Regulation of Tetrahydrobiopterin Biosynthesis

Catalytic Residues of Sepiapterin Reductase, the Terminal Enzyme of BH4-Biosynthesis
  • Setsuko Katoh
  • Hirotaka Yamada
  • Yasumitsu Sakamoto
  • Takamasa Nonaka
  • Kengo Fujimoto
Part of the Advances in Behavioral Biology book series (ABBI, volume 53)

Abstract

Tetrahydrobiopterin (6R-(L-erythro-dihdroxypropyl)-5,6,7,8-tetrahydropterin; BH4) is required as an essential intracellular cofactor of aromatic amino acid hydroxylases in the formation of catecholamines. This compound is a very unstable substance having a very fast turnover in vivo, and its tissue level is controlled at least by the rate of de novo synthesis. BH4 is biosynthesized from GTP through two intermediates, which are 7,8-dihydroneopterin triphosphate (H2NTP) and 6-pyruvoyl-5,6,7,8-tetrahydropterin (PTP) and the three processes are mediated in turn by GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase (SPR) (Fig 1). Crystallographic studies have revealed the subunit conformations of these three enzymes1–3; and their corresponding genes (GCH1, PTS, & SPR) have been cloned and each of the genes is located on a different human chromosome (14q22.1–22.2, 11q22.3–23.3, & 2p13, respectively). So far, only the gene expression of GTPCH has been found to be regulated by cytokines4 or cAMP5, whereas PTPS and SPR genes have housekeeping functions and are expressed constitutively. Depending on the cell or tissue type, however, all three enzymes are thought to be constitutively expressed, such as in some brain regions and in the liver. And various interesting systems for post-translational modifications have been observed to affect the activities of all enzymes. Feedback regulation is known to occur for GTPCH and SPR (Fig 1). End product BH4 regulates both GTPCH and SPR.

Keywords

Unstable Substance Nicotinamide Nucleotide Sepiapterin Reductase Double Point Mutant Aromatic Amino Acid Hydroxylase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    H. Nar, R. Huber, W. Meining, C. Schmid, S. Weinkauf, and A. Bacher, Structure 3, 459–466 (1995).PubMedCrossRefGoogle Scholar
  2. 2.
    T. Ploom, B. Thöny, J. Yim, S. Lee, H. Nar, W. Leimbacher, J. Richardson, R. Huber, and G. Aüerbach, J. Mol. Biol. 286, 851–860 (1999).PubMedCrossRefGoogle Scholar
  3. 3.
    G. Aüerbach, A. Herrmann, M. Gutlich, M. Fisher, U. Jacob, A. Bacher, and R. Huber, EMBO J. 16, 7219–7230 (1997).PubMedCrossRefGoogle Scholar
  4. 4.
    E. R. Werner, G. Werner-Felmayer, G. Weiss, and H. Wachter, Adv. Exp. Med. Biol. 338, 203–209 (1993).PubMedCrossRefGoogle Scholar
  5. 5.
    G. Kapatos, S. L. Stegenga, and K. Hirayama, J. Biol. Chem. 275(8), 5947–5957 (2000).PubMedCrossRefGoogle Scholar
  6. 6.
    T. Harada, H. Kagamiyama and K. Hatakeyama, Science 260, 1507–1510 (1993).PubMedCrossRefGoogle Scholar
  7. 7.
    S. Katoh, T. Sueoka, and S. Yamada, Biochem.Biophys. Res. Commun, 105, 75–81 (1982).PubMedCrossRefGoogle Scholar
  8. 8.
    S. Katoh, and T. Sueoka, Biochem. Biophys. Res. Commun. 118, 859–866 (1984).PubMedCrossRefGoogle Scholar
  9. 9.
    R. Oyama, S. Katoh, T. Sueoka, M. Suzuki, H. Ichinose, T. Nagatsu, and K. Titani, Biochem. Biophys. Res. Commun. 173, 627–631 (1990).PubMedCrossRefGoogle Scholar
  10. 10.
    H. Jörnvall, B. Persson, M. Krook, S. Atrian, R. Gonzalez-Duarte, J. Jeffery, and D. Ghosh, Biochem. 34, 6003–6013 (1995).CrossRefGoogle Scholar
  11. 11.
    K. Fujimoto, H. Ichinose, T. Nagatsu, T. Nonaka, Y. Mitsui, and S. Katoh, Biochim. Biophys. Acta, 1431, 306–314 (1999).PubMedCrossRefGoogle Scholar
  12. 12.
    J. M. Jez, M. J. Bennett, B. P. Schlegel, M. Lewis, and T. M. Penning, Biochem. J. 326, 625–636 (1997).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Setsuko Katoh
    • 1
  • Hirotaka Yamada
    • 1
  • Yasumitsu Sakamoto
    • 2
  • Takamasa Nonaka
    • 2
  • Kengo Fujimoto
    • 1
  1. 1.Department of BiochemistryMeikai University School of DentistrySakado, SaitamaJapan
  2. 2.Department of BioEngineeringNagaoka University of TechnologyNagaoka, NiigataJapan

Personalised recommendations