Regulation of Melanin Biosynthesis in the Human Epidermis by Tetrahydrobiopterin

Schallreuter, Karin U.; Wood, John M.; Pittelkow, Mark R.; Gütlich, Markus; Lemke, K Regina; Rödl, Wolfgang; Swanson, Norma N.; Hitzemann, K; Ziegler, Irmgard

doi:10.1126/science.8128228

Cited by 330 publications

(333 citation statements)

References 15 publications

Supporting

Mentioning

305

Contrasting

Unclassified

Order By: Relevance

“…An alternative degradation pathway would include MAO with the production of 5HTPOL and 5HIAA as intermediate products. This interpretation is consistent with the work of Schallreuter et al [49][50][51] showing cutaneous synthesis of tetrahydrobiopterin (a necessary cofactor for TPH) and expression of MAO-A activity, and of Debiec-Rychter et al [36] demonstrating NAT-1 gene expression in rodent epidermis.…”

Section: Discussionsupporting

confidence: 81%

Characterization of the serotoninergic system in the C57BL/6 mouse skin

Slominski

Pisarchik

Semak

et al. 2003

European Journal of Biochemistry

127

View full text Add to dashboard Cite

We showed expression of the tryptophan hydroxylase gene and of tryptophan hydroxylase protein immunoreactivity in mouse skin and skin cells. Extracts from skin and melanocyte samples acetylated serotonin to N-acetylserotonin and tryptamine to N-acetyltryptamine. A different enzyme from arylalkylamine N-acetyltransferase mediated this reaction, as this gene was defective in the C57BL6 mouse, coding predominantly for a protein without enzymatic activity. Serotonin (but not tryptamine) acetylation varied according to hair cycle phase and anatomic location. Serotonin was also metabolized to 5-hydroxytryptophol and 5-hydroxyindole acetic acid, probably through stepwise transformation catalyzed by monoamine oxidase, aldehyde dehydrogenase and aldehyde reductase. Activity of the melatonin-forming enzyme hydroxyindole-O-methyltransferase was notably below detectable levels in all samples of mouse corporal skin, although it was detectable at low levels in the ears and in Cloudman melanoma (derived from the DBA/2 J mouse strain). In conclusion, mouse skin has the molecular and biochemical apparatus necessary to produce and metabolize serotonin and N-acetylserotonin, and its activity is determined by topography, physiological status of the skin, cell type and mouse strain.Keywords: mouse skin; serotonin acetylation; arylalkylamine N-acetyltransferase; tryptophan hydroxylase; hair cycle.The skin is the largest body organ and functions as a metabolically active biological barrier regulating internal homeostasis and separating the internal milieu from noxious environmental factors [1]. These functions are mediated by the skin immune, pigmentary, neuroendocrine, adnexal and vascular systems [1][2][3][4][5][6][7]. Most recently we have uncovered local serotoninergic and melatoninergic systems as novel elements of the cutaneous neuroendocrine components of human and hamster skin [8][9][10][11][12]. Serotonin is the product of a multistep metabolic pathway that starts with the hydroxylation of the aromatic aminoacid L-tryptophan by tryptophan hydroxylase (TPH) [13,14]. Serotonin can be acetylated by arylalkylamine N-acetyltransferase (AANAT) to N-acetylserotonin (NAS), which is further transformed to melatonin by hydroxyindole-O-methyltransferase (HIOMT) [13,15].Serotonin can act as a neurohormone, regulator of vascular tone, immunomodulator and growth factor, while melatonin can act as a hormone, neurotransmitter, cytokine or biological modifier [2,[15][16][17]. Some of these functions may be pertinent to skin physiology, which exhibits basic differences among the mammalian species. In rodents (mostly nocturnal animals) the skin is shielded from the damaging effect of solar radiation by fur [18], and the morphology of the entire mouse skin changes in close coordination with the cyclic activity of the hair follicle [19]. Mouse hair follicle cycling is characterized by a precisely regulated, time frame-restricted and differential pattern in the expression and activity of melanogenesis related proteins, PH, pterins and thioredoxin ...

show abstract

Section: Discussionsupporting

confidence: 81%

Characterization of the serotoninergic system in the C57BL/6 mouse skin

Slominski

Pisarchik

Semak

et al. 2003

European Journal of Biochemistry

127

View full text Add to dashboard Cite

show abstract

“…The first one leads from GTP to H 4 biopterin (reviewed in Ref. 12), providing H 4 biopterin as the essential cofactor for neurotransmitter synthesis in the developing neurons (13,15) and for phenylalanine hydroxylation in the melanophores (21). This de novo synthetic pathway is well understood in Drosophila (53) and in mammalian cells (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

“…The supply with this rate-limiting substrate depends on the hydroxylation of phenylalanine and thus on the availability of the essential cofactor H 4 biopterin. Several years ago it was suggested that, in differentiating melanophores of fish, H 4 biopterin is involved as the essential cofactor for tyrosine formation (20), and more recently it has been demonstrated that, in the human epidermis, H 4 biopterin does indeed regulate the supply of tyrosine required for melanin synthesis (21). The third type of pigment cells found in the zebrafish are the 1 The abbreviations used are: H 4 biopterin, (6R)5,6,7,8-tetrahydrobiopterin; pterin, 2-amino-4-hydroxypteridine; neopterin, 6-(D-erythro-1Ј,2Ј,3Ј-trihydroxypropyl)pterin; H 2 neopterin, 6-(D-erythro-1Ј,2Ј,3Ј-trihydroxypropyl)-7,8-dihydropterin; biopterin, 6-(L-erythro-1Ј,2Ј-dihydroxypropyl)pterin; H 2 biopterin, 7,8-dihydrobiopterin; 6-pyruvoyl-H 4 pterin, 6-(1Ј,2Ј-dioxopropyl)-5,6,7,8-tetrahydropterin (also 6-lactoyl-5,6,7,8-tetrahydropterin and 6-(1Ј-oxo-2Ј-hydroxypropyl)-5,6,7,8-tetrahydropterin); sepiapterin, 6-lactoyl-7,8-dihydropterin; 2,4,7-trioxopteridine, 7-oxolumazine; isoxanthopterin, 7-oxopterin; xanthine oxidoreductase, xanthine:oxygen oxidoreductase (EC 1.1.3.22).…”

mentioning

confidence: 99%

Development of the Pteridine Pathway in the Zebrafish,Danio rerio

Ziegler¹,

McDonald²,

Heßlinger³

et al. 2000

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

In the zebrafish, the peripheral neurons and the pigment cells are derived from the neural crest and share the pteridine pathway, which leads either to the cofactor tetrahydrobiopterin or to xanthophore pigments. The components of the pteridine pattern were identified as tetrahydrobiopterin, sepiapterin, 7-oxobiopterin, isoxanthopterin, and 2,4,7-trioxopteridine. The expression of GTP cyclohydrolase I activity during the first 24-h postfertilization, followed by 6-pyruvoyl-5,6,7,8-tetrahydropterin synthase and sepiapterin reductase, suggest an early supply of tetrahydrobiopterin for neurotransmitter synthesis in the neurons and for tyrosine supply in the melanophores. At 48-h postfertilization, sepiapterin formation branches off the de novo pathway of tetrahydrobiopterin synthesis. Sepiapterin, via 7,8-dihydrobiopterin and biopterin, serves as a precursor for the formation of 7-oxobiopterin, which may be further catabolized to isoxanthopterin and 2,4,7-trioxopteridine. Neither 7,8-dihydrobiopterin nor biopterin is a substrate for xanthine oxidoreductase. In contrast, both of these compounds are oxidized at C-7 by a xanthine oxidase variant form, which is inactivated by KCN, but is insensitive to allopurinol. The oxidase and the dehydrogenase form of xanthine oxidoreductase as well as the xanthine oxidase variant have specific developmental patterns. It follows that GTP cyclohydrolase I, the formation of sepiapterin, and the xanthine oxidoreductase family control the pteridine pathway in the zebrafish.

show abstract

“…PCD is involved in the regeneration of tetrahydrobiopterin (BH4), an essential cofactor of phenylalanine hydroxylase (PAH) and other mono-oxygenases, and catalyses the conversion of 4a-hydroxytetrahydrobiopterin to quinoid-dihydrobiopterin [4][5][6][7][8]. Certain human diseases like a mild form of hyperphenylalaninemia [9] and the depigmentation disorder vitiligo [10] are linked to a lack or deficiency of PCD activity. This leads to an accumulation of 7-substituted pterins, which act as inhibitors of PAH [11] and thereby interfere with the phenylalanine catabolism and the biosynthesis of melanin pigments.…”

Section: Introductionmentioning

confidence: 99%