Abstract:Tryptophan Synthase (TSase) is an emergent therapeutic target in the treatment of tuberculosis. Interest in TSase as a drug target arose from the fact that this enzyme is not present in humans, while in bacteria, like M. tuberculosis, it catalyses the last two steps in the tryptophan biosynthetic pathway. Several inhibitors of TSase have recently been developed, with promising results. However, the exact catalytic mechanism of this enzyme has remained unexplained at the atomic level. The fact that TSase is a m… Show more
“…This general approach has been used with success in the detailed atomic-level study of the catalytic mechanism of several enzymes. [64][65][66][67][68][69] Activation and reaction Gibbs free energies for each reaction step were determined by the difference between the Gibbs free energies of TS and reactant, or product and reactant, respectively.…”
Section: Catalysis Science and Technology Papermentioning
Plastic accumulation is one of the main environmental issues of our time. In 2016, two enzymes capable of degrading Polyethylene terepthtalate (PET) , one of the most common plastic polymers,...
“…This general approach has been used with success in the detailed atomic-level study of the catalytic mechanism of several enzymes. [64][65][66][67][68][69] Activation and reaction Gibbs free energies for each reaction step were determined by the difference between the Gibbs free energies of TS and reactant, or product and reactant, respectively.…”
Section: Catalysis Science and Technology Papermentioning
Plastic accumulation is one of the main environmental issues of our time. In 2016, two enzymes capable of degrading Polyethylene terepthtalate (PET) , one of the most common plastic polymers,...
“…On the other hand, the reaction Gibbs free energies (∆G R ) were calculated through the difference between the energy of product and reactant for each step. This computational approach has already been successfully employed to study the catalytic mechanism of several enzymes [56][57][58][59][60][61][62], including proteases [63][64][65].…”
SARS-CoV-2 M pro , also known as the main protease or 3C-like protease, is a key enzyme involved in the replication process of the virus that is causing the COVID-19 pandemic. It is also the most promising antiviral drug target targeting SARS-CoV-2 virus. In this work, the catalytic mechanism of M pro was studied using the full model of the enzyme and a computational QM/MM methodology with a 69/72-atoms QM region treated at DLPNO-CCSD(T)/CBS//B3LYP/6-31G(d,p):AMBER level and including the catalytic important oxyanion-hole residues. The transition state of each step was fully characterized and described together with the related reactants and products. The rate-limiting step of the catalytic process is the hydrolysis of the thioester-enzyme adduct, and the calculated barrier closely agrees with the available kinetic data. The calculated Gibbs free energy profile, together with the full atomistic detail of the structures involved in catalysis, can now serve as valuable models for the rational drug design of transition state analogs as new inhibitors targeting the SARS-CoV-2 virus.
“…There are many PLP-dependent enzymes that catalyse many different reactions and they are grouped into seven structural classes 16 . SR is a type II PLP-dependent enzyme and other members of the family include the β-subunit of tryptophan synthase 17 , aspartate racemase 18 , threonine deaminases and serine dehydratase (SDH) 19 . Fig.…”
Human serine racemase (hSR) catalyses racemisation of L-serine to D-serine, the latter of which is a co-agonist of the NMDA subtype of glutamate receptors that are important in synaptic plasticity, learning and memory. In a ‘closed’ hSR structure containing the allosteric activator ATP, the inhibitor malonate is enclosed between the large and small domains while ATP is distal to the active site, residing at the dimer interface with the Tyr121 hydroxyl group contacting the α-phosphate of ATP. In contrast, in ‘open’ hSR structures, Tyr121 sits in the core of the small domain with its hydroxyl contacting the key catalytic residue Ser84. The ability to regulate SR activity by flipping Tyr121 from the core of the small domain to the dimer interface appears to have evolved in animals with a CNS. Multiple X-ray crystallographic enzyme-fragment structures show Tyr121 flipped out of its pocket in the core of the small domain. Data suggest that this ligandable pocket could be targeted by molecules that inhibit enzyme activity.
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