Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo.
Patients with the depigmentation disorder vitiligo lack the capacity to synthesize the melanins from L-tyrosine via the essential activity of tyrosinase. The aim of this study has been to examine both the supply of the substrate (L-tyrosine) and the regulation of tyrosinase in the epidermis of subjects with vitiligo. Patients with this depigmentation disorder have a 3- to 5-fold increase in GTP-cyclohydrolase I activity leading to an excessive de novo synthesis of (6R)5,6,7,8 tetrahydrobiopterin (6-BH4). Continuous production of 6-BH-4 leads to: (1) an accumulation of the non-enzymatic byproduct 7-tetrahydropterin (7-BH4) in the epidermis, and (2) increased synthesis of the catecholamines in keratinocytes, leading to an excess of norepinephrine in both the plasma and urine of these patients. In vitiligo, the time-dependent production of 7-BH4 is caused by decreased 4a-hydroxytetrahydrobiopterin dehydratase activity; the essential enzyme for recycling and maintaining normal levels of 6-BH-4. In the epidermis and in cultured melanocytes, 7-BH4 is a potent competitive inhibitor of phenylalanine hydroxylase (Ki = 10(-6) M) and its accumulation in the epidermis of patients with vitiligo blocks the supply of L-tyrosine from L-phenylalanine. 4a-hydroxytetrahydrobiopterin dehydratase has a dual function as the activator/dimerization catalyst for the transcription factor hepatocyte nuclear factor I (HNF-I). HNF-I binds to a 16-base inverted palindrome which seems to be present on the promoters of both the tyrosinase and phenylethanolamine-N-methyl transferase (PNMT) genes. Therefore, defective 4a-hydroxytetrahydrobiopterin dehydratase in vitiligo influences not only the supply of L-tyrosine but also the transcription of the tyrosinase gene in melanocytes. Furthermore, a similar transcriptional regulation of the PNMT gene in keratinocytes offers a possible explanation for the accumulation of norepinephrine in these patients.
Schallreuter
K U
KU
Department of Dermatology, University of Hamburg, Germany.
Wood
J M
JM
Ziegler
I
I
Lemke
K R
KR
Pittelkow
M R
MR
Lindsey
N J
NJ
Gütlich
M
M
D001483:Base Sequence; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis; D002395:Catecholamines / Q000096:biosynthesis* / Q000097:blood / Q000652:urine; D006136:GTP Cyclohydrolase / Q000032:analysis; D006801:Humans; D006836:Hydro-Lyases / Q000032:analysis; D015603:Keratinocytes / Q000378:metabolism; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000378:metabolism; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000235:genetics; D010651:Phenylalanine Hydroxylase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics; D010625:Phenylethanolamine N-Methyltransferase / Q000032:analysis; D011622:Pterins / Q000378:metabolism; D012867:Skin / Q000737:chemistry / Q000378:metabolism*; D014820:Vitiligo / Q000378:metabolism*
D002395:Catecholamines; D008543:Melanins; D011622:Pterins; D001708:Biopterins; D010651:Phenylalanine Hydroxylase; D014442:Monophenol Monooxygenase; D010625:Phenylethanolamine N-Methyltransferase; D006136:GTP Cyclohydrolase; D006836:Hydro-Lyases; C076392:pterin-4a-carbinolamine dehydratase; C003402:sapropterin