Kinases catalysis

Stabilize skeletal matter, muscle and nerve triggering, activation of kinases, catalysis... 

Fong TAT, Shawver LK, Sun L, et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-l/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 1999 59 99-106. 

Thiamine is synthesized biologically from the pyrimidine derivative 4-amino-5-hydroxymethyl-2-mcthyl pyrimidine methylpyrimidine and 5-( hydtoxycthyl)-4-methylthia-zole. These two precursors are converted to phosphate derivatives under kinase catalysis, which requires ATP. The respective phosphate derivatives then interact to form thiamine phosphate in a reaction catalyzed by thiamine phosphate pyr-ophosphotyla.se. 

In the human, nicotinic acid reacts with 5-phosphoribosyl-I-pyrophosphate to form nicotinic acid mononucleotide, which then reacts with ATP to produce desamido-NADIthc intermediate dinucleotide with the nicotinic acid moiety). Finally, the latter intermediate is converted to NAD (originally called coenzyme I) by transformation of the emboxyl of the nicotinic acid moiety to the amide by glutamine. Thb final step is catalyzed by NAD synthetase NADP is produced from NAD by ATT under kinase catalysis. ... 

CMP-N-acetylneuraminic acid (CMP-NeuAc). CMP-N-acetylneuraminic acid has been prepared enzymatically on small scales (> 0.5 mmol) from CTP and NeuAc, under catalysis by CMP-NeuAc synthetase (EC 2.7.7.43) [131l An improvement in this procedure, involving in situ production of CTP from CMP under adenylate kinase and pyruvate kinase catalysis, is suitable for multigram-scale synthesis11321. Adenylate kinase catalyzes the equilibration of CTP and CMP to CDP, which is subsequently phosphorylated by pyruvate kinase to provide CTP. A one-pot synthesis of CMP-NeuAc based on this procedure involves the in situ synthesis of NeuAc from N-acetylmannosamine and pyruvate, catalyzed by sialic acid aldolase (Fig. 11.3-12)[10S1. Chemical syntheses of CMP-NeuAc have also been reported11421. 

To summarize, all the above studies clearly indicate the existence of multiple timescales in the hydration-layer dynamics. While a large fraction of hydration-layer water remains almost as fast as its bulk counterpart, a sizable fraction is slow. It is conceivable that the slow water molecules reside near the hydrophilic residues that provide stability to the enzymes, while the fast water molecules participate in the biological activities. For example, in adenylate kinase catalysis, one finds that water molecules play an important functional role, which has been discussed earlier in Chapter 7, section 7.2. 

Left side of Fig. 4 shows a ribbon model of the catalytic (C-) subunit of the mammalian cAMP-dependent protein kinase. This was the first protein kinase whose structure was determined [35]. Figure 4 includes also a ribbon model of the peptide substrate, and ATP (stick representation) with two manganese ions (CPK representation). All kinetic evidence is consistent with a preferred ordered mechanism of catalysis with ATP binding proceeding substrate binding. 

Figure 5.9 Models of hexo-kinase in space-filling and wireframe formats, showing the cleft that contains the active site where substrate binding and reaction catalysis occur. At the bottom is an X-ray crystal structure of the enzyme active site, showing the positions of both glucose and ADP as well as a lysine amino acid that acts as a base to deprotonate glucose.

Like the protein and inositide kinases, the 3D structures of APHs display two distinct domains The N-terminal P-sheet region is responsible for ATP binding, and the a-helical C-terminal provides the aminoglycoside recognition site. The active site, where phosphate transfer occurs, lies at the interface of the two domains. APHs also contain the H-G/N-D-XXXX-N sequence motif, which is common among protein kinases and involved in phosphate transfer catalysis. Structural homology to protein kinases is extended to function, as it has been demonstrated that APHs have weak but measurable protein kinase activity. ... 

This phosphotransferase [EC 2.7.2.1] catalyzes the thermodynamically favored phosphorylation of ADP to form ATP Aeq = [ATP][acetate]/ [acetyl phosphate] [ADP] = 3000). GDP is also an effective phosphoryl group acceptor. This enzyme is easily cold-denatured, and one must use glycerol to maintain full catalytic activity. Initial kinetic evidence, as well as borohydride reduction experiments, suggested the formation of an enzyme-bound acyl-phosphate intermediate, but later kinetic and stereochemicaT data indicate that the kinetic mechanism is sequential and that there is direct in-line phosphoryl transfer. Incidental generation of a metaphosphate anion during catalysis may explain the formation of an enzyme-bound acyl-phosphate. Acetate kinase is ideally suited for the regeneration of ATP or GTP from ADP or GDP, respectively. 

Both ATP and the phosphoryl acceptor become reversibly and selectively bound to the enzyme during catalysis. So far, kinases that have been shown to react by direct phosphoryl transfer between ATP and the co-substrates show strict inversion of configuration at phosphorus, while those with a phosphorylated enzyme Intermediate show retention of configuration at phosphorus (1,2). 

Maniatis,T. Catalysis by a multiprotein IxB kinase complex (1997) Science 278, 818-819... 

The catalytic center is formed by residues from both lobes. Sequence comparisons, mutation experiments and biochemical studies indicate an essential fimction in catalysis of phosphate transfer for the conserved amino acids Lys72, Aspl66 and Aspl84 (numbering of PKA). However, the catalytic mechanism of phosphate transfer is not definitely established. It is generally assumed that Aspl66, which is invariant in all protein kinases, serves as a catalytic base for activation of the Ser/Thr hydroxyl and that the reaction takes place by an in-line attack of the Ser-OH at the y-phosphate. 

The catalytic loop is the region of divergence between Ser/Thr and Tyr kinases. In cAPK and all Ser/Thr Kinases, Lysl68 interacts with the phosphate of ATP during catalysis [12]. The role of Lys is replaced by Arg [9] and the insulin receptor tyrosine kinase structure [3] shows Argl 136 in a similar position as Lys 168 in the active site of cAPK. 

Phosphoglycerate kinase (PGK) catalysis, 376-377 crystal structure, 376-377, 388 human, 377 sequence, 377... 

Hawes, J.W. Schnepf, R.J. Jenkins, A.E. Shimomura, Y. Popov, K.M. Harris, R.A. Roles of amino acid residues surrounding phosphorylation site 1 of branched-chain cr-ketoacid dehydrogenase (BCKDH) in catalysis and phosphorylation site recognition by BCKDH kinase. J. Biol. Chem., 270, 31071-31076 (1995)... 

Ramon-Maiques, S. Marina, A. Gil-Ortiz, F. Fita, I. Rubio, V. Structure of acetylglutamate kinase, a key enzyme for arginine biosynthesis and a prototype for the amino acid kinase enzyme family, during catalysis. Structure, 10, 329-342 (2002)... 

Mourad-Terzian, T. Steghens, J.P. Min, K.L. Collombel, C. Bozon, D. Creatine kinase isoenzymes specificities histidine 65 in human CK-BB, a role in protein stability, not in catalysis. FEBS Lett., 475, 22-26 (2000)... 

Bazaes, S. Beytia, E. Jabalquinto, A.M. Solis de Ovando, E Gomez, I. Pig liver phosphomevalonate kinase. 2. Participation of cysteinyl and lysyl groups in catalysis. Biochemistry, 19, 2305-2310 (1980)... 

Wild, K. Grafmuller, R. Wagner, E. Schulz, G.E. Structure, catalysis and supramolecular assembly of adenylate kinase from maize. Eur. J. Biochem., 250, 326-331 (1997)... 

---