Tetrahydropterin cofactor

Phenylalanine Hydroxylase (EC 1.14.16.1). In arene hydroxylation of phenylalanine to produce tyrosine, mammalian phenylalanine hydroxylase (PAH) requires nonheme iron and tetrahydropterin cofactor. The role of the metal is... 

Oxidation of the tetrahydropterin cofactor during the hydroxylase-catalyzed... 

Tyrosine is converted to dopa by the cytoplasmic enzyme tyrosine hydroxylase. This is the rate-limiting step 5 x 10 M) in DA synthesis, it requires molecular O2 and Fe + as well as tetrahydropterine (BH-4) cofactor and is substrate-specific. It can be inhibited by a-methyl-p-tyrosine, which depletes the brain of both DA and NA and it is particularly important for the maintenance of DA synthesis. Since the levels of tyrosine are above the for tyrosine hydroxylase the enzyme is normally saturated and so it is not possible to increase DA levels by giving tyrosine. 

Dioxygenases often have broad substrate specificity and require only a minimal characteristic structure for substrate recognition [310], Transition metal or an organic cofactor mediates dioxygen activation needed by the oxygenases action. Iron and copper, in their lower oxidation states are the metals most commonly used, but also organic co-factors like dihydroflavin and tetrahydropterin are able to activate the oxygen molecule. 

Recently it was discovered that cofactor activity with phenylalanine hydroxylase is not limited to tetrahydropterin derivatives. Thus, the substituted pyrimidines 2,4,5-triamino-6-hydroxypyrimidine (21) and 5-(benzylamino)-2,4-diamino-6-hydroxypyrimidine (22) are active in the L-phenylalanine hydroxylating system (78BBR(85)1614, 79JBC(254)5150, 80JBC(255)7774). The amine substituent at C-5 of (21) and (22) is apparently required for... 

Structural correlations on the basis of CD spectra provide good information about the stereochemistry of chiral molecules. The structure of (—)-tetrahydrobiopterin, the cofactor for hydroxyl-ations of aromatic amino acids, was determined by x-ray crystallographic analysis as (6R,l, 2 5)-6-(L -dihydroxypropyO-S J -tetrahydropterin (135). Its CD spectrum exhibits a negative Cotton... 

The 1.25 A-crystal structure of the mouse SR in complex with NADP has been solved. The 261 amino acids of the monomer fold into a single domain a//3-structure. A seven-stranded parallel /3-sheet in the center of the molecule is sandwiched by two arrays of three a-helices. The association of two monomers to the active homodimeric SR leads to the formation of a four-helix bundle (Figure 13). Owing to the two-folded crystallographic symmetry of the homodimeric molecule, the parallel /3-sheets in monomer A is in an antiparallel orientation relative to the /3-sheet of monomer B enclosing an angle of 90°. The overall dimensions of the SR dimer are 40 A X 50 A x 80 A. The two substrate pockets bind sepiapterin (or 6-pyruvoyl-tetrahydropterin 42), and the cofactor NADP/NADPH from opposite sides to the enzyme. 

This tolerance to structural changes has culminated in the demonstration that various amino-substituted pyrimidines can fimction as cofactors [98,101]. They exhibit values similar to those found with the corresponding tetrahydropterin analogs, although the relative values are only 1-5%. Thus the minimal... 

Support for the intermediacy of the carbonyl oxide mechanism stems mainly from the observation of stoichiometric 5-amino group expulsion from the pyrimidine cofactors during PAH turnover regardless of the extent of coupling [106]. However, an attempt to demonstrate PAH-catalyzed cyclization of 25 to 26 proved unsuccessful, despite the requirements for such a process if the tetrahydropterin follows a similar reaction course [102]. Thus the case for their intermediacy is flawed. Carbonyl oxides are rather poor electrophilic reagents so that the hydroxylation of an aromatic ring probably proceeds via a radical species [115]. 

C9H,5N303, Mr 241.25 hydrochloride mp. 245 - 246°C, [a] -6.81° (0.1 m HCl). T. plays a central role as cofactor of phenylalanine, tyrosine, and tryptophan hydroxylases ftat are necessary for the biosynthesis of catecholamine neurotransmitters. In addition, T. is a cofactor of NO synthase (see nitrogen monoxide). The biosynthesis of T. proceeds from GTP and leads by means of GTP cyclohydrolase I to dihydroneopterin triphosphate (H2-neopterin-TP). In the presence of the latter is transformed to tetrahydropterin-1. Tetra-hydrobiopterin-2 is then formed in two consecutive, NADPH-dependent steps. 

The tetrahydropterin-dithioiene iigand generated considerabie excitement and speculation. It was unique in biochemistry, and is unusual in chemistry. While dithiolenes were well-known ligands for molybdenum and other metals, this was the first time a dithioiene was proposed to play a role in biochemistry. On the other hand, tetrahydropterins were already known molecules in biochemical processes, such as the tetrahydrobiop-terin cofactor used by aromatic amino acid hydroxylases and tetrahydro-folate in Cl transfer in methionine synthesis (Figure 2.3). Certainly, this was the first time a pterin was found to be in combination with a dithioiene an where in chemistry. 

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