Tyrosinase related protein 1 (TRP1) functions as a DHICA oxidase in melanin biosynthesis.

Kobayashi, Takashi; Urabe, Kazunori; Winder, Alison J.; Jiménez‐Cervantes, Celia; Imokawa, Genji; Brewington, Timothy; Solano, Francisco; García‐Borrón, José C.; Hearing, Vincent J.

doi:10.1002/j.1460-2075.1994.tb06925.x

Cited by 453 publications

(347 citation statements)

References 53 publications

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“…[22,23] In addition, it appearst of unction as ad opachrome tautomerase [24] and DHICA (5,6-dihydroxyindole-2-carboxylic acid) oxidase. [25] In contrast, human TYRP1 seems to display only tyrosine hydroxylase activity [26] and not DHICA oxidase activity. [27] Intriguingly,p urified, recombinanti ntra-melanosomal human TYRP1 produced in insect cells does not exhibit hydroxylase nor oxidase activities, in agreement with the crystal structure containing two redox-inactivez inc ions in the active site instead of copper.…”

Section: Tyrp1mentioning

confidence: 98%

Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

Lai

Wichers

Soler-López

et al. 2017

Chemistry A European J

209

208

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Melanin is the main pigment responsible for the color of human skin, hair and eye. Its biosynthesis requires three melanogenic enzymes,t yrosinase (TYR), andt he tyrosinase-relatedp roteins TYRP1 and TYRP2. Thed ifficulty of isolating pure and homogeneous proteins from endogenous sources has hampered their study,and resulted in many contradictory findings regarding their physiological functions. In this review,w es ummarize recent advances on the structure and function of TYR and TYRPs by virtue of the crystal structure of human TYRP1, which is the first available structureo f am ammalian melanogenic enzyme. This structure, combined with tyrosinase structures from other lower eukaryotes and mutagenesis studies of key actives ite residues,s heds light on the mechanism of TYR and TYRPs. Furthermore, a TYRP1-based homology model of TYR provides ah igh-quality platform to map and analyze albinism-related mutations, as wella st he design of specific antimelanogenic compounds. Finally,w ep rovide perspectives for future structure/ functionstudies of TYR and TYRPs.

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Section: Tyrp1mentioning

confidence: 98%

Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

Lai

Wichers

Soler-López

et al. 2017

Chemistry A European J

209

208

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“…Based on these results, it was speculated that human TYRP1 is involved in conversion of L-tyrosine to DOPA with low turnover rates, sufficient to prime the system by the generation of low amounts of DOPA, a necessary co-factor for tyrosinase activity (67). Tyrp1 has also been attributed with various other catalytic functions including Dct (68), dihydroxyindole (DHI) oxidase (69) and dihydroxyindole carboxylic acid (DHICA) oxidase (70). It is now generally accepted that Tyrp1 in the murine system functions as DHICA oxidase based on the demonstration that in murine melanocytes, mutant at the brown locus, do not exhibit DHICA oxidase activity during eumelanogenesis (70,71).…”

Section: Tyrp1 Its Functionmentioning

confidence: 99%

Tyrp1 and Oculocutaneous Albinism Type 3

Sarangarajan

Boissy

2001

Pigment Cell Research

113

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addition to its role in eumelanin synthesis, Tyrp1 is involved in Tyrosinase-related protein 1 (Tyrp1) is a melanocyte-specific maintaining stability of tyrosinase protein and modulating its gene product involved in eumelanin synthesis. Mutations in the catalytic activity. Tyrp1 is also involved in maintenance of mouse Tyrp1 gene are associated with brown pelage, and in the human TYRP1 gene with oculocutaneous albinism type 3 melanosome ultrastructure and affects melanocyte prolifera-(OCA3). In the murine system, Tyrp1 expresses significant tion and melanocyte cell death. The current review is an dihydroxyindole carboxylic acid oxidase (i.e. DHICA oxattempt to consolidate our understanding of the role of Tyrp1 idase) activity. However, in humans, TYRP1 is enigmatic in in the melanocyte. that despite extensive efforts focused on the study of its Key words: Pigmentation, Tyrosine hydroxylase, Brown/Rufunction, its actual role in the human melanocyte is still fous Albinism, Brown locus, Protein trafficking unclear. There is mounting evidence demonstrating that in Mutations in the genes encoding some of the enzymes and regulatory proteins involved in melanin synthesis result in various forms of oculocutaneous albinism (OCA). OCA1 correlates with mutations in the tyrosinase (TYR) gene (7). Most individuals with OCA1 have completely amelanotic skin, hair and eyes with the inability to tan (i.e. OCA1A). However, some nucleotide lesions of the TYR gene result in a partially functional enzyme so that individuals with this subtype of OCA1 can exhibit moderate levels of skin and hair pigmentation and the ability to tan (i.e. OCA1B). OCA2 correlates with mutations in the P gene (8). Individuals with OCA2 present with minimal to moderate amounts of pigment remaining in the skin, hair and eyes, many of whom can develop pigmented freckles, lentigines and/or nevi with age. OCA3 correlates with mutations in the TYRP1 gene (9). Individuals with OCA3 present with minimal pigment reduction in the skin, hair and eyes. This form of albinism was previously referred to as Rufous and possibly some forms of Brown albinism.

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“…Tyrosinase (TYR) is the critical and rate‐limiting enzyme; it catalyzes the hydroxylation and subsequent oxidation of tyrosine. Tyrosinase‐related protein 2 (TYRP2) is a tautomerase,2 and tyrosinase‐related protein 1 (TYRP1) has been suggested to catalyze the oxidation of 5,6‐dihydroxyindole‐2‐carboxylic acid (DHICA) in mice,3 although this activity has been challenged in humans 4. All three enzymes are metal‐containing glycoproteins localized in melanosomes where melanin synthesis takes place.…”

mentioning

confidence: 99%

Structure of Human Tyrosinase Related Protein 1 Reveals a Binuclear Zinc Active Site Important for Melanogenesis

et al. 2017

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Tyrosinase‐related protein 1 (TYRP1) is one of three tyrosinase‐like glycoenzymes in human melanocytes that are key to the production of melanin, the compound responsible for the pigmentation of skin, eye, and hair. Difficulties with producing these enzymes in pure form have hampered the understanding of their activity and the effect of mutations that cause albinism and pigmentation disorders. Herein we show that the typical tyrosinase‐like subdomain of TYRP1 contains two zinc ions in the active site instead of copper ions as found in tyrosinases, which explains why TYRP1 does not exhibit tyrosinase redox activity. In addition, the structures reveal for the first time that the Cys‐rich subdomain, which is unique to vertebrate melanogenic proteins, has an epidermal growth factor‐like fold and is tightly associated with the tyrosinase subdomain. Our structures suggest that most albinism‐related mutations of TYRP1 affect its stability or activity.

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Tyrosinase related protein 1 (TRP1) functions as a DHICA oxidase in melanin biosynthesis.

Cited by 453 publications

References 53 publications

Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

Tyrp1 and Oculocutaneous Albinism Type 3

Structure of Human Tyrosinase Related Protein 1 Reveals a Binuclear Zinc Active Site Important for Melanogenesis

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