Tyrosine discovery

Single protein kinases such as PKA, PKC, and Ca +-calmodulin (CaM)-kinases, which result in the phosphorylation of serine and threonine residues in target proteins, play a very important role in hormone action. The discovery that the EGF receptor contains an intrinsic tyrosine kinase activity that is activated by the binding of the hgand EGF was an important breakthrough. The insuhn and IGF-I receptors also contain intrinsic... 

In spite of having no intrinsic catalytic domains, activation of T lymphocytes commences with tyrosine phosphorylations, activation of PLC-v with production of IP3 and DAG, and elevation of cytosolic free Ca2+. Thus, the consequences of receptor ligation are not dissimilar from those induced by the receptors for EGF or PDGF. An early study trying to explain the induction of tyrosine kinase activity resulted in the discovery of the nonreceptor protein tyrosine kinase Lck (p56lck), a T-cell-specific member of the Src family. Lck is associated with the cytosolic tail of CD4 (in helper T cells) or CD8 (in cytotoxic T cells) (Figure 8.14). As mentioned, the extracellular domains of these... 

The reaction of peroxynitrite with the biologically ubiquitous C02 is of special interest due to the presence of both compounds in living organisms therefore, we may be confident that this process takes place under in vivo conditions. After the discovery of this reaction in 1995 by Lymar [136], the interaction of peroxynitrite with carbon dioxide and the reactions of the formed adduct nitrosoperoxocarboxylate ONOOCOO has been thoroughly studied. In 1996, Lymar et al. [137] have shown that this adduct is more reactive than peroxynitrite in the reaction with tyrosine, forming similar to peroxynitrite dityrosine and 3-nitrotyrosine. Experimental data were in quantitative agreement with free radical-mediated mechanism yielding tyrosyl and nitric dioxide radicals as intermediates and were inconsistent with electrophilic mechanism. The lifetime of ONOOCOO was estimated as <3 ms, and the rate constant of Reaction (42) k42 = 2 x 103 1 mol 1 s 1. 

Protein phosphorylation is one of the most important mechanisms in the regulation of cellular function. Proteins can be phosphorylated on serine, threonine or tyrosine residues. Most phosphorylation occurs on serine and threonine, with less than 1% on tyrosine (see Ch. 23). This perhaps accounts for the late discovery of tyrosine phosphorylation, which was found first on polyoma virus middle T antigen in 1979 by Hunter and colleagues [1,2]. 

Discovery of New Protein Targets Involved in Tyrosine Kinase Signaling... 

Watts KT, Mijts BN, Lee PC, Manning AJ, Schmidt-Dannert C (2006) Discovery of a substrate selectivity switch in tyrosine ammonia-lyase, a member of the aromatic amino acid lyase family. Chem Biol 13(12) 1317-1326... 

Another strategy of some interest is to deplete biogenic amines such as OA by inhibiting their biosynthesis. Inhibitors of such enzymes in the biosynthetic pathway as aromatic amino acid decarboxylase which converts tyrosine to tyramine, or dopamine 3 -hydroxylase which converts tyramine to OA are known and have interesting effects in insects (e.g. see 52,53)t but a discussion of this area lies outside the scope of this paper. Nevertheless, it is a particularly interesting one since these or related enzymes are also needed to produce catecholamines for cuticular sclerotiza-tion, thus offering dual routes to the discovery of compounds with selectively deleterious actions on insects. 

Herpin TF, Yu G, Carlson KE, et al. Discovery of tyrosine-based potent and selective melanocortin-1 receptor small-molecule agonists with anti-inflammatory properties, / Med Chem 2003 46 1123-26. 

Craven RJ, Lightfoot H, Cance WG. A decade of tyrosine kinases from gene discovery to therapeutics. Surg Oncol 2003 12 39-49. 

Stadeler s discovery of the formation of chloranil from tyrosine led to the supposition that tyrosine was a derivative of salicylic acid, and on this assumption Schmidt and Nasse attempted to synthesise tyrosine from ethylamine and iodosalicylic acid, and from amidosalicylic and ethyl iodide, but did not succeed. On heating tyrosine they obtained a base CgHuNO, which they thought analogous to the one Schmidt had obtained by heating amidosalicylic acid on this account they held to the accuracy of the theory that tyrosine was ethylamidosalicylic acid. 

In comparison to the level of cellular serine or threonine phosphorylation, protein tyrosine phosphorylation occurs at quite low levels in normal cells but dramatically increases upon oncogenic transformation or stimulation. Since the first discovery in 1978 that the transforming protein from Rous sarcoma virus (pp60vsrc) exhibited intrinsic kinase activity/5 protein kinase activity has also been shown to be inherent to other growth factor receptors such as epidermal growth factor receptor and the insulin receptor,[6 91 and to involve autophosphorylation processes. The diverse biochemical activity exhibited by protein tyrosine phosphorylation has stimulated the development of chemical methods for the preparation of phosphorylated peptides for use as substrates in elucidating the biochemical and physiological activity of phosphorylated site(s). 

After the early discovery of a tyrosine 0-sulfate residue in bovine fibrinopeptide B, 15 this posttranslational modification which occurs ubiquitously in proteins was also detected in a series of biologically active peptides such as the neurohormones of the gastrin/cholecysto-kinin (CCK) family of peptides, phyllokinin, Leu-enkephalin, and the thrombin inhibitor hirudin listed in Table 1. 

Some representatives of the retroviruses cause tumors in animals such as mice or chickens. The discovery of oncogenes initiated from the src gene of Rous sarcoma virus, which could be identified as the tumor causing principle of this retrovirus. The src gene codes for the Src tyrosine kinase (see 8.3). The gene sections of retroviruses responsible for tumor formation were designated oncogenes. 

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