4 research outputs found

    Transition States and Control of Substrate Preference in the Promiscuous Phosphatase PP1

    Get PDF
    Catalytically promiscuous enzymes are an attractive frontier for biochemistry, because enzyme promiscuities not only plausibly explain enzyme evolution through the mechanism of gene duplication but also could provide an efficient route to changing the catalytic function of proteins by mimicking this evolutionary process. PP1γ is an effectively promiscuous phosphatase for the hydrolysis of both monoanionic and dianionic phosphate ester-based substrates. In addition to its native phosphate monoester substrate, PP1γ catalyzes the hydrolysis of aryl methylphosphonates, fluorophosphate esters, phosphorothioate esters, and phosphodiesters, with second-order rate accelerations that fall within the narrow range of 10(11)-10(13). In contrast to the different transition states in the uncatalyzed hydrolysis reactions of these substrates, PP1γ catalyzes their hydrolysis through similar transition states. PP1γ does not catalyze the hydrolysis of a sulfate ester, which is unexpected. The PP1γ active site is tolerant of variations in the geometry of bound ligands, which permit the effective catalysis even of substrates whose steric requirements may result in perturbations to the positioning of the transferring group, both in the initial enzyme-substrate complex and in the transition state. The conservative mutation of arginine 221 to lysine results in a mutant that is a more effective catalyst toward monoanionic substrates. The surprising conversion of substrate preference lends support to the notion that mutations following gene duplication can result in an altered enzyme with different catalytic capabilities and preferences and may provide a pathway for the evolution of new enzymes

    Inhibitors of Serine/Threonine Protein Phosphatases: Biochemical and Structural Studies Provide Insight for Further Development

    No full text

    Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

    No full text
    10.1371/journal.pone.0139981PLoS ONE1010e013998
    corecore