Moreover studies on subcellular localization of FBPase in ca

Moreover, studies on subcellular localization of FBPase in carp heart and smooth muscle revealed nuclear localization of the enzyme. Previously, we have unequivocally demonstrated the presence of FBPase in the nuclei of mammalian cardiomyocytes (Gizak and Dzugaj, 2003) and myocytes (Gizak et al., 2005). Similar localization of the enzyme has been observed in chicken heart (Zmojdzian et al., 2005) and, quite recently, also in kidney and liver (Yanez et al., 2003). From the enzymes of carbohydrate metabolism found so far in cell nucleus: glucokinase (Miwa et al., 1990), aldolase (Saez and Slebe, 2000, Mamczur and Dzugaj, 2004), glyceraldehyde 3-phosphate dehydrogenase, lactate dehydrogenase, phosphoglycerate kinase (for review see: Ronai, 1993), and glycogen synthase (Ferrer et al., 1997), only the last plays probably the same role in nucleus and in cytoplasm. The other are involved in DNA synthesis, transcription and reparation, or in cell cycle progression (for review see: Kim and Dang, 2005). Therefore, also different physiological role of FBPase in the two subcellular compartments might be expected and the enzyme appears to be more complicated, multifunctional protein rather than simple component of the glyconeogenic pathway. Nuclear transport of muscle FBPase is an active process requiring the presence of cytosolic factors and proceeding through the nuclear pore complex (Gizak et al., 2004). In the process, amino Dabigatran sequence: KKKGK (aa 203–207) possibly plays a role of Nuclear Localization Signal (NLS) (Gizak and Dzugaj, 2003). The sequence, found in all known mammalian muscle FBPases, is also present in carp muscle FBPase (Panserat et al., 2002). Therefore, one could speculate that presumably FBPase shuttling between cytoplasm and nucleus constitute a part of an ancient signalling pathway, linking cellular metabolism with regulation of genes expression. In recent years, more and more evidence has come into light revealing that enzymes which were considered to be involved primarily in carbohydrates metabolism have much broader functional repertoire, and are engaged also in “nuclear” processes. In the light of our current findings, FBPase–a regulatory enzyme of glucose and glycogen synthesis–seems to join the team of the multifaceted enzymes in vertebrates. Unlike mammals and birds, lower vertebrates are insensitive neither to hyper nor to hyperglycemia (De Roos and Rumpf, 1987), nevertheless the similar mechanisms of carbohydrate metabolism regulation in fish like in higher vertebrates are observed. Further studies are necessary to elucidate physiological role of FBPase in nuclei of cardiomyocytes.
Introduction The synthesis of glucose from non-glucidic precursors, such as lactate, amino acids and glycerol [1], [2], occurs mainly in liver and kidney and is essential for glucose homeostasis during fasting. Fructose-1,6-bisphosphatase (FBPase, EC 3.1.3.11) is a key enzyme in the gluconeogenic pathway as it catalyzes the irreversible hydrolysis of fructose-1,6-bisphosphate (Fru-1,6-P2) to fructose-6-phosphate and Pi[3]. On the basis of immunological and kinetic data, at least three distinct forms of FBPase isoenzymes have been proposed: brain, muscle and liver [3], [4], [5]. The liver isoform is the main regulatory enzyme of gluconeogenesis in liver and kidney [1], [2]; however, the physiological roles of the brain and muscle isoenzymes are not fully understood [6], [7]. Liver FBPase has been isolated from several species and presents a homotetrameric structure (36–41 kDa per subunit) and is regulated mainly at the posttranslational level by two synergistic negative effectors, AMP and fructose-2,6-bisphosphate (Fru-2,6-P2) [8], [9]. These metabolites play a crucial function by modulating the rate of gluconeogenic/glycolytic fluxes. Although the liver isoform is found in various human and rat tissues [10], it is expressed mainly in liver and kidney, bi-functional organs that perform glycolysis and gluconeogenesis. In addition, FBPase exhibits a cellular compartmentation in these two tissues, with almost exclusive expression in kidney proximal tubules and higher expression levels in periportal hepatocytes than the perivenous region [11]. In these tissues, FBPase also shows a particular subcellular distribution. In kidney, it is distributed throughout the cytoplasm and in an apical peripheral compartment of proximal epithelial cells. Similar results are observed in liver, where the enzyme is mainly localized in the cytoplasm of periportal hepatocytes, and in a specific compartment close to the plasma membrane of adjacent hepatocytes [11]. Interestingly, FBPase is also observed in the nuclei of hepatocytes and proximal epithelial cells.