Sugar kinases

We will discuss small molecule inhibitors of three main classes of nonprotein kinases sugar kinases, nucleoside kinases and lipid kinases. This chapter will be limited to discussion of the inhibition of human kinases. Several non-human non-protein kinases have been the focus of drug development efforts as well, including choline kinase for inhibition of Plasmodium, uridine-cytidine kinase as an anti-parasitic target and thymidine kinase inhibitors as an anti-mycobacterial treatment or for treatment of Herpes simplex viral infections. These applications will not be discussed in this chapter. Peptide... 

P, the seven-carbon sugar serving as the transketolase substrate. Likewise, phosphoribulose kinase carries out the unique plant function of providing RuBP from Ru-5-P (reaction 15). The net conversion accounts for the fixation of six equivalents of carbon dioxide into one hexose at the expense of 18 ATP and 12 NADPH. 

Fig. 6. Vectorial phosphorylation by a mechanism in which translocation and phosphorylation of the sugar are two distinct steps. The product binding site of the translocator T (domain C of II ") would be the substrate binding site of the kinase K (domains A and B). Since both the left-hand cycle and the right-hand cycle are catalyzed by the same enzyme they will very likely be kinetically dependent. Note that the kinetic cycle on the left-hand side of the figure is identical to Fig. 5.

Miller, B.G. and Raines, R.T. (2004) Identifying latent enzyme activities substrate ambiguity within modem bacterial sugar kinases. Biochemistry, 43, 6387-6392. 

Since the first report of cameleon, sensors based on the same approach have been designed to detect small molecules (including cAMP [162, 163], cGMP [164], Ins(l,4,5)P3 [165, 166], lipids [167, 168], and sugars [169]) and the activity of a wide variety of kinases [122, 168, 170, 171]. 

Cruz-Aguado, J.A., Chen, Y., Zhang, Z., Brook, M.A. and Brennan, J.D. (2004) Entrapment of Src protein tyrosine kinase in sugar-modified silica. Analytical Chemistry, 76, 4182— 4188. 

FIGURE 49-3 Proposed transmembrane disposition of bovine rhodopsin. Sugar moieties at asparagine-2 and asparagine-15 are shown with red arrows. Palmitoyl groups at cysteine-322 and cysteine-323 are indicated with broken lines. Hydroxyamino acid residues that may be phosphorylated by rhodopsin kinase are clustered in a C-terminal domain of the molecule. 

Bork, P., Sander, C., and Valencia, A. (1992). An ATPase domain common to prokaryotic cell cycle proteins, sugar kinases, actin, and hsp70 heat shock proteins. Proc. Natl. Acad. Sci. U.S.A. 89, 7290-7294. 

Aciclovir is a member of a group of nucleoside derivatives termed acyclonucleosides, in that there is an incomplete sugar ring. The structural relationship to 2 -deoxyguanosine should be very clear. Aciclovir is converted into its monophosphate by the viral enzyme thymidine kinase - some viruses also possess enzymes that facilitate their replication in the host cell. The viral enzyme turns out to be much more effective than that of the host cell, and conversion is, therefore, mainly in infected cells. The monophosphate is subsequently converted into the triphosphate hy the host cell enzymes. Aciclovir triphosphate inhibits viral DNA polymerase, much more so than it does the host enzyme, and so terminates DNA replication. 

This enzyme [EC 2.7.1.11], also known as phosphohexo-kinase and phosphofructokinase 1, catalyzes the reaction of ATP with D-fructose 6-phosphate to produce ADP and D-fructose 1,6-bisphosphate. Both D-tagatose 6-phosphate and sedoheptulose 7-phosphate can act as the sugar substrate. UTP, CTP, GTP, and ITP all can act as the nucleotide substrate. This enzyme is distinct from that of 6-phosphofructo-2-kinase. See also ATP GTP Depletion... 

The second group of compounds includes the protein kinase C (PKC) inhibitors, such as staurosporine and its derivatives. Usually, they contain a sugar moiety linked... 

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