Has Removal of Excess Cysteine Led to the Evolution of Pheomelanin?

Insights & Perspectives da Speculations & Ideas

Has removal of excess cysteine led to the evolution of pheomelanin?

Pheomelanogenesis as an excretory mechanism for cysteine

Ismael Galva´n1)Ã, Ghanem Ghanem2) and Anders P. Møller1)

Introduction Most of the research into melanins has that tawny owls Strix aluco belonging to focused on eumelanin [4]. However, the pheomelanic morph have lower via- Melanins are the most common pig- there is increasing knowledge of the bility during adverse environmental ments in animals, and are mostly found physical and chemical properties of conditions than conspecifics belonging in the integument. The color traits they pheomelanin and pheomelanogenesis, to the eumelanic morph [8]. In humans generate fulfill a diversity of functions and it is known that most natural mel- and mice, pheomelanin increases the that range from protection against dam- anins are mixed polymers of eumelanin photosensitization of cells to UV- aging ultraviolet (UV) radiation to cryp- and pheomelanin [3, 4]. Furthermore, induced oxidative damage [9], its con- sis and signaling of individual quality recent studies of birds suggest that the tent being positively related to cancer [1, 2]. Higher vertebrates (birds and production of pheomelanin is involved risk in humans [10]. Overall, these mammals) synthesize two chemically in physiological trade-offs, as judged by results indicate that pheomelanin is a distinct forms of melanin, eumelanin, negative relationships between the limiting pigment that may have import- and pheomelanin, in melanosomes, extent of integument colored by pheo- ant evolutionary consequences. specialized organelles of melanocytes melanin and brain size [5] and inter- The limiting nature of pheomelanin [3]. Eumelanin is a polymer of dihydroxy- specific differences in the capacity to is probably caused by the chemical indole and carboxylic acid units that resist the effects of ionizing radiation pathway of pheomelanogenesis. The generate traits responsible for black linked to pheomelanic color [6]. It has first steps of the process are shared with and gray (i.e. darker) colors, while pheo- also been reported that more-pheome- eumelanogenesis and consist of the melanin is produced by benzothiazine lanic individual barn owls (Tyto alba) hydroxylation of the amino acid L-tyro- derivatives and leads to the production are particularly sensitive to physiologi- sine by the enzyme tyrosinase to pro- of yellowish, reddish and chestnut, and cal stress caused by corticosterone com- duce dopaquinone. Dopaquinone then brown (i.e. lighter) colors [4]. pared to less-pheomelanic birds [7], and reacts with thiol groups to synthesize pheomelanin, or, in the absence of thiol groups, suffers a cyclization that leads Keywords: to the synthesis of eumelanin [3]. Thiol .excess amino acids; oxidative stress; pheomelanogenesis; pigmentation groups that react with dopaquinone are provided by free cysteine or by the cysteine-containing tripeptide glutathione DOI 10.1002/bies.201200017 (GSH) [11], which is the main physiological reservoir of cysteine and the most 1) Laboratoire d’Ecologie, Syste´ matique et Abbreviations: important intracellular antioxidant [12]. Evolution, Universite´ Paris-Sud 11, Orsay, CDO, cysteine dioxygenase; GSH, glutathione. This means that pheomelanogenesis France requires a constant supply of cysteine 2) Laboratoire d’Oncologie et de Chirurgie Expe´ rimentale (L.O.C.E.), Institut Jules Bordet, via GSH, thus lowering the levels of Universite´ Libre de Bruxelles, Brussels, this important antioxidant [13]. Belgium Furthermore, pheomelanin is phototoxic because it produces reactive oxygen species when exposed to UV *Corresponding author: Ismael Galva´ n radiation [9, 14]. In contrast, the bio- E-mail: [email protected] logical benefits conferred by pheomela-

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nin are unknown. For example, the above-mentioned phototoxicity of pheomelanin suggests that any photoprotec- tive role of melanins is better fulfilled by eumelanin. Therefore, if pheomelanin production is associated with so important physiological costs and its biological benefits are not evident, what are the factors that have promoted the evolution of pheomelanin? As far as we know, this question has only been tangentially addressed. Indeed, pheomelanin has been con- sidered ‘‘an accident of nature’’, its adaptive value being obscure [10]. One answer may be related to the potential of pheomelanin-based traits to signal abil- Ideas & Speculations ity to cope with oxidative stress (i.e. the imbalance between the production of pro-oxidative compounds and the availability of antioxidant substances, tipped Figure 1. Chart showing the physiological activity of dietary cysteine. This amino acid is used toward the former). Since pheomelano- for protein synthesis, and can be recovered by protein breakdown. It is also used for the genesis consumes GSH [3, 13], which synthesis of reduced glutathione (GSH), which is the main storage of cysteine and thus also acts as a source of cysteine. When the levels of cysteine are higher than required for these cannot then be used to combat oxidative functions, especially for protein synthesis, excess cysteine occurs. This excess, which can be stress, only individuals with a high anti- toxic, is partly eliminated by cysteine sulfoxidation, a process mainly catalyzed by cysteine oxidant capacity should be able to pro- dioxygenase (CDO) in which less toxic products than cysteine such as sulfate and taurine are duce large amounts of pheomelanin to formed. In birds, excess dietary amino acids are also diverted to the synthesis of uric acid, color their integument under high the main product of excretion in birds. Cysteine also reacts with dopaquinone thus participat- environmental oxidative stress [15]. ing in the synthesis of pheomelanin that takes place in melanosomes. If cysteine incorporated Pheomelanin-based color is also necess- into the pheomelanogenesis pathway comes from an excess pool, then pheomelanogenesis could represent an excretory mechanism of cysteine and an adaptive process that may ary to produce skin, coat and plumage explain the evolution of pheomelanin. patterns that confer camouflage or concealment, and in fact it has been suggested that the persistence of pheomelanin is mainly due to its camouflage and esthetic properties [10]. These decrease GSH levels [19, 20]. Some excess cysteine has been associated properties may favor the evolution of enzymes can convert the oxidized form with rheumatoid arthritis, Parkinson’s pheomelanin, but certainly not all pheo- of cysteine back to its unmodified form, disease, Alzheimer’s disease, systemic melanin-based color traits act as quality but the presence of cysteine residues in lupus erythematosus, increased risk of signals [16], nor are they involved in proteins makes them susceptible to oxi- cardiovascular disease, and adverse concealment patterns [17]. Thus, these dative stress and associated damage pregnancy outcomes in humans properties can only partly, at best, [21]. Indeed, cysteine metabolism fulfils (ref. [22] and cited references). Any explain the evolutionary origin and an important function by keeping cys- mechanism that contributes to the the maintenance of pheomelanin. teine levels below the threshold of removal of excess cysteine might thus Here we propose a new hypothesis toxicity [22]. This is achieved by cysteine be of adaptive value; we propose that that may help to understand the evol- sulfoxidation, a process mainly cata- pheomelanogenesis represents such a ution of pheomelanin. Since pheomela- lyzed by cysteine dioxygenase (CDO) mechanism. In the case of human dis- nogenesis occurs as long as cysteine/ in which molecular oxygen is added to eases that manifest themselves long GSH are present in melanocytes and the sulfhydryl group of cysteine to form after the reproductive age has been the thiol group of cysteine is incorpor- less toxic products than cysteine such as reached, such as Parkinson’s and ated in the structure of pheomelanin [3], sulfate and taurine [22] (Fig. 1). Despite Alzheimer’s diseases, natural selection the synthesis of this pigment implies a the existence of this process, excess cys- may still indirectly affect a mechanism removal of cysteine (Fig. 1). Although teine can occur when its content in diet that contributes to the removal of excess cysteine used for GSH synthesis can is higher than needed for protein syn- cysteine via selection for grand-parental be obtained from protein breakdown, thesis, or probably also as a reaction to care of offspring. This is because grand- its availability mainly depends on the constant oxidative stress. In birds, parental care increases child survival in cysteine content of the diet [18]. excess cysteine contributes to metabolic many societies [24], and individuals However, cysteine also causes toxicity acidosis and a variety of associated with Parkinson’s or Alzheimer’s disease related to its autoxidation of the corre- problems such as thinning of egg shells cannot normally provide high quality sponding disulfide, which can even and poor growth [23]. In mammals, grand-parental care.

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Pheomelanogenesis as an lanin and small amounts of eumelanin nation for how pheomelanic traits have are characteristic of red hair, fair skin, prevailed in northern human popu- excretory mechanism freckling, and green irides [25], pheno- lations, as excess cysteine is likely to da Speculations & Ideas types that are more common at high occur more frequently at high latitudes It is likely that some adaptive mechan- latitudes [10]. If the removal of excess where thermal stress and parasite loads isms have evolved in vertebrates to cysteine has adaptive value, this should may be relatively low. Humans with a avoid the toxicity of excess sulfur- be reflected in human pigmentation pheomelanic phenotype may thus containing amino acids. It would not patterns. benefit from a better capacity to remove be surprising, however, if the adaptive Currently, the most accepted expla- excess cysteine, which would poten- mechanisms to avoid the toxicity of nation for the geographical distribution tially confer a greater ability to avoid excess cysteine are more diverse than of human skin pigmentation patterns diseases caused by excess cysteine such those previously mentioned. Although refers to two natural selection press- as Parkinson’s and Alzheimer’s diseases our proposed mechanism implies that ures that create a trade-off between or systemic lupus erythematosus excess cysteine is removed in melano- the protection of UV radiation and (ref. [22] and cited references). As these cytes, where pheomelanogenesis takes the cutaneous synthesis of vitamin D3 diseases might obviously affect both place, and melanocytes only represent a [26]. Eumelanin protects skin from UV reproductive success and survival, our small portion of all cells of organisms, radiation, which generates skin cancer, hypothesis suggests that human integu- this adaptive benefit may contribute to but UV radiation also stimulates ment coloration may be under natural the efficient performance of the detox- vitamin D3 synthesis [26]. However, this selection, something that some authors ification activity of animals. view ignores older studies highlighting have disputed [26]. Despite the huge advances made in the fact that the spectral distribution of the fields of melanocyte biology and sunlight at the earth’s surface is insuf- melanogenesis in recent decades, the ficient to explain the distribution of Challenges evolution of pheomelanin remains a human skin color classes [27], as well mystery. This pigment is phototoxic as the occurrence of two chemically To formally test our hypothesis, future [9] and its production consumes GSH, distinct melanins (i.e. eu- and pheome- studies should provide direct measure- a key intracellular antioxidant [13]. lanin) in the skin that cause its color ments of excess cysteine and pheome- Probably as a consequence, different variation not just to be a continuous lanin content in feathers or hair. studies conducted on birds have shown gradient from light to dark. Our Particular environmental factors that individuals or species producing hypothesis may serve as a complement increasing the susceptibility to excess large amounts of pheomelanin present for a general explanation of the geo- cysteine should be identified. We do a limited capacity to cope with physio- graphical distribution of human skin not propose our hypothesis as the only logical processes or environmental con- color. explanation for the evolution of pheo- ditions that generate high levels of Thermal stress depletes GSH levels melanin, as this is likely more complex oxidative stress [5–8]. Under our current in human erythrocytes [28]. As thermal than the background behind our understanding of evolutionary theory stress caused by high temperatures is hypothesis. For example, it may be it is difficult to explain the evolution likely to decrease with latitude, and cys- suggested that all excess cysteine could of a pigment whose production is teine-GSH promotes pheomelanogene- be transferred to GSH synthesis so that associated with the above-mentioned sis and inhibits eumelanogenesis [3], no alternative mechanisms of removal physiological costs without the exist- conditions favoring the production of such as pheomelanogenesis would ence of any adaptive benefit. Our pro- pheomelanin may prevail at high lati- be required. However, it may also posal represents a novel hypothesis tudes, as is indeed observed [15]. A be argued that GSH serves as both a that, together with the role of pheome- higher prevalence of human parasites storage mechanism and a continuous lanin in camouflage, may explain the at low latitudes [29] may also contribute source of cysteine (i.e. it cannot be a persistence of this pigment in higher to this, as parasites generate oxidative real excretory mechanism of cysteine; vertebrates. Thus, the synthesis of pheo- stress in their hosts [30]. Indeed, it has ref. [18]). Thus, pheomelanogenesis melanin may be favored in individual been suggested that high levels of may be the only excretory mechanism animals that, due to environmental human skin eumelanization have that is specific to cysteine, thus making conditions, are susceptible to excess evolved as a response to high parasite its evolution likely because of this cysteine. abundance and diversity in the tropics function. [31]. While this may contribute to An important challenge is to test our explain the origin of pheomelanin- hypothesis specifically in humans. In Implications for based traits in human populations, it particular, if pheomelanogenesis has alone does not explain the maintenance adaptive value because it removes understanding human of such traits given the physiological excess cysteine, do pheomelanic pigmentation patterns costs of pheomelanin (phototoxicity, humans (i.e. phenotypes typically hav- carcinogenesis, and GSH consumption). ing red hair, fair skin, freckles, and Our hypothesis has implications for all We propose that our view of pheomela- green irides) avoid risk of diseases higher vertebrates, including humans. nogenesis as an excretory mechanism of associated with excess cysteine more In humans, large amounts of pheome- excess cysteine may provide an expla- easily than eumelanic individuals?

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