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    • Graduate School - MU Theses and Dissertations (MU)
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    • 2019 Dissertations (MU)
    • 2019 MU dissertations - Freely available online
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    Molecular mechanisms of enzyme dysfunction in human phosphoglucomutase-1 deficiency

    Stiers, Kyle Matthew
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    [PDF] StiersKyle.pdf (3.780Mb)
    Date
    2019
    Format
    Thesis
    Metadata
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    Abstract
    Human phosphoglucomutase-1 (PGM1) belongs to the [alpha]-D-phosphohexomutase superfamily, an ancient lineage of enzymes critical for carbohydrate metabolism. PGM1 catalyzes the interconversion of glucose-1-phosphate and glucose-6-phosphate, acting as the pivot between energy storage and utilization. Recently, PGM1 has been implicated as the monogenic cause of an inherited metabolic disease in humans, called PGM1 deficiency. The disease presents with highly variable phenotype in patients and is difficult to diagnose. Furthermore, genotype-phenotype relationships remain unclear-even in siblings with the same missense variants, no obvious correlation exists. PGM1 deficiency is a unique research opportunity due to the lack of clear rationale for varying effects of missense variants, availability of patient data, favorable in vitro behavior of recombinantly expressed PGM1, and the limited number of structural studies characterizing individual missense variants. In this work we have characterized multiple molecular mechanisms of disease through X-ray crystallography and biochemistry. Thus, this work provides a foundation for physicians to make much more accurate prognostic decisions when advising patients, identifies variants with possible therapeutic interventions, and informs us of key dynamics and structural features required for proper functioning of human PGM1.
    URI
    https://hdl.handle.net/10355/69983
    Degree
    Ph. D.
    Thesis Department
    Biochemistry (MU)
    Rights
    OpenAccess.
    This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.
    Collections
    • 2019 MU dissertations - Freely available online
    • Biochemistry electronic theses and dissertations (MU)
    • Biochemistry electronic theses and dissertations (MU)

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