A flexible loop in tyrosine hydroxylase controls coupling of amino acid hydroxylation to tetrahydropterin oxidation.

Journal of Molecular Biology
S Colette DaubnerP F Fitzpatrick

Abstract

The role of a polypeptide loop in tyrosine hydroxylase (TyrH) whose homolog in phenylalanine hydroxylase (PheH) takes on a different conformation when substrates are bound has been studied using site-directed mutagenesis. The loop spans positions 177 to 191; alanine was introduced into those positions, introducing one alanine substitution per TyrH variant. Mutagenesis of residues in the center of the loop resulted in alterations in the KM values for substrates, the Vmax value for dihydroxyphenylalanine (DOPA) synthesis, and the coupling of tetrahydropterin oxidation to tyrosine hydroxylation. The variant with the most altered KM value for 6-methyltetrahydropterin was TyrH F184A. The variants with the most affected K(tyr) values were those with substitutions in the center of the loop, TyrH K183A, F184A, D185A, P186A and D187A. These five variants also had the most reduced Vmax values for DOPA synthesis. Alanine substitution in positions 182-186 resulted in lowered ratios of tyrosine hydroxylation to tetrahydropterin oxidation. TyrH F184Y and PheH Y138F, variants with the residue at the center of the loop substituted with the residue present at the homologous position in the other hydroxylase, were also studied. The V/K(tyr) to V...Continue Reading

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Citations

Dec 23, 2009·Biochemistry·Bekir E Eser, Paul F Fitzpatrick
May 29, 2014·Journal of Neural Transmission·Izel TekinKent E Vrana
Feb 18, 2016·Proceedings of the National Academy of Sciences of the United States of America·Emilia C ArturoEileen K Jaffe
Aug 15, 2015·Science·Stephanie GalanieChristina D Smolke
Jul 15, 2015·Metabolic Engineering·Isis J TrenchardChristina D Smolke
Oct 22, 2008·Biochemistry·Michael S WindahlPernille Harris
Oct 17, 2017·Biochemistry·Kasper D TidemandHans E M Christensen

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