Phenylthiourea Binding to Human Tyrosinase-Related Protein 1

Lai, Xuelei; Wichers, Harry J.; Soler-López, Montserrat; Dijkstra, Bauke W.

doi:10.3390/ijms21030915

Cited by 14 publications

(8 citation statements)

References 35 publications

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“…However, accurate identification of the residues is illusive as the protein is fixed during docking calculations. Docked positions are in accordance with a very recent publication where the X‐ray structure of TRP1‐phenylthiourea (PTU) adduct demonstrated that PTU pointed outward from the di‐metallic center [35] . Neither nitrogen atoms (amine or thioamide groups) or sulfur atoms interact with the dinuclear zinc center.…”

Section: Resultssupporting

confidence: 86%

Ditopic Chelators of Dicopper Centers for Enhanced Tyrosinases Inhibition

Buitrago

Faure

Challali

et al. 2021

Chemistry A European J

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Tyrosinase enzymes (Tys) are involved in the key steps of melanin (protective pigments) biosynthesis and molecules targeting the binuclear copper active site on tyrosinases represent a relevant strategy to regulate enzyme activities. In this work, the possible synergic effect generated by a combination of known inhibitors is studied. For this, derivatives containing kojic acid (KA) and 2‐hydroxypyridine‐N‐oxide (HOPNO) combined with a thiosemicarbazone (TSC) moiety were synthetized. Their inhibition activities were evaluated on purified tyrosinases from different sources (mushroom, bacterial, and human) as well as on melanin production by lysates from the human melanoma MNT‐1 cell line. Results showed significant enhancement of the inhibitory effects compared with the parent compounds, in particular for HOPNO‐TSC. To elucidate the interaction mode with the dicopper(II) active site, binding studies with a tyrosinase bio‐inspired model of the dicopper(II) center were investigated. The structure of the isolated adduct between one ditopic inhibitor (KA‐TSC) and the model complex reveals that the binding to a dicopper center can occur with both chelating sites. Computational studies on model complexes and docking studies on enzymes led to the identification of KA and HOPNO moieties as interacting groups with the dicopper active site.

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Section: Resultssupporting

confidence: 86%

Ditopic Chelators of Dicopper Centers for Enhanced Tyrosinases Inhibition

Buitrago

Faure

Challali

et al. 2021

Chemistry A European J

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“…Tyrosinase is a key regulatory enzyme in the biosynthesis of melanin through melanogenesis, located in the membrane of melanosome with an internal, a transmembrane, and a cytoplasmic domain. , It is belonging to the family of metalloenzymes, known as copper-containing enzyme that catalyzes three distinct reactions of the melanogenic pathway: l -tyrosine hydroxylation and dehydrogenation of l -DOPA and DHI (5,6-dihydroxyindole). , Tyrosinase level is closely correlated with the malignancy level; hence, it became an important biomarker in the melanoma tumor. , Collectively, the tyrosinase enzyme is involved in several melanogenic pathways and hence it has become the most important target for melanogenesis inhibitors that are involving in direct inhibition of the tyrosinase catalytic activity . Phenylthiourea (PTU) is one of the most prominent and well-known tyrosinase inhibitors. , In recent years, compounds containing specific-enzyme inhibitors conjugated to chemotherapeutics, photosensitizers, etc. have gain much attention due to its increased targetability as well as therapeutic potency in the eradication of tumor.…”

Section: Introductionmentioning

confidence: 99%

Phenylthiourea-Conjugated BODIPY as an Efficient Photosensitizer for Tyrosinase-Positive Melanoma-Targeted Photodynamic Therapy

Jung

Shim

et al. 2020

ACS Appl. Bio Mater.

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Melanoma is the most threatening form of metastatic skin cancer that develops from melanocytes and causes a large majority of deaths due to poor therapeutic prognosis. It has significant limitations in treatment because it shows great resistance to chemotherapy, radiotherapy, and other therapeutic methods. A noninvasive and clinically accepted therapeutic modality, photodynamic therapy (PDT), is a promising treatment option, but it is limitedly applied for melanoma skin cancer treatment. This is because most of the photosensitizers are unlikely to be expected to have a remarkable effect on melanoma due to drug efflux by melanin pigmentation and intrinsic antioxidant defense mechanisms. Moreover, melanin is a dominant absorber in the spectral region of 500–600 nm that can cause the decreased photoreaction efficiency of photosensitizers. Herein, to overcome these drawbacks, we have developed a phenylthiourea-conjugated BODIPY photosensitizer (PTUBDP) for tyrosinase-positive melanoma-targeted PDT. In light of our results, it exhibited an enhanced cytotoxic efficacy compared to BDP, a parallel PDT agent that absence of phenylthiourea unit. PTUBDP shows outstanding effects of increased oxidative stress by an enhanced cellular uptake of the tyrosinase positive melanoma cell line (B16F10). This work presents increased therapeutic efficacy through the combined therapeutic approach, enabling enhanced reactive oxygen species (ROS) generation as well as overcoming the critical limitations of melanoma.

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“…These species finally polymerize to form eumelanin. In addition to the enzymatic activity, TRP1 is also a stabilizing protein for tyrosinase, as its role is still unclear depending on the metal cofactor found at the active site [14,15]. DHI as well DHICA can be oxidized in the absence of any enzyme to their respective o-quinones by oxygen and ROS generated during previous reactions [16].…”

Section: Natural Skin Pigments For Photoprotection: Melanin and Melanmentioning

confidence: 99%

Photoprotection and Skin Pigmentation: Melanin-Related Molecules and Some Other New Agents Obtained from Natural Sources

2020

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Direct sun exposure is one of the most aggressive factors for human skin. Sun radiation contains a range of the electromagnetic spectrum including UV light. In addition to the stratospheric ozone layer filtering the most harmful UVC, human skin contains a photoprotective pigment called melanin to protect from UVB, UVA, and blue visible light. This pigment is a redox UV-absorbing agent and functions as a shield to prevent direct UV action on the DNA of epidermal cells. In addition, melanin indirectly scavenges reactive oxygenated species (ROS) formed during the UV-inducing oxidative stress on the skin. The amounts of melanin in the skin depend on the phototype. In most phenotypes, endogenous melanin is not enough for full protection, especially in the summertime. Thus, photoprotective molecules should be added to commercial sunscreens. These molecules should show UV-absorbing capacity to complement the intrinsic photoprotection of the cutaneous natural pigment. This review deals with (a) the use of exogenous melanin or melanin-related compounds to mimic endogenous melanin and (b) the use of a number of natural compounds from plants and marine organisms that can act as UV filters and ROS scavengers. These agents have antioxidant properties, but this feature usually is associated to skin-lightening action. In contrast, good photoprotectors would be able to enhance natural cutaneous pigmentation. This review examines flavonoids, one of the main groups of these agents, as well as new promising compounds with other chemical structures recently obtained from marine organisms.

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Phenylthiourea Binding to Human Tyrosinase-Related Protein 1

Cited by 14 publications

References 35 publications

Ditopic Chelators of Dicopper Centers for Enhanced Tyrosinases Inhibition

Ditopic Chelators of Dicopper Centers for Enhanced Tyrosinases Inhibition

Phenylthiourea-Conjugated BODIPY as an Efficient Photosensitizer for Tyrosinase-Positive Melanoma-Targeted Photodynamic Therapy

Photoprotection and Skin Pigmentation: Melanin-Related Molecules and Some Other New Agents Obtained from Natural Sources

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