Properties of Kinases

Proteins at ambient temperature exhibit conformational dynamics on a wide range of time-scales (Fig. 10), and studies of such dynamics have been shown to be particularly important to understand the pharmaceutical properties of kinases (vide infra). 

Hereditary deficiency of phosphoglycerate kinase (PGK) is associated with hereditary hemolytic anemia and often with central nervous system dysfunction and/or myopathy. The first case, reported by Kraus et al. (K24), is a heterozygous female, and the results are not so clear. The second family, reported by Valentine et al. (V3), is a large Chinese family, whose pedigree study indicates that PGK deficiency is compatible with X-linked inheritance. To date, 22 families have been reported (04, T25, Y3). Nine of these have manifested both symptoms five have shown only hemolysis seven have shown the central nervous system dysfunction and/or myopathy but without hemolysis and one case, PGK Munchen, is without clinical symptoms (F5). PGK II is an electrophoretic variant found in New Guinea populations (Y2). Red blood cell enzyme activity, specific activity, and the kinetic properties of this polymorphic variant are normal. 

T21. Tougard, P., Le, T. H., Minard, P Desmadril, M., Yon, J. M., Bizebard, T., Lebras, G and Dumas, C., Structural and functional properties of mutant Arg203Pro from yeast phosphoglycerate kinase, as a model of phosphoglycerate kinase-Uppsaia. Protein Eng. 9, 181-187... 

Yamada, Y., Goto, H. 8r Ogasawara, N. (1980). Purification and properties of adenosine kinase from rat brain. Biochim. Biophys. Acta 616 (2), 199-207. 

Sugimoto T, Itagaki K, Irie K (2008) Design and physicochemical properties of new fluorescent ligands of protein kinase C isozymes focused on CH/7t interaction. Bioorg Med Chem 16 650-657... 

The synthesis of 5-HT can increase markedly under conditions requiring more neurotransmitter. Plasticity is an important concept in neurobiology. In general, this refers to the ability of neuronal systems to conform to either short- or long-term demands placed upon their activity or function (see Plasticity in Ch. 53). One of the processes contributing to neuronal plasticity is the ability to increase the rate of neurotransmitter synthesis and release in response to increased neuronal activity. Serotonergic neurons have this capability the synthesis of 5-HT from tryptophan is increased in a frequency-dependent manner in response to electrical stimulation of serotonergic soma [7]. The increase in synthesis results from the enhanced conversion of tryptophan to 5-HTP and is dependent on extracellular calcium ion. It is likely that the increased 5-HT synthesis results in part from alterations in the kinetic properties of tryptophan hydroxylase, perhaps due to calcium-dependent phosphorylation of the enzyme by calmodulin-dependent protein kinase II or cAMP-dependent protein kinase (PKA see Ch. 23). 

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