Is the catalytic activity of triosephosphate isomerase fully optimized? An investigation based on maximization of entropy production

Abstract

Triosephosphate isomerase (TIM) is often described as a fully evolved housekeeping enzyme with near-maximal possible reaction rate. The assumption that an enzyme is perfectly evolved has not been easy to confirm or refute. In this paper, we use maximization of entropy production within known constraints to examine this assumption by calculating steady-state cyclic flux, corresponding entropy production, and catalytic activity in a reversible four-state scheme of TIM functional states. The maximal entropy production (MaxEP) requirement for any of the first three transitions between TIM functional states leads to decreased total entropy production. Only the MaxEP requirement for the product (R-glyceraldehyde-3-phosphate) release step led to a 30% increase in enzyme activity, specificity constant k/K, and overall entropy production. The product release step, due to the TIM molecular machine working in the physiological direction of glycolysis, has not been identified before as the rate-limiting step by using irreversible thermodynamics. Together with structural studies, our results open the possibility for finding amino acid substitutions leading to an increased frequency of loop six opening and product release.

Maximum Entropy Production Theorem for Transitions between Enzyme Functional States and Its Applications

“…The maximal entropy production (MTEP) optimization for any of the first three transitions between TIM functional states leads to decreased total entropy production. Only the MTEP optimization for the last, the product (R-glyceraldehyde-3-phosphate) release step, increases enzyme activity, specificity constant k cat /K M , and overall entropy production in comparison with experimental values ( Table 2 and Table 3 of Bonačić Lošić et al 2017 [ 11 ]). The product release step is associated with proton transport.…”

“…Different enzymes and kinetic schemes have been considered through the years to examine these questions ( Table 1 ). The steady-state kinetic and thermodynamic formalism, developed by Terrel Hill [ 25 ] to study free energy transduction in biology, has been recently applied to calculate entropy productions associated with all transitions between enzyme functional states in two particularly simple cases: β-lactamases [ 13 ] and triosephosphate isomerase [ 11 ]. Corresponding 3-state ( Figure 1 a) and 4-state kinetic schemes ( Figure 1 b) are just simple single-cycle schemes with only one flux.…”

“…The TIM enzyme catalyzes the isomerization of dihydroxyacetone phosphate (DHAP) to D-glyceraldehyde 3-phosphate (GAP), an essential process in the glycolytic pathway, because only GAP physiological substrate can be subsequently used for glycolysis-derived ATP synthesis. We compared the prediction of optimal kinetic constants, catalytic constant k cat , specificity constant k cat /K M , and total EP applying MTEP for all four transitions between functional states, with the experimental observations for all these transitions [ 11 , 39 ]. The maximal entropy production (MTEP) optimization for any of the first three transitions between TIM functional states leads to decreased total entropy production.…”

“…There are different formulations of the maximum entropy production principle (MEP) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Applications to biochemical systems leading to some optimal parameters are still rare [ 9 , 10 , 11 , 12 , 13 ]. The apparent contradiction between minimum entropy production theorem (MinEP) [ 14 ] and MEP has been examined on a number of occasions [ 15 , 16 ].…”

Theoretical Improvements in Enzyme Efficiency Associated with Noisy Rate Constants and Increased Dissipation

“…We stressed in our previous contributions [74,75] that increasing the TPI catalytic turnover and efficiency above observed "perfect" values is theoretically possible when enzyme kinetics is connected to the maximal partial entropy production principle from irreversible thermodynamics [4]. Regarding the simulation of TPI kinetics, we shall attempt to answer the following questions: (a) Does TPI performance change after noise is considered?…”