Balancing the stability and the catalytic specificities of OP hydrolases with enhanced V-agent activities

Protein Engineering, Design & Selection : PEDS
Tony E ReevesJ R Wild

Abstract

Rational site-directed mutagenesis and biophysical analyses have been used to explore the thermodynamic stability and catalytic capabilities of organophosphorus hydrolase (OPH) and its genetically modified variants. There are clear trade-offs in the stability of modifications that enhance catalytic activities. For example, the H254R/H257L variant has higher turnover numbers for the chemical warfare agents VX (144 versus 14 s(-1) for the native enzyme (wild type) and VR (Russian VX, 465 versus 12 s(-1) for wild type). These increases are accompanied by a loss in stability in which the total Gibb's free energy for unfolding is 19.6 kcal/mol, which is 5.7 kcal/mol less than that of the wild-type enzyme. X-ray crystallographic studies support biophysical data that suggest amino acid residues near the active site contribute to the chemical and thermal stability through hydrophobic and cation-pi interactions. The cation-pi interactions appear to contribute an additional 7 kcal/mol to the overall global stability of the enzyme. Using rational design, it has been possible to make amino acid changes in this region that restored the stability, yet maintained effective V-agent activities, with turnover numbers of 68 and 36 s(-1) for VX an...Continue Reading

Citations

Nov 22, 2011·The Journal of Physical Chemistry. B·Diego E B GomesThereza A Soares
May 16, 2014·Biochemical and Biophysical Research Communications·Young-Su JeongHak-Sung Kim
Jan 20, 2016·Bioscience, Biotechnology, and Biochemistry·Kosuke NakayamaKazuyoshi Kawahara
Mar 1, 2016·The Journal of General and Applied Microbiology·Kosuke NakayamaKazuyoshi Kawahara
Aug 6, 2015·Protein Engineering, Design & Selection : PEDS·Gurdip K DaffuJoanne Macdonald
Mar 1, 2012·Drug Testing and Analysis·Melinda E Wales, Tony E Reeves
Jan 17, 2015·Annales pharmaceutiques françaises·A-C CuquelP Burnat
Oct 20, 2015·ACS Applied Materials & Interfaces·Nathan J AlvesScott A Walper
Aug 20, 2020·Annals of the New York Academy of Sciences·Priya KatyalJin Kim Montclare
Oct 9, 2020·Journal of Toxicology·Sudisha Mukherjee, Rinkoo Devi Gupta
Feb 14, 2021·International Journal of Molecular Sciences·Ilya Lyagin, Elena Efremenko
Sep 18, 2013·ACS Chemical Biology·Izhack ChernyDan S Tawfik
Nov 14, 2012·Chemical Reviews·A Subha Mahadevi, G Narahari Sastry
Jun 25, 2013·Journal of the American Chemical Society·Andrew N BigleyFrank M Raushel

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.