Developing Pharmacological Modulators of STAT Signaling
Jr., Richard H. Bell in JAK-STAT Pathway in Disease, 2006
Abstract s cancer continues to cause over 500,000 deaths per year in the United States alone, it is clear that the cytotoxic drugs commonly in use for cancer treatment are not adequately effective. As we have increased our understanding of the molecular abnormalities in cancer cells, the opportunity arises to target these specifically to achieve greater efficacy and decreased toxicity. Kinase inhibitors have begun to show activity in a number of tumors, but with a few exceptions, the kinases activated in a given tumor are not known. Since STATs are key mediators of many activated tyrosine kinases, developing inhibitors of these transcription factors holds the promise to have widespread applicability in cancer. In addition, drugs that can activate specific STATs may have clinical benefit in certain circumstances as well. In recent years, a number of strategies have been used to develop modulators of STATs for therapeutic purposes and these drugs may be important additions to the repertoire of cancer therapies.
The Modification of Tyrosine
Roger L. Lundblad, Claudia M. Noyes in Chemical Reagents for Protein Modification, 1984
The specific modification of tyrosyl residues in proteins has provided considerable information regarding the participation of these residues in the catalytic processes of enzymes as well as specific binding processes of proteins. There are a number of reagents which may result in the modification of tyrosyl residues. The reaction of chymotrypsinogen A with diazotized arsanilic acid has been investigated. Diazotization of arsanilic acid is accomplished by treatment of p -arsanilic acid with nitrous acid. Iodination is somewhat infrequently used for the modification of tyrosyl residues in protein. The reaction is still of considerable value since the process of the radiolabeling of proteins with either of the iodine radioisotopes primarily involves the modification of tyrosine residues in proteins. The extent of modification of tyrosyl residues by tetranitromethane in proteins can be assessed by either the spectophotometric means or by amino acid analysis.
Testicular immunoregulation
C. Yan Cheng in Spermatogenesis, 2018
Understanding the mechanisms underlying testicular immunoregulation aids the development of strategies for the prevention and treatment of immunological impairment of spermatogenesis. Studies have revealed that Tyro3, Axl, and Mer (TAM) receptor tyrosine kinases and pattern recognition receptors (PRRs) play important roles in the maintenance of the testicular immunoprivileged status and local innate immune responses against microbial infections. This chapter focuses on the mechanisms by which TAM receptors and PRRs regulate testicular immune homeostasis. Receptor tyrosine kinases belong to a superfamily of transmembrane proteins with diverse extracellular regions and a common highly conserved intracellular tyrosine kinase domain. Genetic mutations in TAM receptors result in chronic inflammatory and autoimmune diseases in mice, suggesting that TAM signaling plays an important role in maintaining immune homeostasis. TAM signaling contributes to immune homeostasis by regulating two biological processes: the inhibition of innate immune responses and the promotion of phagocytic clearance of apoptotic cells.
-Tyrosine Production by Analog-resistant Mutants Derived from a Phenylalanine Auxotroph of
Published in Agricultural and Biological Chemistry, 1973
Hiroshi Hagino, Kiyoshi Nakayama
Mutants resistant to various phenylalanine- or tyrosine-analogs were isolated from a phenylalanine auxotroph of Corynebacterium glutamicum KY 10233 by treatment with N- methyl-N′-nitro-N-nitrose guanidine (NTG) and screened for L-tyrosine production. A mutant, 98–Tx–71, which is resistant to 3-aminotyrosine, p-aminophenylalanine, p-fluoro-phenylalanine, and tyrosine hydroxamate was found to produce L-tyrosine at a concentration of 13.5 mg/ml in the cane molasses medium containing 10% of sugar calculated as glucose. A tyrosine-sensitive mutant, pr–20 which was derived from 98–Tx–71 produced L-tyrosine at a concentration of 17.6 mg/ml. L-Tyrosine formation in the strain pr–20 was found to be still inhibited by L-phenylalanine though it was not inhibited by L-tyrosine. The L-tyrosine formation in the mutant was repressed neither by L-phenylalanine nor by L-tyrosine.
Association of plasma
Published in Redox Report, 2014
Szilárd Kun, Esztella Mikolás, Gergo˝ A. Molnár, Eszter Sélley, Boglárka Laczy, Botond Csiky, Tibor Kovács, István Wittmann
Objectives Patients with end-stage renal failure (ESRF) treated with erythropoiesis-stimulating agents (ESAs) are often ESA-hyporesponsive associated with free radical production. Hydroxyl free radical converts phenylalanine into ortho-tyrosine, while physiological isomer para-tyrosine is formed enzymatically, mainly in the kidney. Production of ‘para-tyrosine’ is decreased in ESRF and it can be replaced by ortho-tyrosine in proteins. Our aim was to study the role of tyrosines in ESA-responsiveness. Methods Four groups of volunteers were involved in our cross-sectional study: healthy volunteers (CONTR; n = 16), patients on hemodialysis without ESA-treatment (non-ESA-HD; n = 8), hemodialyzed patients with ESA-treatment (ESA-HD; n = 40), and patients on continuous peritoneal dialysis (CAPD; n = 21). Plasma ortho-, para-tyrosine, and phenylalanine levels were detected using a high performance liquid chromatography (HPLC)-method. ESA-demand was expressed by ESA-dose, ESA-dose/body weight, and erythropoietin resistance index1 (ERI1, weekly ESA-dose/body weight/hemoglobin). Results We found significantly lower para-tyrosine levels in all groups of dialyzed patients when compared with control subjects, while in contrast ortho-tyrosine levels and ortho-tyrosine/para-tyrosine ratio were comparatively significantly higher in dialyzed patients. Among groups of dialyzed patients the ortho-tyrosine level and ortho-tyrosine/para-tyrosine ratio were significantly higher in ESA-HD than in the non-ESA-HD and CAPD groups. There was a correlation between weekly ESA-dose/body weight, ERI1, and ortho-tyrosine/para-tyrosine ratio (r = 0.441, P = 0.001; r = 0.434, P = 0.001, respectively). Our most important finding was that the ortho-tyrosine/para-tyrosine ratio proved to be an independent predictor of ERI1 (β = 0.330, P = 0.016). In these multivariate regression models most of the known predictors of ESA-hyporesponsiveness were included. Discussion Our findings may suggest that elevation of the ratio of ortho-tyrosine/para-tyrosine could be responsible for decreased ESA-responsiveness in dialyzed patients.
Production of 3,4-Dihydroxyphenyl-
Published in Agricultural and Biological Chemistry, 1973
Hajime Yoshida, Yoshitake Tanaka, Kiyoshi Nakayama
Six strains of bacteria belonging to Vibrio and Pseudomonas were selected as good producers of L-DOPA from L-tyrosine out of various bacteria. The condition for the formation of L-DOPA by Vibrio tyrosinaticus ATCC 19378 was examined and the following results were obtained. (1) Intermittent addition of L-tyrosine in small portions gave higher titer of L-DOPA than single addition of L-tyrosine. (2) Higher amount of L-DOPA was produced in stationary phase of growth than in logarithmic phase. (3) Addition of antioxidant, chelating agent or reductant such as L-ascorbic acid, araboascorbic acid, hydrazine, citric acid and 5-ketofructose increased the amount of L-DOPA formed. (4) L-Tyrosine derivatives such as N-acetyl-L-tyrosine amide, N-acetyl-L-tyrosine, L-tyrosine amide, L-tyrosine methyl ester and L-tyrosine benzyl ester were converted to the corresponding L-DOPA derivatives. In the selected condition about 4 mg/ml of L-DOPA was produced from 4.3 mg/ml of L-tyrosine.
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