Biosynthesis of (6R)-5,6,7,8-tetrahydro-l-biopterin (H4-biopterin), an essential cofactor for aromatic amino acid hydroxylases and NO synthases, is effectively induced by cytokines in most of the cell types. However, human monocytes/macrophages form only a little H4-biopterin, but release neopterin/7,8-dihydroneopterin instead. Whereas 6-pyruvoyl tetrahydropterin synthase (PTPS) activity, the second enzyme of H4-biopterin biosynthesis, is hardly detectable in these cells, PTPS mRNA levels were comparable with those of cell types containing intact PTPS activity. By screening a THP-1 cDNA library, we identified clones encoding the entire open reading frame (642 bp) as well as clones lacking the 23 bp exon 3, which results in a premature stop codon. Quantification of the two mRNA species in different cell types (blood-derived cells, fibroblasts and endothelial cells) and cell lines showed that the amount of exon-3-containing mRNA is correlated closely to PTPS activity. The ratio of exon-3-containing to exon-3-lacking PTPS mRNA is not affected by differential mRNA stability or nonsense-mediated mRNA decay. THP-1 cells transduced with wild-type PTPS cDNA produced H4-biopterin levels and expressed PTPS activities and protein amounts comparable with those of fibroblasts. We therefore conclude that exon 3 skipping in transcription rather than post-transcriptional mechanisms is a major cause of the low PTPS protein expression observed in human macrophages and related cell types.
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August 2003
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Research Article|
August 01 2003
Low tetrahydrobiopterin biosynthetic capacity of human monocytes is caused by exon skipping in 6-pyruvoyl tetrahydropterin synthase
Karin L. LEITNER;
Karin L. LEITNER
1
∗Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria
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Martina MEYER;
∗Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria
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Walter LEIMBACHER;
Walter LEIMBACHER
†Department of Clinical Chemistry and Biochemistry, University Children's Hospital, University of Zürich, CH-8032 Zürich, Switzerland
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Anja PETERBAUER;
Anja PETERBAUER
∗Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria
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Susanne HOFER;
Susanne HOFER
‡Department of Dermatology, University of Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria
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Christine HEUFLER;
Christine HEUFLER
‡Department of Dermatology, University of Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria
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Angelika MÜLLER;
Angelika MÜLLER
§Clinic for Pediatry, Friedrich-Schiller University of Jena, D-07740 Jena, Germany
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Regine HELLER;
Regine HELLER
‖Department of Molecular Cell Biology, Friedrich-Schiller University of Jena, D-99089 Erfurt, Germany
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Ernst R. WERNER;
Ernst R. WERNER
∗Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria
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Beat THÖNY;
Beat THÖNY
†Department of Clinical Chemistry and Biochemistry, University Children's Hospital, University of Zürich, CH-8032 Zürich, Switzerland
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Gabriele WERNER-FELMAYER
Gabriele WERNER-FELMAYER
3
∗Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria
3To whom correspondence should be addressed (e-mail gabriele.werner-felmayer@uibk.ac.at).
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Publisher: Portland Press Ltd
Received:
February 18 2003
Revision Received:
March 25 2003
Accepted:
April 23 2003
Accepted Manuscript online:
April 23 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 373 (3): 681–688.
Article history
Received:
February 18 2003
Revision Received:
March 25 2003
Accepted:
April 23 2003
Accepted Manuscript online:
April 23 2003
Citation
Karin L. LEITNER, Martina MEYER, Walter LEIMBACHER, Anja PETERBAUER, Susanne HOFER, Christine HEUFLER, Angelika MÜLLER, Regine HELLER, Ernst R. WERNER, Beat THÖNY, Gabriele WERNER-FELMAYER; Low tetrahydrobiopterin biosynthetic capacity of human monocytes is caused by exon skipping in 6-pyruvoyl tetrahydropterin synthase. Biochem J 1 August 2003; 373 (3): 681–688. doi: https://doi.org/10.1042/bj20030269
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