Regulation of glycogen metabolism in response to the autotrophy-heterotrophy switch in Cyanobacteria

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The synthesis and turn-over of carbon reserve polymers plays a pivotal role in the autotrophy-heterotrophy switch in cyanobacterial metabolism. In collaboration with SCyCode partners Gutekunst, Hagemann and Macek, major advances in our understanding of carbon-storage metabolism and its regulation could be achieved in our recent work. Using the model organism Synechocystis PCC 6803 we could show that the two carbon storage polymers, glycogen and polyhydroxybutyrate (PHB) are interconnected by glycolytic flux through the Emden-Meyerhof-Parnas pathway. Carbon flux between glycogen and PHB is critically controlled at the phosphoglycerate mutase catalyzed interconversion of 3-phosphoglycerate (3-PGA) to 2-PGA, which turns out as a major control point of the heterotrophy-autotrophy switch. Glycogen storage becomes essential, when Synechocystis is starved for combined nitrogen sources. Metabolism switches rapidly to glycogen-consuming, heterotrophic mode, when combined nitrogen sources become available again. In this situation, energy homeostasis is initially based on sodium-motif force-dependent ATP regeneration at the cytoplasmic membrane. The activation of nitrogen-assimilatory reactions then initiates glycogen degradation, which is catalyzed by only one of the two glycogen phosphorylase isoenzymes (GlgP2). We found that the subsequent conversion of Glucose-1P (Glc-1P) to Glc-6P through phosphoglucomutase (PGM) is tightly controlled by a regulatory PGM-seryl-phosphorylation that appears to be conserved in mammalian PGM. Moreover, PGM forms a redox-dependent transient complex (a metabolon) with the subsequent catabolic enzyme, the Glc-6P dehydrogenase (G6PDH), mediated by a redox-controlled connector protein (OpcA). We hypothesize that formation of this complex directs the glycolytic carbon flow towards the oxidative pentose phosphate pathway. This regulatory complex should prevent flux into the glycolytic EMP pathway, dispensable during the re-greening of nitrogen-starved cells. In the second funding period, we aim towards a structure-functional elucidation of PGM-OpcA-G6PDH metabolon formation and moreover aim towards resolving apparently novel regulatory properties of the glycogen metabolic machinery and its integration in the overall cellular processes aided by model-based approaches.