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Advances in Biological Functions of Tyrosinase
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Advances in Biological Functions of Tyrosinase

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 13412

Special Issue Editor

Prof. Dr. Yuri V. Sergeev

E-Mail Website
Guest Editor
Head Biochemistry and Molecular Modeling Group, Ophthalmic Genetics and Visual Sciences Branch, National Eye Institute, NIH, Bethesda, MD, USA
Interests: biochemistry; function and structure of tyrosinases; molecular modeling of proteins from inherited eye disease; global computational mutagenesis; protein biochemistry; molecular biophysics; structural and computational biology

Special Issue Information

Dear Colleagues,

Human tyrosinases are membrane glycoproteins localized in melanosomes. A loss of tyrosinase protein stability is often associated with crucial changes in melanin production. These changes are critical for inherited human diseases such as some forms of oculocutaneous albinism and skin cancer. However, very little is known on how individual genetic mutations change melanin production and contribute to the diverse pigmentation phenotypes. Recently, recombinant human tyrosinases and mutant variants were successfully expressed, purified, and characterized using a combination of biochemical, biophysical, and structural methods. In the future, using recombinant tyrosinases in an in vitro system will help to verify the molecular mechanisms of tyrosinase functions to find new drugs and evaluate how individual mutations could quantitatively contribute, from the molecular level, to human disease.

This Special Issue of the International Journal of Molecular Sciences titled “Advances in Biological Functions of Tyrosinases”, will focus on recent advances in the understanding of the function and structure of human tyrosinases, the molecular mechanisms of tyrosinase reactions and melanin production, the changes in tyrosinase protein stability caused by genetic mutations, tyrosinases as specific drug targets, and the role of genetic mutations in inherited forms of albinism. Contributions on these and related topics are welcomed, including original research articles and full  and mini-reviews. We also very much welcome papers from postdocs, PhD students, and young researchers.

Dr. Yuri V. Sergeev
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tyrosinase
  • tyrosinase-related protein 1
  • tyrosinase-related protein 2
  • oculocutaneous albinism
  • disease-causing mutation
  • skin cancer
  • melanin production
  • protein function
  • protein biochemistry
  • atomic structure

Published Papers (3 papers)

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Research

11 pages, 1216 KiB  
Article
Phenylthiourea Binding to Human Tyrosinase-Related Protein 1
by Xuelei Lai, Harry J. Wichers, Montserrat Soler-López and Bauke W. Dijkstra
Int. J. Mol. Sci. 2020, 21(3), 915; https://doi.org/10.3390/ijms21030915 - 30 Jan 2020
Cited by 14 | Viewed by 5475
Abstract
Tyrosinase-related protein 1 (TYRP1) is one of the three human melanogenic enzymes involved in the biosynthesis of melanin, a pigment responsible for the color of the skin, hair, and eyes. It shares high sequence identity with tyrosinase, but has two zinc ions in [...] Read more.
Tyrosinase-related protein 1 (TYRP1) is one of the three human melanogenic enzymes involved in the biosynthesis of melanin, a pigment responsible for the color of the skin, hair, and eyes. It shares high sequence identity with tyrosinase, but has two zinc ions in its active site rather than two copper ions as in tyrosinase. Typical tyrosinase inhibitors do not directly coordinate to the zinc ions of TYRP1. Here, we show, from an X-ray crystal structure determination, that phenylthiourea, a highly potent tyrosinase inhibitor, does neither coordinate the active site zinc ions, but binds differently from other structurally characterized TYRP1-inhibitor complexes. Its aromatic ring is directed outwards from the active site, apparently as a result from the absence of polar oxygen substituents that can take the position of water molecules bound in the active site. The compound binds via hydrophobic interactions, thereby blocking substrate access to the active site. Full article
(This article belongs to the Special Issue Advances in Biological Functions of Tyrosinase)
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11 pages, 1130 KiB  
Article
Human Tyrosinase: Temperature-Dependent Kinetics of Oxidase Activity
by Kenneth L. Young II, Claudia Kassouf, Monika B. Dolinska, David Eric Anderson and Yuri V. Sergeev
Int. J. Mol. Sci. 2020, 21(3), 895; https://doi.org/10.3390/ijms21030895 - 30 Jan 2020
Cited by 11 | Viewed by 4300
Abstract
Human tyrosinase (Tyr) is involved in pigment biosynthesis, where mutations in its corresponding gene TYR have been linked to oculocutaneous albinism 1, an autosomal recessive disorder. Although the enzymatic capabilities of Tyr have been well-characterized, the thermodynamic driving forces underlying melanogenesis remain unknown. [...] Read more.
Human tyrosinase (Tyr) is involved in pigment biosynthesis, where mutations in its corresponding gene TYR have been linked to oculocutaneous albinism 1, an autosomal recessive disorder. Although the enzymatic capabilities of Tyr have been well-characterized, the thermodynamic driving forces underlying melanogenesis remain unknown. Here, we analyze protein binding using the diphenol oxidase behavior of Tyr and van ’t Hoff temperature-dependent analysis. Recombinant Tyr was expressed and purified using a combination of affinity and size-exclusion chromatography. Michaelis-Menten constants were measured spectrophotometrically from diphenol oxidase reactions of Tyr, using L-3,4-dihydroxyphenylalanine (L-DOPA) as a substrate, at temperatures: 25, 31, 37, and 43 °C. Under the same conditions, the Tyr structure and the L-DOPA binding activity were simulated using 3 ns molecular dynamics and docking. The thermal Michaelis-Menten kinetics data were subjected to the van ‘t Hoff analysis and fitted with the computational model. The temperature-dependent analysis suggests that the association of L-DOPA with Tyr is a spontaneous enthalpy-driven reaction, which becomes unfavorable at the final step of dopachrome formation. Full article
(This article belongs to the Special Issue Advances in Biological Functions of Tyrosinase)
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18 pages, 2920 KiB  
Article
Protein Stability and Functional Characterization of Intra-Melanosomal Domain of Human Recombinant Tyrosinase-Related Protein 1
by Monika B. Dolinska, Kenneth L. Young II, Claudia Kassouf, Emilios K. Dimitriadis, Paul T. Wingfield and Yuri V. Sergeev
Int. J. Mol. Sci. 2020, 21(1), 331; https://doi.org/10.3390/ijms21010331 - 3 Jan 2020
Cited by 9 | Viewed by 3038
Abstract
Pigmentation is the result of a complex process by which the biopolymer melanin is synthesized and packed into melanosomes of melanocytes. Various types of oculocutaneous albinism (OCA), a series of autosomal recessive disorders, are associated with reduced pigmentation in the skin, eyes, and [...] Read more.
Pigmentation is the result of a complex process by which the biopolymer melanin is synthesized and packed into melanosomes of melanocytes. Various types of oculocutaneous albinism (OCA), a series of autosomal recessive disorders, are associated with reduced pigmentation in the skin, eyes, and hair due to genetic mutations of proteins involved in melanogenesis. Human tyrosinase (Tyr) and tyrosinase-related protein 1 (Tyrp1) drives the enzymatic process of pigment bio-polymerization. However, within the melanogenic pathway, Tyrp1 has catalytic functions not clearly defined and distinct from Tyr. Here, we characterize the biochemical and biophysical properties of recombinant human Tyrp1. For this purpose, we purified and analyzed the intra-melanosomal domain (Tyrp1tr) for protein stability and enzymatic function in conditions mimicking the environment within melanosomes and the endoplasmic reticulum. The study suggests that Tyrp1tr is a monomeric molecule at ambient temperatures and below (<25 °C). At higher temperatures, >31 °C, higher protein aggregates form with a concurrent decrease of monomers in solution. Also, Tyrp1tr diphenol oxidase activity at pH 5.5 rises as both the pre-incubation temperature and the higher molecular weight protein aggregates formation increases. The enhanced protein activity is consistent with the volume exclusion change caused by protein aggregates. Full article
(This article belongs to the Special Issue Advances in Biological Functions of Tyrosinase)
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