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• W1973549601 endingPage "1075" @default.
• W1973549601 startingPage "1065" @default.
• W1973549601 abstract "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 and 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 Data Bank), we have used molecular docking to model the binding of 6( R )‐ l ‐erythro‐5,6,7,8‐tetrahydrobiopterin (BH 4 ) and the substrates phenylalanine and tyrosine to the catalytic domains of PAH and TH. The amino acid substrates were placed in positions common to both enzymes. The productive position of tyrosine in TH·BH 4 was stabilized by a hydrogen bond with BH 4 . Despite favorable energy scores, tyrosine in a position trans to PAH residue His290 or TH residue His336 interferes with the access of the essential cofactor dioxygen to the catalytic center, 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 in TH. Electrostatic forces play a key role in hindering the bidentate binding of the immediate reaction product l ‐DOPA to TH, thereby saving the enzyme from direct feedback inhibition." @default.
• W1973549601 created "2016-06-24" @default.
• W1973549601 creator A5004280473 @default.
• W1973549601 creator A5019071463 @default.
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• W1973549601 date "2003-02-24" @default.
• W1973549601 modified "2023-10-18" @default.
• W1973549601 title "Modeled ligand-protein complexes elucidate the origin of substrate specificity and provide insight into catalytic mechanisms of phenylalanine hydroxylase and tyrosine hydroxylase" @default.
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• W1973549601 doi "https://doi.org/10.1046/j.1432-1033.2003.03429.x" @default.
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