology

UR - http://www.scopus.com/inward/record.url?scp=85124136567&partnerID=8YFLogxK

U2 - 10.1021/acssynbio.1c00272

DO - 10.1021/acssynbio.1c00272

M3 - Journal article

C2 - 35073044

AN - SCOPUS:85124136567

VL - 11

SP - 596

EP - 607

JO - ACS Synthetic Biology

JF - ACS Synthetic Biology

SN - 2161-5063

IS - 2

ER -