Tetrahydrobiopterin structure

Finally, a quinonoid 6,7,8-trihydropterin structure (49) absorbing at 303 nm plays an important role as a labile intermediate in the tetrahydrobiopterin-dependent enzymatic hydroxylation of phenylalanine <67JBC(242)3934). 

The two oxidation states of (17) that are relevant in biopterin-dependent redox reactions are the four-electron and two-electron reduced forms, tetrahydrobiopterin (19) and p-quinonoid dihydrobiopterin (20), respectively. The oxidation state between these two, i.e. a radical, may also be relevant though it has not been detected as an intermediate in enzymatic reactions. Structurally, pteridines and flavins are rather similar and hence show similar chemical behavior in many respects. As a redox coenzyme, (19) is not encountered nearly as frequently as nicotinamides or flavins. It is, however, the cofactor of three very... 

Tire tetrahydrobiopterin formed in this reaction is similar in structure to a reduced flavin. The mechanism of its interaction with 02 could reasonably be the same as that of 4-hydroxybenzoate hydroxylase. However, phenylalanine hydroxylase, which catalyzes the formation of tyrosine (Eq. 18-45), a dimer of 451-residue subunits, contains one Fe per subunit,113 313i whereas flavin monooxygenases are devoid of iron. Tyrosine hydroxylase416 193 and tryptophan hydroxylase420 have very similar properties. All three enzymes contain regulatory, catalytic, and tetramerization domains as well as a common Fe-binding motif in their active sites.413 421 4213... 

Sequential keto-enol tautomeric isomerization (Eq. 7) could convert 118 to the tetrahydropterin derivative, the structure of which is widely accepted as (6R)-pyruvoyltetrahydropterin (124). Contrary to the importance of 124 in the biosynthesis of tetrahydrobiopterin (43) (Sect. 5.1), thus far, only a few... 

PTPS (6-Pyruvoyl Tetmhydropterin Synthase). 6-Pyruvoyl tetrahy-dropterin synthase catalyzes formation of tetrahydrobiopterin biosynthesis. Tetrahydrobiopterin is a cofactor for several important enzymes, such as aromatic amino acid hydroxylases and nitric oxide synthase (57). H. pylori protein HPAG1 0913 shares homology with members of the protein domain family PTPS. H. pylori protein shares poor sequence identity of 14% with the PTPS profile at an E-value of 10 10 and covers about 95% of the length of the profile. Fold recognition results also confirm the relationship between H. pylori protein and the PTPS protein domain family. A fold recognition algorithm ensures fitness of the H. pylori protein sequence on the three-dimensional structure of PTPS from... 

Nar H, Huber R, Heizmann CW et al (1994) Three-dimensional structure of 6-pyruvoyl tet-rahydropterin synthase, an enzyme involved in tetrahydrobiopterin biosynthesis. EMBO J 13 1255-1262... 

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... 

Metal-free models showing special structural features can be seen in the crystal structures of A2,l,2,3, 4/-0-pentaacetyl-6-(D-arabino-l,2, 3, 4/-tetrahydroxybutyl)pterin <93AX(C)413>, its 5-benzyloxycarbonyl-5,6,7,8-tetrahydro derivative <93AX(C)1649> and (6R)-N2,N2,N(- ),04,, 2 heptaacetyl-5-ethyl-5,6,7,8-tetrahydro-D-neopterin <86HCA2lo>. The x-ray analysis of the naturally occurring tetrahydrobiopterin is also available in the form of its dihydrochloride salt <85MI 718-10). The side chain attached to C-6 takes the equatorial conformation and the hydroxy groups are in the trans orientation. 

The first step in the liver pathway is catalyzed by phenylalanine hydroxylase. Tetrahydrobiopterin is a cofactor. This redox cofactor is also required for the hydroxylation of tyrosine to form L-dopa (Chapter 16) and for the hydroxylation of tryptophan to form 5-hydroxy tryptophan. The structure of tetrahydrobiopterin is given in Figure 20.23. In the process of phenylalanine hydroxylation, the tetrahydrobiopterin is oxidized to dihydrobiopterin. The reduced form is then recovered via NADH and dihydrobiopterin reductase, as shown in Figure 20.23. Dihydrobiopterin, although similar in structure to folic acid, is synthesized in the human organism from GTP. 

Andersen OA, Flatmark T, Hough E Crystal structure of the ternary complex of the catalytic domain of human phenylalanine hydroxylase with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine, and its implications for the mechanism of catal-... 

Figure 10.1 also shows the structures of the folate antagonist methotrexate (iV -methyl aminopterin) and the pterin coenzymes tetrahydrobiopterin (Section 10.4) and molybdopterin (Section 10.5). 

The rapid technological progress in X-ray crystallography has enabled the structural analysis of numerous enzymes involved in coenzyme biosynthesis. Complete sets of structures that cover all enzymes of a given pathway are available in certain cases such as riboflavin, tetrahydrobiopterin, and folic acid biosynthesis. Stmctures of orthologs from different taxonomic groups have been reported in certain cases. X-ray structures of enzymes in complex with substrates, products, and analogs of substrates, products, or intermediates have been essential for the elucidation of the reaction mechanisms. Structures of some coenzyme biosynthesis enzymes have been obtained by NMR-structure analysis. 

Several imidazoles have been found to inhibit NOS, including 1-phenylimidazole, 2-phenylimidazole, and 4-phenylimidazole. These imidazoles bind heme in NOS and other enzymes. A search for isoform-specific inhibitors based on an imidazole structure has led to the discovery of l-(trifluoromethylphenyl) imidazole, N-(4-nitrophenacyl) imidazole, and N-(4-nitrophenyIacyl)-2-methyI-imidazole, below (54). The nitrophenylacylimidazoles are selective for nNOS rather than eNOS inhibition. They appear to bind to the tetrahydro-biopterin site and are competitive inhibitors of tetrahydrobiopterin binding. They are noncompetitive inhibitors of arginine binding. It appears that electron-withdrawing N-1 substituents enhance activity and nNOS selectivity. 

Structure of folic acid showing its components. The numbered part participates in one-carbon transfer reactions. In nature, folate occurs largely as polyglutamyl derivatives in which the glutamate residues are attached by isopeptide linkages via the y-carboxyl group. The pteridine ring structure is also present in tetrahydrobiopterin, a coenzyme in the hydroxylation of phenylalanine, tyrosine, and tryptophan (Chapter 17). 

Matter, H., Kumar, H. S. A., Fedorov, R., Frey, A., Kotsonis, P., Hartmann, E., Froeh-lich, L. G., Reif, A., Pfeiderer, W., Scheu-rer, P., Ghosh, D. K., Schlichting, I., and Schmidt, H. H. (2005) Structural analysis of isoform-specific inhibitors targeting the tetrahydrobiopterin binding site of human nitric oxide synthases. J. Med. Chem. 48, 4783-4792. 

---