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  • On the other hand Li Zhang et al and

    2021-10-22

    On the other hand, Li+ (Zhang et al., 1996) and Ca2+ (Gizak et al., 2004) cations inhibit FBPases. However, in the case of Ca2+, the inhibition is attributed solely to the muscle isozyme which is over 100 times more susceptible to the cation action than the liver isoform (Gizak et al., 2004). At the amino acids level, this difference results from a single E69Q substitution, (Zarzycki et al., 2007; Gizak et al., 2008; Rakus et al., 2013). The presence of glutamic Tenatoprazole at position 69 ensures strong binding of Ca2+ to the muscle FBPase which in turn, disrupts the proper interaction of catalytic divalent cations (e.g. Mg2+) with the substrate in the catalytic site (Zarzycki et al., 2011; Rakus et al., 2013). Unexpectedly, ectothermal vertebrates FBP2 is significantly less sensitive to Ca2+ than warm-blooded animals (Dziewulska-Szwajkowska et al., 2004) being still more sensitive to the cation than FBP1. Both FBP1 and FBP2 are inhibited by fructose-2,6-bisphosphate which competes for the binding site with FBP (Van Schaftingen and Hers, 1981; Pilkis et al., 1981; Skalecki et al., 1995). Despite the high level of similarity of their primary structures, the two FBPase isozymes differ significantly in susceptibility to inhibition by allosteric effectors, AMP and NAD+. Mammalian and avian FBP2 is about 100 times more susceptible to AMP and NAD+ inhibition than the liver enzyme (Tejwani, 1983; Skalecki et al., 1995; Rakus et al., 2003c; Dziewulska-Szwajkowska et al., 2004) and in physiological concentrations of AMP and NAD+, FBP2 ought to be practically completely inactive (Skalecki et al., 1995). It has been shown that the wild-type FBP1 tetramer exists in at least two distinct quaternary states called R and T (Ke et al., 1991; Zhang et al., 1994) and that the binding of AMP drives the R-to T-state transition where the upper subunit pair rotates about 15° relatively to the bottom subunits within the tetramer (Xue et al., 1994). A proposed mechanism for allosteric regulation of catalysis by allosteric inhibitors involves three conformational states of loop 52–72 called engaged, disengaged, and disordered (Xue et al., 1994; Choe et al., 1998, 2000; Nelson et al., 2001) (Fig. 2). AMP stabilizes the disengaged state whereas metal divalent cations (with the exception of calcium) and the substrate stabilize the engaged state. The enzyme is active if loop 52–72 can cycle between its engaged and disordered conformations (Choe et al., 1998, 2000; Nelson et al., 2001). Binding of at least one molecule of AMP to each half (top/bottom) of the FBP1 tetramer promotes T-state transition of the tetramer and inhibits the activity by precluding the catalytic loop 52–72 to achieve its active, engaged conformation (Nelson et al., 2002) (Fig. 2). The primary and tertiary structures of the AMP binding site of FBP1 and FBP2 are practically indistinguishable and all existing differences are related to the residues forming a relatively weak interactions with the inhibitor (Rakus et al., 2003c). Therefore, the point mutations of such residues in the muscle enzyme towards the liver one only partially lowers the inhibition by AMP (Rakus et al., 2003c). Crystallographic studies have revealed that the quaternary structure of inactive T-states (AMP-saturated) of both FBPase isoforms are very similar, with a small twist of the upper dimer relative to the lower dimer (Shi et al., 2013; Barciszewski et al., 2016). This indicates that the very high sensitivity of FBP2 results from different quaternary arrangements of the active R-state and different trajectories of the T-to-R transition as compared to FBP1 (Barciszewski et al., 2016). Like the liver isozyme, the muscle FBPase is a 222-symmetric homotetramer (Ke et al., 1991; Barciszewski et al., 2016) which may be described as the dimer of two dimers, referred to as the ‘upper’ (subunits C1 and C2) and ‘lower’ (subunits C3 and C4) dimers, with the four subunits labelled C1–C2–C3–C4 in a clockwise manner, starting with C1 at the upper-left corner.