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  • As noted earlier the PfkB

    2023-11-30

    As noted earlier, the PfkB family of carbohydrate kinases can phosphorylate the hydroxymethyl group of a wide variety of sugar moieties [1], [3]. Recent searches of the Swiss-Prot database with the two conserved sequence motifs found in these proteins (Accession nos. PS00583 and PS00584) identified 213 proteins belonging to this family [3]. These proteins included various known members of the PfkB family of proteins (e.g. RKs, AKs, fructokinase, 1-phosphofructokinase, etc.), but also a number of uncharacterized sugar kinases from bacterial sources. Because the sequence identity among these divergent PfkB members is very low (∼20%), the substrate specificity of a new member often cannot be readily predicted. Such was the case for this M. tuberculosis protein, which exhibited greater sequence similarity to RK than to AK, but exhibited very little RK catalytic activity [7]. Although in view of its preference for adenosine over ribose, this protein was suggested to function as AK [7], the results presented here indicate that it seems less likely that this protein carries out adenosine phosphorylation in vivo. It is possible that this protein is involved in the phosphorylation of some other substrate, whose identity remains to be determined.
    Acknowledgment
    Introduction Purinergic systems are well known to regulate neuronal activities in the central atomoxetine hcl (CNS), including the spinal cord, via adenosine and P2 (ATP) receptors (Abbracchio et al., 2009). Adenosine receptors are classified into four subtypes, the A1, A2A, A2B, and A3 receptors (Fredholm et al., 2001). The activation of A1 receptors inhibits neuronal activities (Haas and Selbach, 2000), and also contributes to neuroprotection by suppressing excessive excitation (de Mendonça et al., 2000, Wardas, 2002). Distinct purine turnovers take place inside and outside cells, and transmembrane transport of purines greatly affects the actions of adenosine. Intracellularly, adenosine is degraded to inosine by adenosine deaminase (ADA) and/or is converted to AMP by adenosine kinase (AK). Extracellularly, ATP released from the cell is degraded rapidly to adenosine by a series of ecto-enzymes (Matsuoka and Ohkubo, 2004, Robson et al., 2006). Extracellular adenosine is then incorporated into the cells via nucleoside transporters. Equilibrative nucleoside transporters (ENTs) transport adenosine with bidirectional facilitated diffusion across the membrane (King et al., 2006). Among four ENT isoforms, ENT1 and ENT2 reportedly play major roles in adenosine transport across the cell membrane. ENTs are inhibited by S-(4-nitrobenzyl)-6-thioinosine (NBTI) and some coronary vasodilators, such as dipyridamole (DIP), dilazep and draflazine. ENTs usually function as uptake transporters for adenosine, because intracellular adenosine level is maintained at a lower level than extracellular adenosine level by the activities of AK and ADA. These purine turnover cycles control the extracellular level of adenosine, and thus, they are expected to directly influence CNS functions via adenosine receptors. In the spinal cord, adenosine and its analogs produce analgesia, which is mediated by inhibiting neuronal activities via A1 receptors in the superficial layers of the dorsal horn (Salter et al., 1993: Sawynok, 1998, Sawynok and Liu, 2003). In deep layers of the ventral horn, adenosine likewise inhibits excitatory synaptic transmission, potentially facilitating neuroprotection and/or motor impairment (Miyazaki et al., 2008, Carlsen and Perrier, 2014). Moreover, AK inhibitors release adenosine from the spinal cord (Golembiowska et al., 1995, Golembiowska et al., 1996), and intrathecal administration of these inhibitors yields analgesia (Poon and Sawynok, 1995, McGaraughty et al., 2001, Zhu et al., 2001), although some nucleoside AK inhibitors, such as 5-iodotuberdicin and 5′-amino-5′-deoxyadenosine, have therapeutic limitations because of its adverse effects, poor oral bioavailability or a short half-life in vivo (Ugarkar et al., 2000, McGaraughty et al., 2005).