Role glykolytických enzymů v rozvoji nádorových a metabolických onemocnění

Šimčíková, Daniela

In this Ph.D. thesis, we aimed to focus on molecular mechanisms that underlie the roles of hexokinases in health and disease. First, we focused on the molecular basis of GCK-MODY and possibilities how to predict effects of variations in genes causing Mendelian disorders in general. We performed in vitro experiments on GCK and its variants carrying activating, neutral or inactivating variations. Subsequently, we compared these experimental results with outcomes from the state-of-the-art prediction algorithms with distinct backgrounds. As a result of analyses, we realized that the prediction algorithms commonly suffered from low specificity. Therefore, we suggested a method how to tailor numerical outcomes of these prediction algorithms in order to increase specificity. Furthermore, we determined pH optimum of human GCK and HK2 and investigated the influence of ATP concentrations on buffering capacity of commonly used buffers in hexokinase assays. In the part concerning the role of HKs in tumorigenesis, we studied in vitro somatic cancer-associated variations in GCK, which did not give meaningful evidence for a role of GCK in tumorigenesis, although a subset of somatic cancer-associated variations were activating, thus potentially advantageous for tumors. Therefore, we rather moved to the study of...

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