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By: Peter T. Pugliese, MD
Posted: February 26, 2009, from the March 2009 issue of Skin Inc. magazine.
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Stage I: The premelanosome. Melanosomes are specialized organelles within melanocytes and retinal pigment epithelial cells, in which melanin pigments are generated and stored. The melanosome starts out as a hollow vesicle from a lysosome.g A special protein known as Pmel17 is an integral membrane protein uniquely expressed by melanocytes and is found in the premelanosome matrix. This protein forms a fiberlike network on which the melanosome is constructed. These fibers serve to sequester and concentrate the newly formed melanins in a certain area of the melanocyte. No pigment is present at stage I; the melanosome is forming, but it is colorless.
Stage II: Laying down the matrix. This stage is characterized by the elongation of the melanosomes and completion of the scaffold-like matrix of melanofilaments. No pigment appears at this stage, but the melanosomes are ready to receive the tyrosinase-related proteins that will initiate the production of melanin pigment. The first and second stages prepare the melanosome to become a pigmented particle by preparing the mechanical parts of the particle.
Now a fascinating process is going on during all of this. Up in the Golgi apparatus, tiny structures known as clathrins are busy gathering tyrosinase enzymes to shuttle through the cells to the stage II melansomes. The transfer of manufactured lipids and proteins from the rough endoplasmic reticulum (ER) requires transport vesicles that pinch off from the rough ER and then fuse with the target membranes. These vesicles are about 35–80 nanometers (nm) in size and are coated with a bristlelike lattice of the clathrin subunits. Clathrin, a fairly large protein, is actually one key element of the intracellular transport of proteins. The clathrin’s coat forms a basket around the vesicle, and employs cytoskeletal elements with the actual structure of the clathrin specific to each type of cell. This process is outlined in Figure 3, showing stage II melansomes and the role of clathrins.
Stage III: Tyrosinase-related proteins. This is the beginning of melanin formation because the pigment is laid down on the scaffolding of the stage II melanosomes. From the onset, let me make clear that the last word has yet to be written on melanogenesis, or melanin formation, and what is presented here is simply the best of the current understanding of the process. The formation of melanin is a biochemical event driven by three enzymes and many ancillary stimulators, beginning in stage III melanosomes and continuing in stage IV melanosomes, which are filled with pigment. It all begins with the amino acid phenylalanine, which is converted to amino acid tyrosine by the enzyme phenylalanine hydroxylase.h The next step is to convert the tyrosine to dihydroxyphenylalanine (L-DOPA), which requires the enzyme tyrosine hydroxylase. The third enzyme is tyrosinase, and it converts L-DOPA to L-DOPA quinone. This is the key step in the synthesis of melanin. From the compound L-DOPA quinone, all the other steps are derived, but these are less clearly defined in melanogenesis. One of these final steps involves complexing the melanin with protein. The formative process is diagramed in Figure 4 with some notes on the steps. It is not difficult to understand when you see that tyrosinase is the key enzyme, and that the final product, melanin, is a polymeric material complex with protein. In Figure 5, the active molecules have been identified to make this process clearer.
Major types of melanin
Figure 4 contains the words eumelanin and pheomelanin. These types of melanin have biologically different responses to UV light. The eumelanin is black/brown and the pheomelanin is red/yellow. Both of these pigments arise from the same enzymatic pathway; however, there is a switch that sends more pheomelanin into production, controlled by a gene known as the melanocortin 1 receptor (MC1R) gene that is located in the melanocytes of hair follicles.i When this gene is functioning normally, only eumelanin is produced, but if it functions poorly, then pheomelanin is produced. Most humans with red hair carry a poorly functioning MC1R gene, and individuals who carry this gene, well-functioning or not, have red hair and freckles.