Tyrosinase is an
oxidase that is the
rate-limiting enzyme for controlling the production of
melanin. The enzyme is mainly involved in two distinct reactions of melanin synthesis otherwise known as the Raper Mason pathway. Firstly, the hydroxylation of a monophenol and secondly, the conversion of an o-diphenol to the corresponding o-quinone. o-Quinone undergoes several reactions to eventually form melanin.
Tyrosinase is a
copper-containing enzyme present in plant and animal tissues that catalyzes the production of melanin and other pigments from
tyrosine by oxidation. It is found inside
melanosomes which are synthesized in the skin
melanocytes. In humans, the tyrosinase enzyme is encoded by the ''TYR''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Catalyzed reaction
Tyrosinase carries out the oxidation of phenols such as
tyrosine and
dopamine using
dioxygen (O
2). In the presence of
catechol,
benzoquinone is formed (see reaction below). Hydrogens removed from catechol combine with
oxygen to form
water.
The substrate specificity becomes dramatically restricted in mammalian tyrosinase which uses only L-form of tyrosine or DOPA as substrates, and has restricted requirement for L-DOPA as cofactor.
Active site
The two copper atoms within the active site of tyrosinase enzymes interact with
dioxygen to form a highly reactive chemical intermediate that then oxidizes the
substrate. The activity of tyrosinase is similar to
catechol oxidase, a related class of copper
oxidase. Tyrosinases and
catechol oxidases are collectively termed
polyphenol oxidase
Polyphenol oxidase (PPO; also polyphenol oxidase i, chloroplastic), an enzyme involved in fruit browning, is a tetramer that contains four atoms of copper per molecule.
PPO may accept monophenols and/or ''o''-diphenols as substrates. The ...
s.
Structure
Tyrosinases have been isolated and studied from a wide variety of plant, animal, and fungal species. Tyrosinases from different species are diverse in terms of their structural properties, tissue distribution, and cellular location.
No common tyrosinase protein structure occurring across all species has been found.
The enzymes found in plant, animal, and fungal tissue frequently differ with respect to their
primary structure, size,
glycosylation pattern, and activation characteristics. However, all tyrosinases have in common a
binuclear, type 3 copper centre within their
active sites. Here, two copper atoms are each
coordinated with three
histidine residues.
Plant
''
In vivo'', plant
PPOs are expressed as about 64–68 k
Da proteins consisting of three domains: a chloroplastic transit
peptide (containing a ~4-9 k
Da thylakoid signal peptide), a catalytically active domain (~ 37–42 kDa) containing the
dinuclear copper center, and a
C-terminal domain (~15–19 kDa) shielding the
active site.
Mammalian
Mammalian tyrosinase is a single membrane-spanning
transmembrane protein.
In humans, tyrosinase is sorted into
melanosomes
A melanosome is an organelle found in animal cells and is the site for synthesis, storage and transport of melanin, the most common light-absorbing pigment found in the animal kingdom. Melanosomes are responsible for color and photoprotection ...
and the catalytically active domain of the protein resides within melanosomes. Only a small, enzymatically inessential part of the protein extends into the cytoplasm of the
melanocyte.
As opposed to fungal tyrosinase, human tyrosinase is a membrane-bound
glycoprotein and has 13% carbohydrate content.
The derived TYR allele (rs2733832) is associated with lighter skin pigmentation in human populations. It is most common in
Europe, but is also found at lower, moderate frequencies in
Central Asia, the
Middle East,
North Africa, and among the
San and
Mbuti Pygmies.
Bacterial
In peatlands,
bacterial tyrosinases are proposed to act as key regulators of carbon storage by removing
phenolic compounds, which inhibit the
degradation of
organic
Organic may refer to:
* Organic, of or relating to an organism, a living entity
* Organic, of or relating to an anatomical organ
Chemistry
* Organic matter, matter that has come from a once-living organism, is capable of decay or is the product ...
carbon.
Gene regulation
The gene for tyrosinase is regulated by the
microphthalmia-associated transcription factor (MITF).
Clinical significance
A mutation in the tyrosinase gene resulting in impaired tyrosinase production leads to type I oculocutaneous
albinism, a hereditary disorder that affects one in every 20,000 people.
Tyrosinase activity is very important. If uncontrolled during the
synthesis of melanin, it results in increased melanin synthesis. Decreasing tyrosinase activity has been targeted for the improvement or prevention of conditions related to the
hyperpigmentation
Hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.
Causes
Hyperpigmentation can be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris.James, William; Be ...
of the skin, such as
melasma and
age spots.
Several polyphenols, including
flavonoids or
stilbenoid, substrate analogues, free radical scavengers, and copper chelators, have been known to inhibit tyrosinase. Henceforth, the medical and cosmetic industries are focusing research on tyrosinase inhibitors to treat skin disorders.
Inhibitors
Known Tyrosinase inhibitors are the following:
*
Azelaic acid
Azelaic acid (AzA) is an organic compound with the formula HOOC(CH2)7 COOH. This saturated dicarboxylic acid exists as a white powder. It is found in wheat, rye, and barley. It is a precursor to diverse industrial products including polymers a ...
*
Hydroquinone
*
''L''-ascorbic acid - Vitamin C
*
Tranexamic acid
Tranexamic acid (TXA) is a medication used to treat or prevent excessive blood loss from major trauma, postpartum bleeding, surgery, tooth removal, nosebleeds, and heavy menstruation. It is also used for hereditary angioedema. It is taken ei ...
Genetics
While
albinism is common, there have only been a few studies about the genetic mutations in the tyrosinase genes of animals. One of them was on
''Bubalus bubalis'' (water buffalo). The tyrosinase mRNA sequence of the wild-type ''B. bubalis'' is 1,958 base pairs (bp) with an
open reading frame (ORF) of 1,593 bp long, which translates to 530 amino acids. Meanwhile, the tyrosinase gene of the
albino ''B. bubalis'' (GenBank JN_887463) is truncated at position 477, caused by a
point mutation in nucleotide 1431 which converts a
Tryptophan (TGG) into a
stop codon (TGA), resulting in a shorter and inactive tyrosinase gene. Other albinos have point mutations that appear to inactivate Tyrosinase without truncation (see table and figure for examples).
Knowing that there are a few studies about the genomic data of the tyrosinase gene, there are only a handful of studies on the mutations in albino
amphibians. Miura et al. (2018) investigates the amino acid mutations in the tyrosinase gene in three albino
frogs: ''
Pelophylax nigromaculatus'' (pond frog),
''Glandirana rugosa'' (wrinkled frog) and ''
Fejervarya kawamurai'' (rice frog). In total, five different populations were studied of which three were ''P. nigromaculatus'' and one each of ''G. rugosa'' and ''F. kawamurai''. In two of the three ''P. nigromaculatus'' populations, there was a
frameshift mutation because of the insertion of a
thymine within
exons 1 and 3, and the third population lacked three nucleotides that encoded a
Lysine in exon 1. The population of ''G. rugosa'' had a
missense mutation where there was an amino acid substitution from a
Glycine to
Aspartic acid, and the mutation of ''F. kawamurai'' was also an amino acid substitution from Glycine to
Arginine. The mutation for ''G. rugosa'' and ''F. kawamurai'' occurs in exons 1 and 3. The mutations of the third population of ''P. nigromaculatus'', and the mutations of ''G. rugosa'' and ''F. kawamurai'' occurred in areas that are highly
conserved among
vertebrates which could result in a dysfunctional tyrosinase gene.
Evolution
Tyrosinase is a highly conserved protein in animals and apparently arose already in
bacteria.The tyrosinase related protein(Tyrp1) and
dopachrome
Dopachrome is a cyclization product of L-DOPA and is an intermediate in the biosynthesis of melanin. It may tautomerise to form DHICA.
See also
* Dopachrome tautomerase
Dopachrome tautomerase (dopachrome delta-isomerase, tyrosine-related pro ...
tautomerase (Dtc), which
encode for protein implicated in
melanin synthesis
Synthesis or synthesize may refer to:
Science Chemistry and biochemistry
* Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors
**Organic synthesis, the chemical synthesis of organ ...
which are the common regulatory elements of
exon/intron structure. The
development of the three types of
vertebrate pigment cells, although different, thus
converge at a certain point to allow the expression of members of the
''tyrosinase'' family, in order to produce melanin pigments.
Tyrosinase family related
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s plays an important role in the
evolution, genetics, and
developmental biology of
pigment cells, as well as to approach human disorders associated with
defects in their synthesis, regulation or function in vertebrates three types of
melanin producing pigment cells are well known since
embryonic origin i.e., from the
neural crest,
neural tube and
pineal body. All of them have the capacity to produce melanin pigments. Their biosynthesis is governed by evolutionary
conserved enzymes of the tyrosinase family( tyr, tyr1 and tyr2) also called
DOPAchrome
Dopachrome is a cyclization product of L-DOPA and is an intermediate in the biosynthesis of melanin. It may tautomerise to form DHICA.
See also
* Dopachrome tautomerase
Dopachrome tautomerase (dopachrome delta-isomerase, tyrosine-related pro ...
tautomerase ( dct). Among them Tyr plays significance role in melanin
production. However, sequenced
genome from the different taxa for evolutionary analysis in the depth become more crucial in present study. Similarly, the type-3 copper protein family are preform various
biological function including pigment formation,
innate immunity
Immunity may refer to:
Medicine
* Immunity (medical), resistance of an organism to infection or disease
* ''Immunity'' (journal), a scientific journal published by Cell Press
Biology
* Immune system
Engineering
* Radiofrequence immunity de ...
and oxygen transport. The combine genetic
phylogenetic and structural analysis concluded that the original type-3
copper protein
Copper proteins are proteins that contain one or more copper ions as prosthetic groups. Copper proteins are found in all forms of air-breathing life. These proteins are usually associated with electron-transfer with or without the involvement ...
possessed a single
peptide and grouped into
α subclass. The ancestral protein gene underwent to two duplication i.e., first one prior to divergence of unknot
eukaryotic lineage and second one before
diversification
Diversification may refer to:
Biology and agriculture
* Genetic divergence, emergence of subpopulations that have accumulated independent genetic changes
* Agricultural diversification involves the re-allocation of some of a farm's resources to n ...
. The prior duplication gave rise to
cytosolic
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
form(
β) and latter duplication gave
membrane bound form(
Γ). The structural comparison concluded that active site of
α and
Γ forms are covered by
aliphatic
In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane ...
amino acids and
β form covered with
aromatic residue. Thus, the evolution of these gene family is the lineage of
multicellular eukaryotes due to loss of one or more of these three subclasses and
lineage
Lineage may refer to:
Science
* Lineage (anthropology), a group that can demonstrate its common descent from an apical ancestor or a direct line of descent from an ancestor
* Lineage (evolution), a temporal sequence of individuals, populat ...
specific expansion of one or both of the remaining
subclasses. The
genomic conserved
Nucleotide alignments of the tyrosinase among the
vertebrate family like frogs, snakes and human suggests that it has evolved from one
ancestral tyrosinase gene. The
duplication
Duplication, duplicate, and duplicator may refer to:
Biology and genetics
* Gene duplication, a process which can result in free mutation
* Chromosomal duplication, which can cause Bloom and Rett syndrome
* Polyploidy, a phenomenon also known ...
and
mutation of this gene is probably responsible for the emergence of a tyrosinase-related
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Applications
In the food industry
In the food industry, tyrosinase inhibition is desired as tyrosinase catalyzes the oxidation of
phenolic compounds found in fruits and vegetables into
quinones, which gives an undesirable taste and color and also decreases the availability of certain essential amino acids as well as the digestibility of the products. As such, highly effective tyrosinase inhibitors are also needed in agriculture and the food industry.
Well known tyrosinase inhibitors include
kojic acid,
tropolone,
coumarins,
vanillic acid,
vanillin, and
vanillic alcohol.
In the Cosmetic Industry
Lighter skin complexion has been associated with youth and beauty across various Asian cultures. Recent research by cosmetic companies has been focused on the development of novel whitening agents that selectively suppress tyrosinase activity to reduce
hyperpigmentation
Hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.
Causes
Hyperpigmentation can be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris.James, William; Be ...
while avoiding cytotoxicity of healthy
melanocytes. Traditional pharmacological agents such as
corticosteroids,
hydroquinone, and amino numeric chloride lighten skin through the inhibition of melanocyte maturation. However, these agents are associated with adverse effects. Cosmetic companies have been focused on developing novel whitening agents that selectively suppress the activity of tyrosinase to reduce hyperpigmentation while avoiding melanocyte cytotoxicity as tyrosinase is the rate-limiting step of the melanogenesis pathway.
In insects
Tyrosinase has a wide range of functions in insects, including wound healing,
sclerotization, melanin synthesis and parasite encapsulation. As a result, it is an important enzyme as it is the defensive mechanism of insects. Some insecticides are aimed to inhibit tyrosinase.
[
]
In mussel-glue inspired polymers
Tyrosinase activated polymerization of peptides, containing cysteine and tyrosine residues, lead to mussel-glue inspired polymers. The tyrosine residues are enzymatically oxidized to dopaquinones, to which thiols of cysteine could link by an intermolecular Michael-addition. The resulting polymers adsorb strongly to various surfaces with high adhesion energies.
References
External links
GeneReviews/NCBI/NIH/UW entry on Oculocutaneous Albinism Type 1
*
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EC 1.14.18
Copper enzymes