Conformation-dependent Post-translational Glycosylation of Tyrosinase

Olivares, Concepción; Solano, Francisco; García‐Borrón, José C.

doi:10.1074/jbc.m300658200

Cited by 40 publications

(31 citation statements)

References 54 publications

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“…The known melanosomal proteins are involved in melanogenesis as catalytic and/or structural components and include TYR, TYRP1, DCT, MART-1, and gp100 (60,70). Although the processing and sorting of those proteins are not completely understood, they are known to be synthesized and translocated into the ER and eventually into the Golgi where their post-translational processing and glycosylation take place (36,71). Following that processing, they seem to take distinct routes to traffic to melanosomes, with the majority of melanosomal proteins predominantly going to stage II melanosomes, although that distribution is disrupted in amelanotic melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Tyrosinase Processing and Trafficking by Organellar pH and by Proteasome Activity

Watabe

Valencia

Yasumoto

et al. 2004

Journal of Biological Chemistry

122

105

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Pigmentation of the hair, skin, and eyes of mammals results from a number of melanocyte-specific proteins that are required for the biosynthesis of melanin. Those proteins comprise the structural and enzymatic components of melanosomes, the membrane-bound organelles in which melanin is synthesized and deposited. Tyrosinase (TYR) is absolutely required for melanogenesis, but other melanosomal proteins, such as TYRP1, DCT, and gp100, also play important roles in regulating mammalian pigmentation. However, pigmentation does not always correlate with the expression of TYR mRNA/protein, and thus its function is also regulated at the post-translational level. Thus, TYR does not necessarily exist in a catalytically active state, and its post-translational activation could be an important control point for regulating melanin synthesis. In this study, we used a multidisciplinary approach to examine the processing and sorting of TYR through the endoplasmic reticulum (ER), Golgi apparatus, coated vesicles, endosomes and early melanosomes because those organelles hold the key to understanding the trafficking of TYR to melanosomes and thus the regulation of melanogenesis. In pigmented cells, TYR is trafficked through those organelles rapidly, but in amelanotic cells, TYR is retained within the ER and is eventually degraded by proteasomes. We now show that TYR can be released from the ER in the presence of protonophore or proton pump inhibitors which increase the pH of intracellular organelles, after which TYR is transported correctly to the Golgi, and then to melanosomes via the endosomal sorting system. The expression of TYRP1, which facilitates TYR processing in the ER, is down-regulated in the amelanotic cells; this is analogous to a hypopigmentary disease known as oculocutaneous albinism type 3 and further impairs melanin production. The sum of these results shows that organellar pH, proteasome activity, and down-regulation of TYRP1 expression all contribute to the lack of pigmentation in TYRpositive amelanotic melanoma cells.

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Section: Discussionmentioning

confidence: 99%

Regulation of Tyrosinase Processing and Trafficking by Organellar pH and by Proteasome Activity

Watabe

Valencia

Yasumoto

et al. 2004

Journal of Biological Chemistry

122

105

View full text Add to dashboard Cite

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“…It has been proven in mouse melanoma cells, that inhibition of the early steps of the N-glycosylation process strongly affects tyrosinase activity, thereby changing melanin synthesis. Moreover, the abnormal N-glycosylation process is related to the depigmented phenotype of human melanomas (Negroiu et al, 1999; Branza-Nichita et al, 2000; Olivares et al, 2003; Wang and Hebert, 2006). …”

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confidence: 99%

The consequences of deglycosylation of recombinant intra-melanosomal domain of human tyrosinase

Dolinska

Sergeev

2017

Biological Chemistry

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Tyrosinase, a melanosomal glycoenzyme, catalyzes initial steps of the melanin biosynthesis. While glycosylation was previously studied in vivo, we present three recombinant mutant variants of human tyrosinase, which were obtained using multiple site-directed mutagenesis, expressed in insect larvae, purified and characterized biochemically. The mutagenesis demonstrated the reduced protein expression and enzymatic activity due to possible loss of protein stability and protein degradation. However, the complete deglycosylation of asparagine residues in vitro, including the residue in position 371, interrupts tyrosinase function, which is consistent with a melanin loss in oculocutaneous albinism type 1 (OCA1) patients.

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“…Expression of tyrosinase was then evaluated by Western blot using a specific antibody directed against tyrosinase (αPEP7). Tyrosinase displayed the expected electrophoretic pattern corresponding to the presence of several N -glycosylation forms [50]. No significant changes in basal tyrosinase expression were observed for cells treated with either CAME or LCAME (Figure 5).…”

Section: Resultsmentioning

confidence: 99%

Conjugation with Dihydrolipoic Acid Imparts Caffeic Acid Ester Potent Inhibitory Effect on Dopa Oxidase Activity of Human Tyrosinase

Micillo

Sirés-Campos

García‐Borrón

et al. 2018

IJMS

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Caffeic acid derivatives represent promising lead compounds in the search for tyrosinase inhibitors to be used in the treatment of skin local hyperpigmentation associated to an overproduction or accumulation of melanin. We recently reported the marked inhibitory activity of a conjugate of caffeic acid with dihydrolipoic acid, 2-S-lipoylcaffeic acid (LCA), on the tyrosine hydroxylase (TH) and dopa oxidase (DO) activities of mushroom tyrosinase. In the present study, we evaluated a more lipophilic derivative, 2-S-lipoyl caffeic acid methyl ester (LCAME), as an inhibitor of tyrosinase from human melanoma cells. Preliminary analysis of the effects of LCAME on mushroom tyrosinase indicated more potent inhibitory effects on either enzyme activities (IC50 = 0.05 ± 0.01 μM for DO and 0.83 ± 0.09 μM for TH) compared with LCA and the reference compound kojic acid. The inhibition of DO of human tyrosinase was effective (Ki = 34.7 ± 1.1 μM) as well, while the action on TH was weaker. Lineweaver–Burk analyses indicated a competitive inhibitor mechanism. LCAME was not substrate of tyrosinase and proved nontoxic at concentrations up to 50 μM. No alteration of basal tyrosinase expression was observed after 24 h treatment of human melanoma cells with the inhibitor, but preliminary evidence suggested LCAME might impair the induction of tyrosinase expression in cells stimulated with α-melanocyte-stimulating hormone. All these data point to this compound as a valuable candidate for further trials toward its use as a skin depigmenting agent. They also highlight the differential effects of tyrosinase inhibitors on the human and mushroom enzymes.

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Conformation-dependent Post-translational Glycosylation of Tyrosinase

Cited by 40 publications

References 54 publications

Regulation of Tyrosinase Processing and Trafficking by Organellar pH and by Proteasome Activity

Regulation of Tyrosinase Processing and Trafficking by Organellar pH and by Proteasome Activity

The consequences of deglycosylation of recombinant intra-melanosomal domain of human tyrosinase

Conjugation with Dihydrolipoic Acid Imparts Caffeic Acid Ester Potent Inhibitory Effect on Dopa Oxidase Activity of Human Tyrosinase

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