Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo.

Abstract

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.

• Authors: K U Schallreuter, J M Wood, I Ziegler, K R Lemke, M R Pittelkow, N J Lindsey, M Gütlich
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1226 Issue 2 Pg. 181-92 (May 25 1994) ISSN: 0006-3002 [Print] Netherlands
• PMID: 8204666 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Catecholamines
• Melanins
• Pterins
• Biopterin
• Phenylalanine Hydroxylase
• Monophenol Monooxygenase
• Phenylethanolamine N-Methyltransferase
• GTP Cyclohydrolase
• Hydro-Lyases
• pterin-4a-carbinolamine dehydratase
• sapropterin

Topics

• Base Sequence
• Biopterin (analogs & derivatives, biosynthesis)
• Catecholamines (biosynthesis, blood, urine)
• GTP Cyclohydrolase (analysis)
• Humans
• Hydro-Lyases (analysis)
• Keratinocytes (metabolism)
• Melanins (biosynthesis)
• Melanocytes (metabolism)
• Molecular Sequence Data
• Monophenol Monooxygenase (genetics)
• Phenylalanine Hydroxylase (analysis, antagonists & inhibitors, genetics)
• Phenylethanolamine N-Methyltransferase (analysis)
• Pterins (metabolism)
• Skin (chemistry, metabolism)
• Vitiligo (metabolism)