Comparison of vibrational frequencies of critical bonds in ground-state complexes and in a vanadate-based transition-state analog complex of muscle phosphoglucomutase. Mechanistic implications

Biochemistry ◽  
1993 ◽  
Vol 32 (48) ◽  
pp. 12984-12992 ◽  
Author(s):  
Hua Deng ◽  
William J. Ray ◽  
John W. Burgner ◽  
Robert Callender
Keyword(s):  
Transition State ◽  
Ground State ◽  
Vibrational Frequencies ◽  
Transition State Analog

Effect of Medium on Reactivity for Alkaline Hydrolysis of p-Nitrophenyl Acetate and S-p-Nitrophenyl Thioacetate in DMSO-H2O Mixtures of Varying Compositions: Ground State and Transition State Contributions

2021 ◽  
Author(s):  
Ik-Hwan Um ◽  
Seungjae Kim
Keyword(s):  
Transition State ◽  
Alkaline Hydrolysis ◽  
Ground State ◽  
Rate Constants ◽  
Kinetic Data ◽  
Reaction Medium ◽  
Stepwise Mechanism ◽  
Rate Determining Step ◽  
Leaving Group ◽  
Hydrolysis Of

Second-order rate constants (kN) for reactions of p-nitrophenyl acetate (1) and S-p-nitrophenyl thioacetate (2) with OH‒ have been measured spectrophotometrically in DMSO-H2O mixtures of varying compositions at 25.0 ± 0.1 oC. The kN value increases from 11.6 to 32,800 M‒1s‒1 for the reactions of 1 and from 5.90 to 190,000 M‒1s‒1 for those of 2 as the reaction medium changes from H2O to 80 mol % DMSO, indicating that the effect of medium on reactivity is more remarkable for the reactions of 2 than for those of 1. Although 2 possesses a better leaving group than 1, the former is less reactive than the latter by a factor of 2 in H2O. This implies that expulsion of the leaving group is not advanced in the rate-determining transition state (TS), i.e., the reactions of 1 and 2 with OH‒ proceed through a stepwise mechanism, in which expulsion of the leaving group from the addition intermediate occurs after the rate-determining step (RDS). Addition of DMSO to H2O would destabilize OH‒ through electronic repulsion between the anion and the negative-dipole end in DMSO. However, destabilization of OH‒ in the ground state (GS) is not solely responsible for the remarkably enhanced reactivity upon addition of DMSO to the medium. The effect of medium on reactivity has been dissected into the GS and TS contributions through combination of the kinetic data with the transfer enthalpies (ΔΔHtr) from H2O to DMSO-H2O mixtures for OH‒ ion.

Renin inhibitors. Synthesis of transition-state analog inhibitors containing phosphorus acid derivatives at the scissile bond

1989 ◽  
Vol 32 (7) ◽  
pp. 1652-1661 ◽  
Author(s):  
Mark C. Allen ◽  
Walter Fuhrer ◽  
Brian Tuck ◽  
Roy Wade ◽  
Jeanette M. Wood
Keyword(s):  
Transition State ◽  
Phosphorus Acid ◽  
Transition State Analog ◽  
Renin Inhibitors ◽  
Scissile Bond

Communication: Photodissociation of CH3CHO at 308 nm: Observation of H-roaming, CH3-roaming, and transition state pathways together along the ground state surface

2015 ◽  
Vol 142 (4) ◽  
pp. 041101 ◽  
Author(s):  
Hou-Kuan Li ◽  
Po-Yu Tsai ◽  
Kai-Chan Hung ◽  
Toshio Kasai ◽  
King-Chuen Lin
Keyword(s):  
Transition State ◽  
Ground State

scholarly journals A crystallographic study of the Toho-1 β-lactamase acylation mechanism

2014 ◽  
Vol 70 (a1) ◽  
pp. C1207-C1207
Author(s):  
Leighton Coates
Keyword(s):  
Hydrogen Bonding ◽  
Transition State ◽  
Active Site ◽  
Catalytic Mechanism ◽  
Substrate Binding ◽  
Ligand Complex ◽  
Transition State Analog ◽  
Hydrogen Bonding Interactions ◽  
Active Site Region ◽  
Neutron Crystallography

β-lactam antibiotics have been used effectively over several decades against many types of highly virulent bacteria. The predominant cause of resistance to these antibiotics in Gram-negative bacterial pathogens is the production of serine β-lactamase enzymes. A key aspect of the class A serine β-lactamase mechanism that remains unresolved and controversial is the identity of the residue acting as the catalytic base during the acylation reaction. Multiple mechanisms have been proposed for the formation of the acyl-enzyme intermediate that are predicated on understanding the protonation states and hydrogen-bonding interactions among the important residues involved in substrate binding and catalysis of these enzymes. For resolving a controversy of this nature surrounding the catalytic mechanism, neutron crystallography is a powerful complement to X-ray crystallography that can explicitly determine the location of deuterium atoms in proteins, thereby directly revealing the hydrogen-bonding interactions of important amino acid residues. Neutron crystallography was used to unambiguously reveal the ground-state active site protonation states and the resulting hydrogen-bonding network in two ligand-free Toho-1 β-lactamase mutants which provided remarkably clear pictures of the active site region prior to substrate binding and subsequent acylation [1,2] and an acylation transition-state analog, benzothiophene-2-boronic acid (BZB), which was also isotopically enriched with 11B. The neutron structure revealed the locations of all deuterium atoms in the active site region and clearly indicated that Glu166 is protonated in the BZB transition-state analog complex. As a result, the complete hydrogen-bonding pathway throughout the active site region could then deduced for this protein-ligand complex that mimics the acylation tetrahedral intermediate [3].

Phosphonamidates as transition-state analog inhibitors of thermolysin

Biochemistry ◽  
1983 ◽  
Vol 22 (20) ◽  
pp. 4618-4624 ◽  
Author(s):  
Paul A. Bartlett ◽  
Charles K. Marlowe
Keyword(s):  
Transition State ◽  
Transition State Analog
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