Disease relevance of Tyr

• RESULTS: Differently from other albinism models, Tyr activity was not impaired in Oa1-/- eyes [1].
• Rescue of mice homozygous for lethal albino deletions: implications for an animal model for the human liver disease tyrosinemia type 1 [2].
• Cutaneous melanomas of Tyr-SV40E transgenic mice (mice whose transgene consists of the tyrosinase promoter fused to the coding regions of simian virus 40 early genes) strikingly resemble human melanomas in their development and progression [3].
• Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4 [4].
• Primary liver cultures of newborn albino deletion mutant mice (c14CoS/c14CoS) and of phenotypically normal mice (c14CoS/cch or cch/cch) were infected with SV40 virus and multiplying hepatocytes selected in arginine-deficient medium containing epidermal growth factor (EGF), insulin, and hydrocortisone (HC) [5].

Psychiatry related information on Tyr

• Regulation of tyrosinase trafficking and processing by presenilins: partial loss of function by familial Alzheimer's disease mutation [6].
• The preimplantation and early postimplantation effect of chronic alcohol consumption (at least a month before mating and during pregnancy until killing) and of acute ethanol intoxication during the preimplantation period (i.v. injection of ethanol) was studied on albino rats (Wistar) and albino mice (RAP) [7].
• In albino mammals, lack of pigment in the retinal pigment epithelium is associated with retinal defects, including poor visual acuity from a photoreceptor deficit in the central retina and poor depth perception from a decrease in ipsilaterally projecting retinal fibers [8].
• Immunization with peptide analogues revealed that substitution of Tyr for Phe94 was compatible with Id-lambda 2(315) mimicry, but substitution of Ser for Arg95 or Thr for Asn96 destroyed the Th-recognized Id [9].
• Comparison of kcat in catalysis by Lys 91 and Tyr 131 and the corresponding double mutant showed a strong antagonistic interaction between these sites, suggesting a cooperative behavior in facilitating the proton-transfer step of catalysis [10].

High impact information on Tyr

• Differentiation antigens coded by genes such as tyrosinase are also recognized on human melanoma by autologous CTL [11].
• IFN-alpha/beta receptor is physically associated with the cytoplasmic Tyr kinase JAK1, hence, in addition to ligand binding, it is directly involved in signal transduction [12].
• A highly active competitor peptide analog was synthesized in which Tyr was separated from the Thr-Leu pair by a pentaproline spacer [13].
• These results suggest that two events must occur to activate the full transforming potential of pp60c-src: hypophosphorylation at Tyr 527 and hyperphosphorylation at Tyr 416 [14].
• Modifying Tyr 416 to phenylalanine in the 527 or the 519/527 mutants only partially inhibited their kinase activities yet abolished their ability to induce focus formation and promote growth in soft agar [14].

Chemical compound and disease context of Tyr

• Since, so far no effective therapeutic is available for the treatment of pancreatic cancer patients, we have examined the therapeutic potential of either FK228, the combination of these two Tyr-kinase inhibitors or GL-2003, a water-soluble derivative of AG 879, on human pancreatic cancer (Capan-1) xenograft in mice [15].
• Melanogenesis is regulated in large part by tyrosinase (monophenol monooxygenase; monophenol, L-dopa:oxygen oxidoreductase, EC 1.14.18.1), and defective tyrosinase leads to albinism [16].
• In melanocytes and in melanoma cells, cyclic AMP (cAMP)-elevating agents stimulate melanogenesis and increase the transcription of tyrosinase, the rate-limiting enzyme in melanin synthesis [17].
• Tyrosinase, the primary enzyme in melanin synthesis commonly mutated in albinism, oxidizes l-tyrosine to l-dopaquinone using l-3,4-dihydroxyphenylalanine (L-DOPA) as an intermediate product [18].
• The level of mouse tyrosinase mRNA was elevated after stimulation of Cloudman S-91 melanoma cells with melanotropin and isobutylmethylxanthine and the level of transcript reflected that of tyrosinase activity and melanin content in the cells [19].

Biological context of Tyr

• No difference in diabetes development was observed in Tyr/Tyr(c) heterozygotes, showing that protection was recessive [20].
• Mice homozygous for specific deletions around the albino locus on chromosome 7 die within the first few hours of birth [2].
• Deficiency of an enzyme of tyrosine metabolism underlies altered gene expression in newborn liver of lethal albino mice [21].
• We find that c14CoS homozygotes which express transgenic Fah are complemented for all aspects of the complex lethal albino phenotype [2].
• Transient expression assays showed that TDE confers efficient expression of a firefly luciferase reporter gene linked to the tyrosinase gene promoter in MeWo pigmented melanoma cells but not in HeLa cells, which do not express tyrosinase [22].

Anatomical context of Tyr

• Pulse/chase labeling experiments show that Tyr is degraded more quickly in Tyrp1(b) mutant melanocytes than in melanocytes wild type at that locus [23].
• We have recently shown that mouse melanosomes contain two electrophoretically distinct tyrosinase isoenzymes, termed low electrophoretic mobility tyrosinase (LEMT) and high electrophoretic mobility tyrosinase (HEMT), that can be resolved and purified [24].
• A large number of mutations have been identified in tyrosinase, with many leading to its misfolding, endoplasmic reticulum (ER) retention, and degradation [25].
• Here we describe the folding and maturation of human tyrosinase (TYR) using an in vitro translation system coupled with ER-derived microsomes or with semipermeabilized cells, as an intact ER source [25].
• Taken together, our results show that in OCA4 melanocytes, tyrosinase processing and intracellular trafficking to the melanosome is disrupted and the enzyme is abnormally secreted from the cells in immature melanosomes, which disrupts the normal maturation process of those organelles [4].

Associations of Tyr with chemical compounds

• Here, we characterize immunity against another tyrosinase family glycoprotein TRP-2 (the slaty locus protein), using the same mouse model and method of immunization [26].
• The production of melanin pigment in mammals requires tyrosinase, an enzyme which hydroxylates the amino acid tyrosine to DOPA (3,4-dihydroxyphenylalanine), thus allowing the cascade of reactions necessary to synthesize that biopolymer [27].
• The inhibition affected to similar extents the Dopa oxidase activity associated to tyrosinase-related protein-1 (TRP-1) and tyrosinase [28].
• This mutation is adjacent to another cysteine at which, in the analogous position in tyrosinase a mutation results in the albino phenotype [29].
• Here we demonstrate that topical application of dexamethasone during anagen VI decreased the concentration of POMC, MC1-R, and tyrosinase mRNA in the skin [30].

Physical interactions of Tyr

• In sum, these results suggest that, in addition to its catalytic function in oxidizing DHICA, Tyrp1 may play an important role in stabilizing Tyr, a second potential role in the regulation of melanin formation [23].
• Physical mapping of the albino-deletion complex in the mouse to localize alf/hsdr-1, a locus required for neonatal survival [31].
• These results suggest that melanoma cells possess spare melanotropin receptors and that [Nle4, D-Phe7]-substituted analogues bind almost irreversibly to these receptors or to some other component of the adenylate cyclase enzyme complex responsible for enhancing tyrosinase activity and melanin production [32].

Enzymatic interactions of Tyr

• Fumarylacetoacetate hydrolase (FAH) catalyzes the hydrolytic cleavage of a carbon-carbon bond in fumarylacetoacetate to yield fumarate and acetoacetate as the final step of Phe and Tyr degradation [33].
• The new function of Stat1 does not require the Tyr 701 that is phosphorylated when Stat1 becomes a transcriptional activator [34].
• Recently, the CL100 phosphatase has been shown to inactivate p42mapk in vitro by dephosphorylating Thr 183 and Tyr 185 at similar rates [35].

Regulatory relationships of Tyr

• TRP-1 and tyrosinase probes also detected melanoblasts but were both expressed later in development than TRP-2 [36].
• Our results show that TGF-beta1 significantly inhibits melanin synthesis in a concentration-dependent manner and that it reduces the activity of tyrosinase, the rate-limiting melanogenic enzyme [37].
• Alpha-MSH-induced tyrosinase activation and melanin production were completely inhibited by a 100-fold higher concentration of AP9 l -131; the IC50 values for AP91-131 in thetwo assay systems were 91 +/- 22 nM and 95 +/- 15 nM respectively [38].
• TRP-1 was induced simultaneously with tyrosinase, although its inducibility was lower than that of tyrosinase [39].
• Using two ODNs we corrected an inactivating mutation in the tyrosinase gene and introduced an activating mutation into the c-kit gene in a single albino mouse melanocyte [40].

Other interactions of Tyr

• Mice homozygous for albino deletions encompassing the locus alf/hsdr-1 die shortly after birth [21].
• Recently, we and others showed that the gene for fumarylacetoacetate hydrolase (Fah), an enzyme involved in tyrosine catabolism, was disrupted by the lethal albino deletion c14CoS [2].
• Although the brown locus, encoding TRP1, was actually the first member of the tyrosinase gene family to be cloned, its catalytic function (which results in the production of black rather than brown melanin) has been in general dispute [41].
• Several genes critical to the enzymatic regulation of melanin production in mammals have recently been cloned and mapped to the albino, brown and slaty loci in mice [41].
• Deletion mutations at the albino (c) locus have been useful for continuing the development of fine-structure physical and functional maps of the Fes-Hbb region of mouse chromosome 7 [42].

Analytical, diagnostic and therapeutic context of Tyr

• Western blots demonstrate that in these TPA-treated cells there is a concomitant increase in Tyr, Tyrp1 and glycosylated Dct protein levels [43].
• Finally, they suggest lethal albino mice as an animal model for HT1 [2].
• METHODS: Enzyme activity and protein localization were analyzed by immunohistochemistry of tyrosinase (Tyr) in Oa1-null mice [1].
• To discover safe and effective topical skin-lightening agents, we have evaluated alkyl esters of the natural product gentisic acid (GA), which is related to our lead compound methyl gentisate (MG), and four putative tyrosinase inhibitors, utilizing mammalian melanocyte cell cultures and cell-free extracts [44].
• Purified tyrosinase and TRP1 behaved as homodimers as judged by gel filtration chromatography and electrophoresis [45].

References