Peer-reviewed studies indicate that cysteine or cysteine-related mutations can alter biological pigmentation, such as by modifying hair pigment composition, directly inhibiting tyrosinase activity, or increasing pheomelanin synthesis.
Coat color in Holstein dairy cattle is primarily controlled by the melanocortin 1 receptor (MC1R) gene, a central determinant of black (eumelanin) vs. red/brown pheomelanin synthesis across animal species. The major MC1R alleles in Holsteins are Dominant Black (MC1RD) and Recessive Red (MC1Re). A novel form of dominant red coat color was first observed in an animal born in 1980. The mutation underlying this phenotype was named Dominant Red and is epistatic to the constitutively activated MC1RD. Here we show that a missense mutation in the coatomer protein complex, subunit alpha (COPA), a gene with previously no known role in pigmentation synthesis, is completely associated with Dominant Red in Holstein dairy cattle. The mutation results in an arginine to cysteine substitution at an amino acid residue completely conserved across eukaryotes. Despite this high level of conservation we show that both heterozygotes and homozygotes are healthy and viable. Analysis of hair pigment composition shows that the Dominant Red phenotype is similar to the MC1R Recessive Red phenotype, although less effective at reducing eumelanin synthesis. RNA-seq data similarly show that Dominant Red animals achieve predominantly pheomelanin synthesis by downregulating genes normally required for eumelanin synthesis. COPA is a component of the coat protein I seven subunit complex that is involved with retrograde and cis-Golgi intracellular coated vesicle transport of both protein and RNA cargo. This suggests that Dominant Red may be caused by aberrant MC1R protein or mRNA trafficking within the highly compartmentalized melanocyte, mimicking the effect of the Recessive Red loss of function MC1R allele.
Cysteine plays essential biological roles, but excessive amounts produce cellular oxidative stress. Cysteine metabolism is mainly mediated by the enzymes cysteine dioxygenase and γ‐glutamylcysteine synthetase, respectively coded by the genes CDO1 and GCLC. Here we test a new hypothesis posing that the synthesis of the pigment pheomelanin also contributes to cysteine homeostasis in melanocytes, where cysteine can enter the pheomelanogenesis pathway. We conducted an experiment with the Eurasian nuthatch Sitta europaea, a bird producing large amounts of pheomelanin for feather pigmentation, to investigate if melanocytes show epigenetic lability under exposure to excess cysteine. We increased systemic cysteine levels in nuthatches by supplementing them with dietary cysteine during growth. In feather melanocytes this led to the downregulation of genes involved in intracellular cysteine metabolism (GCLC), cysteine transport to the cytosol from the extracellular medium (Slc7a11) and from melanosomes (CTNS), and regulation of tyrosinase activity (MC1R and ASIP). These changes were mediated by increases in DNA m5C in all genes except Slc7a11, which experienced RNA m6A depletion. Birds supplemented with cysteine synthesized more pheomelanin than controls, but did not suffer higher systemic oxidative stress. These results suggest that excess cysteine activates an epigenetic mechanism that favours pheomelanin synthesis and may protect against oxidative stress.
ration (IC 50 ), 0.66 mM), as well as the DOPA oxidase activity of TYR measured by dopachrome formation [ 82 ]. In addition, cysteine at 0.15 or 0.30 mM inhibited mushroom TYR activity measured by a spectrophotometric method (IC 50 , 0.15 mM) and a polarographic method (IC 50 , 1.44 mM) [ 91 ]. Therefore, cysteine is one of the amino acids whose reactivity is unique, and it can directly inhibit the activity of TYR in addition to reducing the production of dopachrome.
The two Cu 2+ ions are present at the active site of the TYR enzyme, each being coordinated by three histidine residues [ 92 ]. In the study of Jergil et al., cysteine at high concentrations (10 mM) inactivated TYR, whereas the addition of tyrosine and DOPA competitively restored the enzyme activity [ 93 ]. It is presumed that cysteine can bind to copper at the active site of the TYR, inactivating the enzyme, and the substrates block cysteine’s access to the active site of the enzyme.
Tseng et al. compared the inhibitory effects of 20 × 20 dipeptides against mushroom TYR and found that cysteine-containing dipeptides are potent inhibitors and that N -terminal cysteine-containing dipeptides are more potent inhibitors than C- terminal cysteine-containing dipeptides [ 94 ]. In a study by Hsiao et al., cysteine-containing tripeptides, such as arginine-cysteine-tyrosine and cysteine-arginine-tyrosine, exhibited potent inhibitory effects against mushroom TYR activity [ 95 ]. Cysteine-arginine-tyrosine tripeptide containing a cysteine residue at its N -terminus was estimated to be a more potent TYR inhibitor (IC 50 , 6.16 μM) compared with kojic acid (IC 50 , 84.4 μM) and arbutin (IC 50 , 1008.7 μM). These studies suggest that the N -terminal cysteine residue of certain peptides reacts faster with DQ than others. It also suggests a possibility that cysteinyl glycine, a product of the degradation process of glutathione, may react more rapidly with DQ than does γ-glutamyl cysteine, a substrate of the synthesis pr
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