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Glucose Modulation of Glucokinase Activation by Small Molecules

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Download Hi-Res ImageDownload to MS-PowerPointCite This:Biochemistry 2008, 47, 17, 5028-5036
    Article

    Glucose Modulation of Glucokinase Activation by Small Molecules†
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    Biochemical Pharmacology, La Jolla Laboratories, Pfizer Global Research and Development, San Diego, California 92121
    †This work was supported by the Pfizer Global Research and Development La Jolla Postdoctoral Program.
    * To whom correspondence should be addressed. Phone: 858-526-4922 . Fax: 858-526-4240. E-mail: [email protected]
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    Biochemistry

    Cite this: Biochemistry 2008, 47, 17, 5028–5036
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    https://doi.org/10.1021/bi702516y
    Published March 28, 2008
    Copyright © 2008 American Chemical Society
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    Abstract

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    Small molecule activators of glucokinase (GK) were used in kinetic and equilibrium binding studies to probe the biochemical basis for their allosteric effects. These small molecules decreased the glucose K0.5 (∼1 mM vs ∼8 mM) and the glucose cooperativity (Hill coefficient of 1.2 vs 1.7) and lowered the kcat to various degrees (62–95% of the control activity). These activators relieved GK’s inhibition from glucokinase regulatory protein (GKRP) in a glucose-dependent manner and activated GK to the same extent as control reactions in the absence of GKRP. In equilibrium binding studies, the intrinsic glucose affinity to the activator-bound enzyme was determined and demonstrated a 700-fold increase relative to the apoenzyme. This is consistent with a reduction in apparent glucose KD and the steady-state parameter K0.5 as a result of enzyme equilibrium shifting to the activator-bound form. The binding of small molecules to GK was dependent on glucose, consistent with the structural evidence for an allosteric binding site which is present in the glucose-induced, active enzyme form of GK and absent in the inactive apoenzyme [Kamata et al. (2004) Structure 12, 429–438]. A mechanistic model that brings together the kinetic and structural data is proposed which allows qualitative and quantitative analysis of the glucose-dependent GK regulation by small molecules. The regulation of GK activation by glucose may have an important implication for the discovery and design of GK activators as potential antidiabetic agents.

    Copyright © 2008 American Chemical Society

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    Supporting Information

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    Figures showing the representative traces for the DSC experiments, data for KD,GKA determinations by ITC and SPA, a table of kinetic parameters regarding GKRP inhibition, representative structures of previously published GKAs, appendices showing derivations of eqs 5 and 6, and details regarding the kinetic simulation. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cited By

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    Biochemistry

    Cite this: Biochemistry 2008, 47, 17, 5028–5036
    Click to copy citationCitation copied!
    https://doi.org/10.1021/bi702516y
    Published March 28, 2008
    Copyright © 2008 American Chemical Society
    Request reuse permissions

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