Although GpdQ is part of a pathway that is used by bacteria to degrade glycerolphosphoesters, it hydrolyzes a variety of other phosphodiesters and displays low levels of activity against phosphomono- and triesters. Such a promiscuous nature may have assisted the apparent recent evolution of some binuclear metallohydrolases to deal with situations created by human intervention such such as OP pesticides in the environment. OP pesticides were first used approximately 70 years ago, and therefore the enzymes that bacteria use to degrade them must have evolved very quickly on the evolutionary time scale. The promiscuous nature of enzymes such as GpdQ makes them ideal candidates for the application of directed evolution to produce new enzymes that can be used in bioremediation and against chemical warfare.
In this Account, we review Inhibitors,Modulators,Libraries the mechanisms employed by binuclear metallohydrolases and use PAP, the OP-degrading enzyme from Agrobacterium radiobacter (OPDA), and GpdQ as representative systems because they illustrate both the diversity and similarity of the reactions catalyzed by this family of enzymes. The majority of binuclear metallohydrolases utilize metal ion-activated water molecules as nucleophiles to initiate hydrolysis, while some, such as alkaline phosphatase, employ an intrinsic polar amino add. Here we only focus on catalytic strategies applied by the former group.”
“Currently, therapeutics that modify Alzheimer’s disease (AD)are not Inhibitors,Modulators,Libraries available. Increasing age is the primary risk factor for AD and due to an aging global population the urgent need for effective therapeutics increases every year.
This Account presents the development of an AD treatment strategy Inhibitors,Modulators,Libraries that incorporates diverse compounds Inhibitors,Modulators,Libraries with a common characteristic: the ability to redistribute metal ions within the brain.
Central to cognitive decline in AD is the amyloid-beta peptide (A beta) that accumulates in the AD brain. A range of therapeutic strategies have been developed based on the premise that decreasing the brain A beta burden will attenuate the severity of the disease symptoms. Unfortunately these treatments have failed to show any positive outcomes in large-scale clinical trials, raising many questions regarding whether therapeutics for AD can rely solely on decreasing A beta levels.
An alternate strategy is to target the interaction between A beta and metal ions using compounds with the potential Dacomitinib to redistribute selleckchem metal ions within the brain. The original rationale for this strategy came from studies showing that metal ions promote A beta toxicity and aggregation. In initial studies using the prototype metal-chelating compound dioquinol (CQ), CO prevented A beta toxicity in vitro, out-competed A beta for metal ions without affecting the activity of metal-dependent enzymes, and attenuated the rate of cognitive decline in AD subjects in a small phase II clinical trial.