TAILIEUCHUNG - Báo cáo khoa học: Modeled ligand-protein complexes elucidate the origin of substrate specificity and provide insight into catalytic mechanisms of phenylalanine hydroxylase and tyrosine hydroxylase

NMR spectroscopy and X-ray crystallography have provi-ded important insight into structural features of phenyl-alanine hydroxylase (PAH) and tyrosine hydroxylase (TH). Nevertheless, significant problems such as the substrate specificity of PAHand the different susceptibility of TH to feedback inhibition by L-3,4-dihydroxyphenylalanine (L-DOPA) compared with dopamine (DA) remain unre-solved. Based on the crystal structures 5pah for PAHand 2toh for TH(Protein Data Bank), we have used molecular docking to model the binding of 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) and the substrates phenylalanine and tyrosine to the catalytic domains of PAHand TH | Eur. J. Biochem. 270 1065-1075 2003 FEBS 2003 doi Modeled ligand-protein complexes elucidate the origin of substrate specificity and provide insight into catalytic mechanisms of phenylalanine hydroxylase and tyrosine hydroxylase Astrid MaaB1 Joachim Scholz2 3 and Andreas Moser2 1 Fraunhofer-Institute for Algorithms and Scientific Computing SCAI Schloss Birlinghoven Sankt Augustin Germany 2Neurochemistry Reseacch Group Department of Neurology Medical Uviversity of Lubeck Lubeck Germany 3Neural Plasticity Research Group. Depastment of Anestheria and Crinail Caee Masedchusstts Geueau Hoepừol and Harvard Medical School Charlestown Massachusetts USA NMR spectroscopy and X-ray crystallography have provided important insight into structural features of phenylalanine hydroxylase PAH and tyrosine hydroxylase TH . Nevertheless significant problems such as the substrate specificity of PAH add the different susceptibility of TH to feedback inhibition by L-3 4-dihydroxyphenylalanine l-DOPA compared with dopamine DA remain unresolved. Based on the crystal structures 5pah for PAH and 2toh for TH Protein Dahl Bank . we have I iee d molecular docking to model the binding of 6 R -L-erythro-5 6 7 8-tetrahydrobiopterin BH4 and the substrates phenylalanine and tyrosine to the catalytic domains of PAHand TH. The amino acid substrates were placed in positions common to both enzymes. The productive position of tyrosine in TH BH-I was stabilized by a hydrogen bond with BH4. Despite favorable energy scores tyrosine in a position sraee to PAH residue His20O rr TH residue idis33n inte rleres vhth the access of the essential cofactor dioxygen to the catalytic snnter thereby blocking the enzymatic reaction. da and l-DOPA were directly coordinated to the active site iron via the hydroxyl residues of their catechol groups. Two alternative conformations rotated 180 around an imaginary iron-catecholamine axis were found for da and l-DOPA in PAH and for DA m TH. .

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