Regulation of Tetrahydrobiopterin Biosynthesis

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 enzymes^1–3; 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.