Mechanisms Related to Enzyme Catalysis

Entropic and Enthalpic Components of Catalysis in the Mutase and Lyase Activities of Pseudomonas aeruginosa PchB

“…The E. coli chorismate mutase demonstrates a ΔS ‡ value of -3.0 cal/molK 18 , which is within error of the K. pneumoniae and S. aureofaciaens mutase values 14 . These three enzymes are therefore considered to be classic entropy traps: the enzyme achieves the conformational constriction of the substrate during formation of the ES so that conversion of ES to ES ‡ incurs no large entropic penalty 14,24 . The B. subtilis mutase has ΔS ‡ value which is more similar to the uncatalyzed reaction than to the other chorismate mutases (-9.1 cal/molK) 17 , leading to the suggestion that the active site exerts less conformational control and overcomes this deficit with a more significant change in enthalpy 17 .…”

“…14 These three enzymes are therefore considered to be classic entropy traps: the enzyme achieves the conformational constriction of the substrate during formation of the ES so that conversion of ES to ES q incurs no large entropic penalty. 14,24 The B. subtilis mutase has ΔS q value which is more similar to the uncatalyzed reaction than to the other chorismate mutases (À9.1 cal/(mol K)), 17 leading to the suggestion that the active site exerts less conformational control and overcomes this deficit with a more significant change in enthalpy. 17 This compensation allows for the similar ΔG q values for all four mutases (15.0À17.2 kcal/mol).…”

Why Enzymes Are Proficient Catalysts: Beyond the Pauling Paradigm

“…Noncovalent Catalysis and Transition State Binding. A variety of noncovalent factors to explain enzyme efficiencies have been proposed, such as transition state electrostatic stabilization, ground-state destabilization and desolvation, the strong binding of a spectator group accompanied by stress on the reacting part of the molecule (“Circe effect”), a restriction of motion of the reacting fragments of the substrate in the enzyme active site (entropy trap) and related effectsapproximation, proximity, propinquity, and togetherness, , reduction of reorganization energy by binding in near attack conformations (NACs), the spatiotemporal hypothesis, dynamic coupling of protein fluctuations to motions of reactants in the transition state, dynamic enhancement of tunneling, induced fit, noncovalent cooperativity, and enhanced enzyme packing. , These are all specific physical effects that contribute to the greater complementarity of the enzyme for the transition state than the substrate.…”

Ligand efficiency metrics in drug discovery: the pros and cons from a practical perspective

“…Theoretical milestones and drug-like properties Year Efficiency metrics Entropy trap [22] 1962 Anchor principle [23] 1977 Intrinsic binding energies of functional groups [24] 1984 Molecular anchor [25] Patient rule induction method (PRIM) [57] 2014 Lipophilic enthalpy efficiency (LLE H) [58] Lipophilic entropy efficiency (LLE S) [58] Fluorine-corrected molecular weight (MW FC ) [59] 2016 ADMET efficiency index (AEI) [60] Ligand specific efficiency (LSE) [61] a Temptative definition. RBs ≤ 10 Derived from a data set of 1,100 compounds with oral bioavailability in rat; a maximum of seven RBs seem to be optimal for oral bioavailability; these rules should guarantee rat oral bioavailability > 20-40%…”

“…In the seventies, Page and Jencks wondered about the reasons behind the exceptionally high rate of enzyme-catalyzed reactions in comparison with uncatalyzed reactions. They concluded that translational and rotational motions represent the driving force for enzymatic reaction rate 95 enhancement [62]: the catalytic properties of enzymes come from their ability to act as 'entropy traps' [22], © that is, to employ highly oriented substrate-binding interactions [23] to overcome the unfavorable energetic barrier typical of chemical reactions. To evaluate the intrinsic binding energy of the 100 substrate, the 'anchor principle' was introduced: the true binding energy of a group of atoms (or a molecule, A) may be obtained as the difference between the ΔG binding of the molecule presenting A as a substituent (A-B) and the DG binding of the corresponding unsubstituted compound (B, the anchor 105 molecule).…”