The pathway from GTP to tetrahydrobiopterin: three-dimensional structures of GTP cyclohydrolase I and 6-pyruvoyl tetrahydropterin synthase.

The complex organic chemistry involved in the transformation of GTP to tetrahydrobiopterin is catalysed by only three enzymes: GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. The committing reaction step from GTP to dihydroneopterin triphosphate is catalysed by GTP cyclohydrolase I and requires no cofactor. 6-Pyruvoyl tetrahydropterin synthase, a Zn-dependent metalloprotein, transforms dihydroneopterin triphosphate into 6-pyruvoyltetrahydropterin in the presence of Mg(II). Sepiapterin reductase is a NADPH-dependent short-chain dehydrogenase which reduces 6-pyruvoyltetrahydropterin to BH4. Here we review the structural and mechanistic information on the biosynthetic pathway from GTP to BH4 on the basis of the recently determined crystal structures of CYH and PTPS.