Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T lymphocytes recognize antigens consisting of peptides presented by class I and II major histocompatibility complex (MHC) molecules. The peptides identified so far have been predictable from the amino acid sequences of proteins. We have identified the natural peptide target of a CTL clone that recognizes the tyrosinase gene product on melanoma cells. The peptide results from posttranslational conversion of asparagine to aspartic acid. This change is of central importance for peptide recognition by melanoma-specific T cells, but has no impact on peptide binding to the MHC molecule. This posttranslational modification has not been previously described for any MHC-associated peptide and represents the first demonstration of posttranslational modification of a naturally processed class I-associated peptide. This observation is relevant to the identification and prediction of potential peptide antigens. The most likely mechanism for production of this peptide leads to the suggestion that antigenic peptides can be derived from proteins that are translated into the endoplasmic reticulum.
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PMID:An HLA-A2-restricted tyrosinase antigen on melanoma cells results from posttranslational modification and suggests a novel pathway for processing of membrane proteins. 862 64

Oxygen free radical (OFR)-mediated oxidative stress in myocardial cells following ischemia could damage unit membrane and macromolecules such as nucleic acids (DNA). It is being reported that under this condition these cells produce antioxidants and heat shock proteins (HSP 70). It is implied that this family of proteins could function as a "molecular chaperone" in the cell and hence has to be transported to various target sites. This process is comparable to the induction of oxygen free radicals in melanocytes and its response, melanin production following UV light exposure stress. Lamp-1, trp-1 and tyrosinase are melanosomal-associated stress relief proteins which are involved in the production of melanin in the subcellular organelle, melanosomes. UV exposure studies as well as gene transfection studies and antisense hybridization in human melanoma cells clearly indicated an increase and marked coordinated interaction of all these stress relief proteins in melanogenesis. These proteins are synthesized in the endoplasmic reticulum and have to undergo posttranslation modification, sorting and posting to their respective target sites. We simultaneously identified and characterized an ER resident protein, calnexin. It became the potential candidate for "chaperoning" these proteins following translation. Based on the computer analysis of HSP 70 cDNA, we postulate that similar to stress response proteins in melanogenesis, stress relief proteins in myocardial cells may also be modulated by the same ER resident protein, calnexin.
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PMID:Stress relief protein modulation by calnexin. 890 96

Endogenous antigenic epitopes are presented to CD8+ T cells by MHC class I molecules. Many endogenous antigens are glycoproteins, and it is not clear what effect the attachment of carbohydrate to potential immunogenic epitopes has on their processing and presentation (i.e., is the carbohydrate moiety removed prior to presentation, or is it presented along with the peptide to T cells?). A major question in this regard is whether natural antigenic epitopes that possess N-linked carbohydrate can associate with class I molecules during assembly in the endoplasmic reticulum (ER). One such antigenic epitope, corresponding to amino acids 369-377 of the enzyme tyrosinase, possesses an N-linked glycosylation site. We have studied the transport and loading of this epitope in streptolysin O-permeabilized melanoma cells. We show here that that the glycosylated epitope is capable of loading onto newly synthesized HLA-A2 molecules in the ER of two melanoma cell lines. The results are discussed in respect to the processing and presentation of the tyrosinase epitope.
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PMID:An N-glycosylated tyrosinase epitope associates with newly synthesized MHC class I molecules in melanoma cells. 896 Sep 9

To gain insight into how tumor antigens are generated and presented, a panel of peptides corresponding to melanoma-specific T cell epitopes were tested for their transport capacity by the transporter associated with antigen processing (TAP). The melanoma epitopes exhibited differential capacities to be transported by TAP in streptolysin O-permeabilized cells, as well as differential competition for peptide binding to TAP. The data indicate that some melanoma-specific epitopes are good substrates for TAP, while others are poor substrates for TAP. One of the epitopes, derived from tyrosinase, was transported into the endoplasmic reticulum (ER), in spite of being a poor competitor for reporter peptide transport and for peptide binding. These results suggest that the melanoma antigens follow distinct pathways for presentation, along the MHC class I pathway.
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PMID:Binding and transport of melanoma-specific antigenic peptides by the transporter associated with antigen processing. 907 Jun 64

The ink gland of the cuttlefish Sepia officinalis has traditionally been regarded as a convenient model system for investigating melanogenesis. This gland has been shown to contain a variety of melanogenic enzymes including tyrosinase, a dopachrome-rearranging enzyme and peroxidase. However, whether and to what extent these enzymes co-localize in the melanogenic compartments and interact is an open question. Using polyclonal antibodies that recognize the corresponding Sepia proteins, we have been able to demonstrate that peroxidase has a different subcellular localization pattern from tyrosinase and dopachrome-rearranging enzyme. Whereas peroxidase is located in the rough endoplasmic reticulum and in the matrix of premelanosomes and melanosomes, tyrosinase and dopachrome-rearranging enzyme are present in the rough endoplasmic reticulum-Golgi transport system, at the level of trans-Golgi cisternae, trans-Golgi network and coated vesicles, and in melanosomes on pigmented granules. These results fill a longstanding gap in our knowledge of the melanin-producing system in Sepia and provide the necessary background for dissection at the molecular level of the complex interaction between melanogenic enzymes. Moreover, the peculiar and complex organization of melanin in an invertebrate such as Sepia officinalis is surprising and could provide the basis for understanding the process in more evolved systems such as that of mammals.
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PMID:Subcellular localization and function of melanogenic enzymes in the ink gland of Sepia officinalis. 916 9

The loss of tyrosinase, the key enzyme in melanin synthesis, has been implicated in the dedifferentiation of malignant melanocytes. The presence of tyrosinase transcripts and antigenic peptides in melanoma tumors prompted us to investigate whether the basis for the loss of the enzyme was proteolytic degradation. Toward this aim, we followed the kinetics of synthesis, degradation, processing, chaperone binding, inhibitor sensitivity, and subcellular localization of tyrosinase in normal and malignant melanocytes. We found that, in amelanotic melanoma cell lines, tyrosinase failed to reach the melanosome, the organelle for melanin synthesis, because it was retained in the endoplasmic reticulum (ER) and then degraded. Tyrosinase appeared mostly as a 70-kDa core-glycosylated, endoglycosidase H-sensitive, immature form bound to the ER chaperone calnexin and had a life-span of only 25% of normal. Maturation and transit from the ER to the Golgi compartment was facilitated by lowering the temperature of incubation to 31 degrees C. Several proteasome inhibitors caused the accumulation of an approximately 60-kDa tyrosinase doublet that was more prominent in malignant than in normal melanocytes and promoted, to various degrees, the maturation of tyrosinase in melanoma cells and the translocation of the enzyme to melanosomes. The appearance of ubiquitinated tyrosinase after treatment of normal melanocytes with N-acetyl-L-leucinyl-L-leucinal-L-norleucinal reinforced our notion that some tyrosinase is normally degraded by proteasomes. Proteolysis of tyrosinase by proteasomes is consistent with the production of antigenic tyrosinase peptides that are presented to the immune system by major histocompatibility complex class I molecules.
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PMID:Aberrant retention of tyrosinase in the endoplasmic reticulum mediates accelerated degradation of the enzyme and contributes to the dedifferentiated phenotype of amelanotic melanoma cells. 917 96

Tyrosinase is the key enzyme in melanin biosynthesis, catalyzing multiple steps in this pathway. The mature glycoprotein is transported from the Golgi to the melanosome where melanin biosynthesis occurs. In this study, we have investigated the effects of inhibitors of N-glycan processing on the synthesis, transport, and catalytic activity of tyrosinase. When B16 mouse melanoma cells were cultured in the presence of N-butyldeoxynojirimycin, an inhibitor of the endoplasmic reticulum-processing enzymes alpha-glucosidases I and II, the enzyme was synthesized and transported to the melanosome but almost completely lacked catalytic activity. The cells contained only 2% of the melanin found in untreated cells. Structural analysis of the N-glycans from N-butyldeoxynojirimycin-treated B16 cells demonstrated that three oligosaccharide structures (Glc3Man7-9) predominated. Removal of the glucose residues with alpha-glucosidases I and II failed to restore enzymatic activity, suggesting that the glucosylated N-glycans do not sterically interfere with the enzyme's active sites. The mannosidase inhibitor deoxymannojirimycin had no effect on catalytic activity suggesting that the retention of glucosylated N-glycans results in the inactivation of this enzyme. The retention of glucosylated N-glycans does not therefore result in misfolding and degradation of the glycoprotein, as the enzyme is transported to the melanosome, but may cause conformational changes in its catalytic domains.
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PMID:Inhibition of N-glycan processing in B16 melanoma cells results in inactivation of tyrosinase but does not prevent its transport to the melanosome. 918 77

Formation of major histocompatibility complex class I-associated peptides from membrane proteins has not been thoroughly investigated. We examined the processing of an HLA-A*0201-associated epitope, YMDGTMSQV, that is derived from the membrane protein tyrosinase by posttranslational conversion of the sequence YMNGTMSQV. Only YMDGTMSQV and not YMNGTMSQV was presented by HLA-A*0201 on cells expressing full-length tyrosinase, although both peptides have similar affinities for HLA-A*0201 and are transported by TAP. In contrast, translation of YMNGTMSQV in the cytosol, as a minigene or a larger fragment of tyrosinase, led to the presentation of the unconverted YMNGTMSQV. This was not due to overexpression leading to saturation of the processing/conversion machinery, since presentation of the converted peptide, YMDGTMSQV, was low or undetectable. Thus, presentation of unconverted peptide was associated with translation in the cytosol, suggesting that processing of the full-length tyrosinase occurs after translation in the endoplasmic reticulum. Nevertheless, presentation of YMDGTMSQV in cells expressing full-length tyrosinase was TAP (transporter associated with antigen processing) and proteasome dependent. After inhibition of proteasome activity, tyrosinase species could be detected in the cytosol. We propose that processing of tyrosinase involves translation in the endoplasmic reticulum, export of full-length tyrosinase to the cytosol, and retransport of converted peptides by TAP for association with HLA-A*0201.
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PMID:The class I antigen-processing pathway for the membrane protein tyrosinase involves translation in the endoplasmic reticulum and processing in the cytosol. 941 9

Several melanosome membrane proteins have been identified, forming a family of proteins known as tyrosinase related proteins. Human TRP-1/gp75 is sorted to melanosomes through the endoplasmic reticulum and Golgi complex to the endocytic pathway, directed by a sorting signal located in the cytoplasmic tail. This hexapeptide cytoplasmic sequence, which is conserved in the tyrosinase related protein family and through vertebrate evolution, was shown to act also as a sorting signal in mouse gp75, confirming that its sorting and cellular retention function is conserved between human and mouse. The cytoplasmic tail influenced the rate and efficiency of intracellular transport of gp75 from the endoplasmic reticulum to the cis-Golgi. Deletion of 33 or 27 amino acids from the carboxyl end of the 38 amino acid cytoplasmic tail of gp75 caused retention and rapid degradation of the truncated gp75 in the endoplasmic reticulum. This defective movement could be fully corrected by extending the truncated tail with the unrelated cytoplasmic tail of the low density lipoprotein receptor. Thus, the cytoplasmic tail of mouse gp75 not only determines sorting to the endocytic/melanosomal compartment, but also controls export from the endoplasmic reticulum to Golgi.
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PMID:The cytoplasmic tail of the mouse brown locus product determines intracellular stability and export from the endoplasmic reticulum. 954 Sep 69

Many melanoma epitopes are presented to cytotoxic T-lymphocytes (CTLs) by major histocompatibility complex (MHC) class I molecules, and it is reasonable to expect that the epitopes would be good substrates for the transporter associated with antigen processing (TAP), as TAP plays a major role in the transport of peptides into the endoplasmic reticulum (ER) for binding to MHC class I molecules. However, we have previously shown that several melanoma-associated epitopes, such as those derived from tyrosinase, gp100, MAGE-1 and MAGE-2 antigens, are in fact poor substrates for TAP. During the process of determining why these epitopes were capable of eliciting a strong CTL response, yet were poor substrates for TAP, it was observed that the epitopes possessed amino acids at their N-terminus that were deleterious for TAP binding as described for the peptide-binding motif for human TAP. We therefore postulated that the epitopes were transported by TAP as longer precursor molecules, and then trimmed in the ER to the appropriate size for presentation to T-cells. In an effort to test this hypothesis we synthesized a set of peptides, derived from the tyrosinase (YMNGTMSQV) and MAGE-1 (EADPTGHSY) epitopes, which possess N-terminal extensions of up to four amino acids. We show here that the longer peptides are indeed transported into the ER at a significantly higher level than the original epitopes. The data indicate that the longer melanoma-associated peptides are the preferred substrates for TAP, and further support the notion that peptides can be trimmed at the N-terminus in the ER during antigen processing.
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PMID:TAP prefers to transport melanoma antigenic peptides which are longer than the optimal T-cell epitope: evidence for further processing in the endoplasmic reticulum. 976 10


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