Engineering and Functional Activities of Polysialic Acid

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Recent work delivered impressive evidence for multiple functions of the sugar polymer polysialic acid (polySia) in the prevention and therapy of (neuro)inflammatory disorders. Thereby, polySia-functions seem to depend on the chain length. However, the detailed analysis of size-function-relationships of polySia is hampered by the limited availability of these chemically complex compounds. Here we suggest new ways to produce polySia (soluble and protein bound) ideally with defined size and to study in cell-, tissue-, and animal models their biological functions. In more detail we aim to: (i) install polysialylation enzymes with novel enzymatic properties for the synthesis of targeted structures, (ii) generate systems for the efficient in vivo and in vitro synthesis of polySia structures, and (iii) disclose polySia functional activities in selected processes. The objectives will be achieved by: (i) mutational engineering of a bacterial polysialyltransferase, (ii) pathway engineering of Nicotiana benthamiana, a plant species well adapted for glycan engineering and glyco-protein production, (iii) cell and tissue based assays that allow determination of polySia impact on anti-inflammatory activities, (iv) animal models enabling the evaluation of polySias’ impact to protein pharmacokinetic values.This proposal brings together two teams that are leading experts in plant pathway engineering and polySia biology. These complementary expertises allow for a so far unmet multidisciplinary approach to produce polySia-compounds and study functional properties. We expect that the synergistic effect creates a unique competitive advantage, paving new avenues for: (i) the synthesis of complex sugar compounds and the understanding of their biological functions and (ii) the introduction of intricate traits into environmentally friendly organisms (plant pathway engineering).