GTP Cyclohydrolase Feedback Regulatory Protein Controls Cofactor 6-Tetrahydrobiopterin Synthesis in the Cytosol and in the Nucleus of Epidermal Keratinocytes and Melanocytes

(6R)-l-Erythro 5,6,7,8 tetrahydrobiopterin (6BH4) is crucial in the hydroxylation of l-phenylalanine-, l-tyrosine-, and l-tryptophan-regulating catecholamine and serotonin synthesis as well as tyrosinase in melanogenesis. The rate-limiting step of 6BH4de novo synthesis is controlled by guanosine triphosphate (GTP) cyclohydrolase I (GTPCHI) and its feedback regulatory protein (GFRP), where binding of l-phenylalanine to GFRP increases enzyme activities, while 6BH4 exerts the opposite effect. Earlier it was demonstrated that the human epidermis holds the full capacity for autocrine 6BH4de novo synthesis and recycling. However, besides the expression of epidermal mRNA for GFRP, the presence of a functioning GFRP feedback has never been shown. Therefore, it was tempting to investigate whether this important mechanism is present in epidermal cells. Our results identified indeed a functioning GFRP/GTPCHI axis in epidermal keratinocytes and melanocytes in the cytosol, adding the missing link for 6BH4de novo synthesis which in turn controls cofactor supply for catecholamine and serotonin biosynthesis as well as melanogenesis in the human epidermis. Moreover, GFRP expression and GTPCHI activities have been found in the nucleus of both cell types. The significance of this result warrants further investigation.