You probably never thought that how you tan has anything to do with the periodic table. The reality is that two elements, copper and zinc, play an important role in the production of melanin. This means not only your tan, but also conditions related to skin pigmentation, like age spots, for example.
Copper and zinc are the most abundant metals in the human body. Scientists still don't have a clear idea of how they influence the generation of melanin. A collaboration between ESRF, CEA and the University Grenoble Alpes, aims to shed light on this issue and create compounds that could stop or slow down its functioning.
Our bodies are complex machines where millions of chemical reactions take place at the same time. Melanin pigments that give human skin, hair and eyes their color, are produced by multiple step reactions. There are different types of melanins (brown/dark and yellow/red) and skin color depends on the proportion and distribution of each. Melanins are activated thanks to a process called melanogenesis, when three enzymes react.
Three enzymes are responsible for the activation of melanins. They are called tyrosinases (TYR, TYRP1 and TYRP2) and their exact function is unknown. The reason for this is that until now scientists have never managed to purify the human version in large quantities to study them. Instead, they have been using the fungal or plant enzymes to synthesize inhibitor compounds.
In the picture: Crystal structure of TYRP1. Tyrosine (the substrate metabolised) is bound to the active site, which contains the zinc metal ions (red spheres).
Researchers know that TYR initiates the melanin synthesis. It uses copper for the hydroxylation and oxidation of the amino acid tyrosine, creating intermediate products that undergo subsequent reactions before melanins are eventually generated. This is the role of TYRP1 or TYRP2, but it is not clear which protein comes first.
Two years ago, Montse Soler López, together with collaborators from the University of Groningen, solved the structure of TYRP1 and published the results in Angewandte Chemie.
Scientists also unveiled an unexpected result: they found that TYRP1 needs zinc to function, contrary to the established belief in the community that this enzyme needs copper. “We still don’t know exactly what role zinc takes in the interaction with TYRP1 and we need extensive further research to find that out”, explains Montse Soler López, main researcher of the study.
This first study led to the current collaboration with chemists from the UGA and the CEA. Interested by the achievement of solving the structure of TYR/TYRP1, they got in touch with Montse Soler López for a comprehensive project that would put her results to practice. "At the UGA we develop compounds that could work in inhibiting or slowing down the melanogenesis, combining computational and experimental approaches with my colleagues Helene Jamet and Amaury Du Moulinet D'Hardemare", explains Catherine Belle, director of research CNRS at the UGA. "With Montse Soler López and her team solving the structures, we can better design these compounds", she adds.
Printing skin
This is when Walid Rachidi, vice-dean of the faculty of pharmacy at the UGA and researcher at the CEA, comes into the picture. Rachidi is an expert in skin and works with renowned hospitals on heavy burnt cases and face transplants where skin grafts are needed. He is a specialist in skin substitutes and with his colleague Xavier Gidrol they are behind the innovative 3D skin bioprinting project that allows them to replicate human skin.
There are several ways of testing drugs and cosmetics for future use in humans. Since 2013 animal testing for cosmetics is totally forbidden in the EU so the options are either cell culture, which does not recreate the physiological conditions, or reconstructed skin.
His work with Montse Soler López and Catherine Belle's teams consists of testing the compounds developed by Belle's group on pigmented bioprinted skin and it is part of the Cosmethics cross-disciplinary project of the UGA. This is the closest they'll be to a human skin.
So how do you print human skin? Human skin is incredibly complex. The epidermis is made of 90% keratinocytes, 1-3% of immunity cells and 7-9% of melanocytes. One melanocyte distributes melanins to 36 keranocytes. Rachidi and his colleagues try to increase the complexity of the skin's bio-printed models by including other cell types, such as vessel cells, in order to be as close as possible to normal human skin.
Rachidi's team collaborates with industrial partners in developing creams that are safe to whiten the skin and remove marks. With a huge market in Asia and Africa, current whitening creams are toxic not only for the skin, but also for the internal organs. The only inhibitors that are clinically available (hydroquinone, retinoids and arbutin) are toxic and not safe.
We want to be able to decrease the activity of tyrosinase but at the same time have a reversible effect, i.e. if you stop using that cream, your skin gets back to what it was before" WALID RACHIDI
Rachidi's collaboration with Soler López's team at the ESRF and Belle's team at the UGA has still a long way to go. The combination of their different scientific specialities will hopefully open new doors to safer cosmetics to remove pigmentation disorders, as well as new drugs to treat melanin-related diseases.
CREDITS
Text and video by Montserrat Capellas Espuny
Photos and illustrations by Steph Candé, Adam Jones, Montse Soler López.
REFERENCE
Lai X, Soler-Lopez M, Wichers HJ, Dijkstra BW. Large-scale recombinant expression and purification of human tyrosinase suitable for structural studies, PloS One, 11(8): e0161697, 2016
Lai X, Wichers HJ, Soler-Lopez M, Dijkstra BW. Structure of Human Tyrosinase TYRP1 Reveals a Binuclear Zinc Active Site Important for Melanogenesis. Angew. Chem. Int. Ed. 56:1-5, 2017
Lai X, Wichers HJ, Soler-Lopez M, Dijkstra BW. Structure and Function of Human Tyrosinase and Tyrosinase-related Proteins. Chemistry 24(1):47-55, 2018