Inside of chromosomes are genes, or DNA segments that encode RNA and a regulatory sequence. Not all genes code for proteins, and instead may be used for regulatory purposes. Tyrosinases would require the TYR gene, located on chromosome 11 (2). In eukaryotes, the gene has promoter, coding, non-coding, and terminator regions. During transcription in the nucleus, an enzyme called RNA polymerase is responsible for making the pre-mRNA transcript using one of the DNA strands. The final pre-transcript should be similar to one of the strands — with the exception of the nucleotide base thymine being replaced by uracil — and should also be complementary to the other strand.
To make sure the mRNA does not degrade when trying to move it from the nucleus to the cytoplasm for translation, a cap is added to the 5′ (phosphate) end of the DNA and a poly-A tail is added to the 3′ (hydroxyl) end.
Splicing also takes place, where spliceosome — a renowned arts and crafts guru — cuts out non-coding areas called introns while gluing together exons, or coding + regulatory regions. This step is crucial because it makes us more complex human beings (just when you thought we weren’t complicated enough). To explain, there are three different ways to splice together the exons in the TYR gene, and the differences in the transcript account for protein differences which then account for its nine different possible phenotypes (1).
Tyrosinase seems to have eight exons total and you can view the whole loooooong gene sequence structure here (1). Hurry before it gets spliced!!
*Disclosure: our genetic info is not this colorful:( but Skittles is and it’s delicious
The Central Dogma describes the flow of genetic information. In its most simple form, it is DNA → RNA → Protein. However, the diagram above not only shows this simple flow, but also how each step is reached. To begin, DNA would need to be replicated to reproduce and carry on the genetic information to new cells. It would then need to undergo a process called transcription, where its nucleotide base sequence is written in the form of messenger RNA (mRNA). In translation, the mRNA nucleotide base sequence would need to be converted into chains of amino acids. These chains can then be folded up in order to make protein. After some modifications, the protein can then express certain phenotypes, or visible characteristics. And ta-da! The birth of tyrosinase.
What can possibly go wrong?
Lots of stuff. Tyrosinase has a whopping amount of amino acids – 529 to be exact (2)! There were implications that when tyrosinase was not folded properly, it continued to build up in the ER, and the protein misfolding was associated with OCA1 (1). This is an example of how post-translational modification can influence and be reflected in one’s phenotype. It is also important to note that any changes to the DNA sequence can mess up transcription and all the steps that follow (we will hit this topic very soon!). That is why there needs to be enzymes and other regulatory molecules to make sure everything goes smooth(ly) like butter.
References
Dolinska, M. B., Kus, N. J., Farney, S. K., Wingfield, P. T., Brooks, B. P., & Sergeev, Y. V. (2017). Oculocutaneous albinism type 1: link between mutations, tyrosinase conformational stability, and enzymatic activity. Pigment Cell & Melanoma Research, 30(1), 41–52. https://doi.org/10.1111/pcmr.12546
Simeonov, D. R., Wang, X., Wang, C., Sergeev, Y., Dolinska, M., Bower, M., Fischer, R., Winer, D., Dubrovsky, G., Balog, J. Z., Huizing, M., Hart, R., Zein, W. M., Gahl, W. A., Brooks, B. P., & Adams, D. R. (2013). DNA variations in oculocutaneous albinism: An updated mutation list and current outstanding issues in molecular diagnostics. Human Mutation, 34(6), 827–835. https://doi.org/10.1002/humu.22315
To understand the tyrosinase enzyme, we need to first understand the general concept of what an enzyme is. Enzymes are biological catalysts, meaning that their role is to speed up chemical reactions. They do so by decreasing the activation energy, or the energy required to start a chemical reaction. They do NOT, however, affect the change in free energy of the reaction. Most enzymes are made of proteins, but some can be made of RNA.
Woah what in the world? Well imagine, just imagine, that the Pac-Man phony is an enzyme (I do understand that this takes a lot of brain power, but please bear with me). Pac-Man’s mouth is called the active site, and the balls approaching the active site are called substrates. When the balls come in contact with Pac-Man’s mouth, or when the substrate binds to the enzyme’s active site, a miracle happens. As stated before, they lower the chemical reaction’s activation energy! The Pac-Man’s mouth can only accept those particular balls, so the enzyme is substrate-specific in order to perform the function it’s supposed to. If you try to shove a fancy yellow car into Pac-Man’s mouth instead, sadly, nothing or complete bogus would happen.
The left graph shows a chemical reaction without the help of an enzyme, whereas the right graph shows a chemical reaction with an enzyme present. Evidently, the “hill” on the right graph is less steep than the left graph’s “hill” because the enzyme lowered the reaction’s activation energy.
Tyrosinase Structure
Mmm ramen noodles (yeah no). What we have here are strands of alpha helices (the curly spiral structures) and beta-pleated sheets (the zig-zag structures) that comprise the secondary protein structure of tyrosinase. Different electrostatic interactions within the protein allow it to be folded into more complex quaternary structures, and structural complexities are reflected in the enzyme’s functions. Tyrosinase has three domains: they are the cytoplasmic, transmembrane, and inner domains (1).
Function
The cytoplasmic and transmembrane domains help to fuse tyrosinases with melanosomes, while the inner domain is where the active site is present. The substrate that binds to this active site is called…copper (yippee something pronounceable). After the enzyme-substrate complex is formed, by lowering the activation energy, tyrosinase can speed up the process of turning tyrosine into L-dihydroxyphenylalanine (1), or L-Dopa for short as learned in my class lab. The enzyme then helps to quickly convert L-Dopa to dopaquinone so that after a series of subsequent steps, two types of melanin are created: eumelanin and pheomelanin (4).
Side notes: 1) tyrosine is one of our 20 amino acids. 2) eumelanin is a dark, brownish color while pheomelanin is a light, reddish color (1).
A visual of the tyrosinase-catalyzed reaction steps
Optimal pH and Temperature
Each enzyme works the best at certain temperatures and pH levels. For example, Zaidi et al.’s experiment found that the optimal conditions for a button mushroom tyrosinase enzyme (the lab flashbacks are real) are a35°C temperature and 7.0 pH level (3). In this case, temperatures that are higher than 35°C may help tyrosinase to catalyze melanin production at first, but when they get too high, the tyrosinase would denature. Denaturation is when an enzyme temporarily loses its conformation because high heat breaks weaker bonds, such as hydrogen bonds, in the enzyme. Similarly, pH levels that are higher or lower than 7.0 would also denature the button mushroom tyrosinase. As a result of denaturation, enzymes would not be able to complete their jobs as effectively and efficiently.
Inhibitors
Whenever I think of the word “inhibit,” I am always reminded of a scenario in which a strict parent doesn’t allow their kid to have game time. Inhibitors are like the strict parent, blocking the enzyme from conducting its activity. There are two main types of inhibitors: allosteric and competitive. In allosteric or noncompetitive inhibition, the inhibitor binds to a site other than the active site (called the allosteric site) to induce a conformational change in the enzyme so that the substrate cannot bind to the active site. On the other hand, in competitive inhibition, the inhibitor that has similar structural characteristics as the substrate binds directly to the active site to prevent the substrate from binding. For instance, the drug hydroquinone (HQ), which is a skin-whitening agent (2) used as a remedy for hyperpigmentation (1), can competitively inhibit the tyrosinase enzyme to block copper from binding to the active site (4). This in turn helps to slow down melanin synthesis to help lighten the skin.
Hydroquinone looking buff
References
Bae-Harboe, Y.-S. C., & Park, H.-Y. (2012). Tyrosinase: A central regulatory protein for cutaneous pigmentation. Journal of Investigative Dermatology, 132(12), 2678–2680. https://doi.org/10.1038/jid.2012.324
Pillaiyar, T., Manickam, M., & Namasivayam, V. (2017). Skin whitening agents: Medicinal chemistry perspective of tyrosinase inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 32(1), 403–425. https://doi.org/10.1080/14756366.2016.1256882
Zaidi, K. U., Ali, A. S., & Ali, S. A. (2014). Purification and characterization of melanogenic enzyme tyrosinase from Button Mushroom. Enzyme Research, 2014, 1–6. https://doi.org/10.1155/2014/120739
Zolghadri, S., Bahrami, A., Hassan Khan, M. T., Munoz-Munoz, J., Garcia-Molina, F., Garcia-Canovas, F., & Saboury, A. A. (2019). A comprehensive review on tyrosinase inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 34(1), 279–309. https://doi.org/10.1080/14756366.2018.1545767
As shown in this lovely diagram, melanocytes are cells found in the bottom part of our epidermis, or the layer closest to the top of the skin (1). They are eukaryotic, meaning that they have a nucleus (shown in dark purple), many linear DNA chromosomes within the nucleus that are basically a “how to make YOU” recipe, and membrane-bound organelles.
Melanin
Like most of our cells, melanocytes perform a very special(ized) function: they are where melanin is made! Melanin is the pigment that gives us our beautiful color. There is a misconception that the more melanocytes we have, the darker our skin color is. If there is one thing that unites us as one big happy family, it is that we all have roughly the same number of melanocytes. The difference is the amount of pigment we make – the more melanin, the darker our skin color (1).
Melanin also functions to protect us from everyone’s arch-nemesis: the sun’s harmful UV rays (yes we all hate you but still have to bring you up in this very blog…) (1). An example is that I have olive skin and my close friends have pale skin, so they get sunburned a lot easier than I do (sorry, anonymous close friends).
Melanosome
Melanosomes are organelles within melanocytes that make melanin. Once they are full of pigment, they move out of the melanocyte and into nearby keratinocytes with the help of structures called dendrites. This business transaction between melanocytes and keratinocytes allows for our skin to be properly controlled (1).
Other Organelles
We already mentioned that melanocytes have a nucleus and melanosomes, but they also have a rough endoplasmic reticulum (ER), mitochondria, a Golgi apparatus (1), and vesicles (2). The rough ER houses ribosomes, and ribosomes make proteins. The enzyme tyrosinase, which we will discuss about in the next post, is a protein that melanocytic ribosomes make. Vesicles help to move tyrosinase from the rough ER to the Golgi apparatus, where they are packaged and modified. After that, more vesicles help to move them out of the Golgi to fuse with the melanosomes so that they can aid in the melanin-making process (2).
I have to end off with a real-life photo of our melanocytes<3
References
Costin, G.-E., & Menon, G. K. (2018, January 15). Know Your Skin Cells: III. The Melanocytes. The Cosmetic Chemist. http://www.thecosmeticchemist.com/education/skin_science/know_your_skin_cells_iii_the_melanocytes.html
Cox, G. F., & Fulton, A. B. (2010). Albinism. Ocular Disease, 461–471. https://doi.org/10.1016/b978-0-7020-2983-7.00060-7
Let’s first break apart ‘oculocutaneous albinism.’ ‘Oculo-‘ refers to the eye (2), ‘cutaneous’ relates to the skin (5), and ‘albinism’ refers to lack of pigmentation (4). Together, ‘oculocutaneous albinism’ means the lack of pigmentation to the skin, eyes, and hair. We will be focusing on oculocutaneous albinism type 1, or OCA1, which is a more severe type of albinism (8).
Cause
The primary cause of OCA1 is DNA mutations affecting the TYR gene of the tyrosinase enzyme (7). Don’t worry, we will get to this in a later post!
Type of Inheritance Pattern
OCA1 follows the autosomal recessive inheritance pattern, meaning that both parents would need to contribute one mutated gene in order for the disorder to manifest in the baby (8). The parents themselves do not need to display the symptoms of oculocutaneous albinism (1).
Signs and Symptoms
Those with OCA1 can develop symptoms as early as during the newborn and infant stages. Some of the signs and symptoms are very light-colored skin and irises, white hair, vision problems (6), and sensitivity to the sun and other light sources (3).
Socioemotional Difficulties
In elementary school, I heard the term “albino” being thrown around to label and tease kids with light-colored hair, eyes, and skin whether they had albinism or not (I know, that’s messed up). Those with albinism may also be discriminated against for how they look or the devices they use to aid their daily tasks. Heightened feelings of stress and inferiority may result (3).
Treatment
Limiting sun exposure and having a medical support team that can offer advice for taking care of the eyes and skin can help treat symptoms (3).
Collins. (2023). Oculo- Definition and Meaning | Collins English Dictionary. https://www.collinsdictionary.com/dictionary/english/oculo
Mayo Foundation for Medical Education and Research. (2022, December 24). Albinism. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/albinism/symptoms-causes/syc-20369184
U.S. Department of Health and Human Services. (2023, February). Oculocutaneous albinism type 1 – about the disease. Genetic and Rare Diseases Information Center. https://rarediseases.info.nih.gov/diseases/4037/oculocutaneous-albinism-type-1
U.S. National Library of Medicine. (2007, March 1). Tyr Gene. MedlinePlus. https://medlineplus.gov/genetics/gene/tyr/#conditions
U.S. National Library of Medicine. (2023, March 17). Oculocutaneous Albinism. MedlinePlus. https://medlineplus.gov/genetics/condition/oculocutaneous-albinism/
Hi everyone! I hope you all are enjoying your day. If not, then hopefully reading this blog can brighten it up a little. My name is Thy (pronounced “tee”) Nguyen. I plan to major in Biobehavioral Health and minor in Neuroscience. After college, I hope to continue my academic career at med school and am interested in anything pertaining to the brain.
I like to write stuff in my free time (song lyrics, poems, narrative essays, letters, etc.), so this blog site may or may not be another excuse to write more stuff:) I also like to play piano and ukulele for my origami pets, but playing for events on occasion is okay, too.
This blog site focuses on oculocutaneous albinism type 1 (OCA1), a genetic disorder, and is inspired by the stories that my anatomy teacher shared when our class was learning about albinism back in the high school days. The goal of this blog site is to grow a better molecular understanding of OCA1. I would like to dedicate this blog site to my high school anatomy teacher, one of the people along the way who made me realize, wow, humans are actually cool. Yes, I still keep your punny science stickers on my water bottle!
