Wayne D. Beazley

α‐MSH Can Control the Essential Cofactor 6‐Tetrahydrobiopterin in Melanogenesis

ABSTRACT: In the human epidermis both keratinocytes and melanocytes express POMC m‐RNA. Immunohistochemical studies of both cell types demonstrate significantly higher levels of α‐MSH in melanocytes than in keratinocytes. Both cell types also hold the full capacity for de novo synthesis/recycling of the essential cofactor (6R)‐l‐erythro‐5,6,7,8‐tetrahydrobiopterin (6BH4). 6BH4 is critical for the hydroxylation of the aromatic amino acids l‐phenylalanine, l‐tyrosine, and l‐tryptophan, for nitric oxide production and in various immune modulatory processes. Recently it was shown that tyrosinase activity is regulated by 6BH4 through a specific allosteric inhibition. The tyrosinase/6BH4 inhibition can be activated by 1:1 complex formation between 6BH4 and α‐MSH, but an excess of α‐MSH over 6BH4 can inhibit tyrosinase due to complex formation by tyr2 in the α‐MSH sequence. In both melanocytes and keratinocytes 6BH4 controls the l‐tyrosine supply via phenylalanine hydroxylase (PAH). Recently we were able to show that the cellular uptake of l‐phenylalanine and its intracellular turnover to l‐tyrosine is crucial for melanogenesis. α‐MSH can promote the production of l‐tyrosine via PAH due to activation of the PAH tetramer to the more active dimer by removing 6BH4 from the regulatory binding domain on the enzyme. In conclusion, α‐MSH can control (1) intracellular l‐tyrosine formation from l‐phenylalanine in both melanocytes and keratinocytes, and (2) tyrosinase activity, directly, in melanocytes.

Altered catecholamine synthesis and degradation in the epidermis of patients with atopic eczema

Abstract Patients with atopic eczema have significantly higher norepinephrine levels in plasma than healthy controls. In addition, significantly higher levels of the essential cofactor (6 R )- l -erythro-5,6,7,8-tetrahydrobiopterin (6BH 4 ) were found in this patient group. Cell extracts from epidermal suction blister roofs revealed only half the normal activity of phenylethanolamine- N -methyl transferase (PNMT) together with a threefold induction of the norepinephrine-degrading enzyme monoamine oxidase A (MAO-A). Taken together, these results support earlier observations of a defective catecholamine/adrenoceptor signal in patients with atopic eczema.

Determination of Sepiapterin and Sepiapterin Reductase in Human Skin

In the pigmentary disorder vitiligo the epidermal pteridine metabolism is altered concomitantly with highly increased levels of H2O in the millimolar range. The epidermal de novo and recycling biosynthetic pathway of tetrahydrobiopterin shows increased GTP-CH I activity, reduced 4a-OH-tetrahydrobiopterin dehydratase and phenylalanine hydroxylase activity, yielding increased epidermal levels of 6- and 7-biopterin (1). Elevated levels of sepiapterin (Sep) have also been reported (2), but this compound was later identified as pterin-6-carboxylic acid (P-6-COOH).