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A Foundational Shift in Models for Enzyme Function
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DOI：10.1021/jacs.5c02388.png)
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Abstract
En 中文
This Perspective addresses the unresolved, and still hotly contested, question of how enzymes transition from stable enzyme-substrate (ES) complexes to successful, femtosecond barrier crossings. By extending Marcus theory to enzyme-catalyzed reactions, we argue that environmental reorganization of the protein scaffold, together with associated water molecules, achieves the intersection of reactant and product potential energy surfaces. After discussing the experimentally demonstrated importance of reduced activation enthalpy in enzyme-catalyzed transformations, we describe new methodologies that measure the temperature dependence of (i) time-averaged hydrogen/deuterium exchange into backbone amides and (ii) time-dependent Stokes shifts to longer emission wavelengths in appended chromophores at the protein/water interface. These methods not only identify specific pathways for the transfer of thermal energy from solvent to the reacting bonds of bound substrates but also suggest that collective thermally activated protein restructuring must occur very rapidly (on the ns-ps time scale) over long distances. Based on these findings, we introduce a comprehensive model for how barrier crossing takes place from the ES complex. This exploits the structural preorganization inherent in protein folding and subsequent conformational sampling, which optimally positions essential catalytic components within ES ground states and correctly places reactive bonds in the substrate(s) relative to embedded energy transfer networks connecting the protein surface to the active site. The existence of these anisotropic energy distribution pathways introduces a new dimension into the ongoing quest for improved de novo enzyme design.
Keywords:
HYDROGEN-DEUTERIUM EXCHANGE
COUPLED ELECTRON-TRANSFER
STRUCTURE-REACTIVITY CORRELATIONS
PROTEIN CONFORMATIONAL ENSEMBLES
TRANSITION-STATE STABILIZATION
ACTIVE-SITE LOOP
C-H ACTIVATION
SOYBEAN LIPOXYGENASE
TEMPERATURE-DEPENDENCE
ADENOSINE-DEAMINASE
Journal
IF:
15.6
Papers:
20.0W
Citations:
60.2W