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Mechanisms of tryptophan and tyrosine hydroxylase.

ABSTRACT: The aromatic amino acid hydroxylases tryptophan hydroxylase and tyrosine hydroxylase are responsible for the initial steps in the formation of serotonin and the catecholamine neurotransmitters, respectively. Both enzymes are nonheme iron-dependent monooxygenases that catalyze the insertion of one atom of molecular oxygen onto the aromatic ring of their amino acid substrates, using a tetrahydropterin as a two electron donor to reduce the second oxygen atom to water. This review discusses the current understanding of the catalytic mechanism of these two enzymes. The reaction occurs as two sequential half reactions: a reaction between the active site iron, oxygen, and the tetrahydropterin to form a reactive Fe(IV) O intermediate and hydroxylation of the amino acid by the Fe(IV) O. The mechanism of formation of the Fe(IV) O is unclear; however, considerable evidence suggests the formation of an Fe(II) -peroxypterin intermediate. The amino acid is hydroxylated by the Fe(IV) O intermediate in an electrophilic aromatic substitution mechanism.

SUBMITTER: Roberts KM

PROVIDER: S-EPMC4270200 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Mechanisms of tryptophan and tyrosine hydroxylase.

Roberts Kenneth M KM Fitzpatrick Paul F PF

IUBMB life 20130226 4

The aromatic amino acid hydroxylases tryptophan hydroxylase and tyrosine hydroxylase are responsible for the initial steps in the formation of serotonin and the catecholamine neurotransmitters, respectively. Both enzymes are nonheme iron-dependent monooxygenases that catalyze the insertion of one atom of molecular oxygen onto the aromatic ring of their amino acid substrates, using a tetrahydropterin as a two electron donor to reduce the second oxygen atom to water. This review discusses the curr ...[more]

PMID: 23441081

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Project description:Phenylalanine hydroxylase (PheH) and tryptophan hydroxylase (TrpH) catalyze the aromatic hydroxylation of phenylalanine and tryptophan, forming tyrosine and 5-hydroxytryptophan, respectively. The reactions of PheH and TrpH have been investigated with [4-(2)H]-, [3,5-(2)H(2)]-, and (2)H(5)-phenylalanine as substrates. All (D)k(cat) values are normal with Delta117PheH, the catalytic core of rat phenylalanine hydroxylase, ranging from 1.12-1.41. In contrast, for Delta117PheH V379D, a mutant protein in which the stoichiometry between tetrahydropterin oxidation and amino acid hydroxylation is altered, the (D)k(cat) value with [4-(2)H]-phenylalanine is 0.92 but is normal with [3,5-(2)H(2)]-phenylalanine. The ratio of tetrahydropterin oxidation to amino acid hydroxylation for Delta117PheH V379D shows a similar inverse isotope effect with [4-(2)H]-phenylalanine. Intramolecular isotope effects, determined from the deuterium contents of the tyrosine formed from [4-(2)H]-and [3,5(2)H(2)]-phenylalanine, are identical for Delta117PheH and Delta117PheH V379D, suggesting that steps subsequent to oxygen addition are unaffected in the mutant protein. The inverse effects are consistent with the reaction of an activated ferryl-oxo species at the para position of the side chain of the amino acid to form a cationic intermediate. The normal effects on the (D)k(cat) value for the wild-type enzyme are attributed to an isotope effect of 5.1 on the tautomerization of a dienone intermediate to tyrosine with a rate constant 6- to7-fold that for hydroxylation. In addition, there is a slight ( approximately 34%) preference for the loss of the hydrogen originally at C4 of phenylalanine. With (2)H(5)-indole-tryptophan as a substrate for Delta117PheH, the (D)k(cat) value is 0.89, consistent with hydroxylation being rate-limiting in this case. When deuterated phenylalanines are used as substrates for TrpH, the (D)k(cat) values are within error of those for Delta117PheH V379D. Overall, these results are consistent with the aromatic amino acid hydroxylases all sharing the same chemical mechanism, but with the isotope effect for hydroxylation by PheH being masked by tautomerization of an enedione intermediate to tyrosine.

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Mechanisms of tryptophan and tyrosine hydroxylase.

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Mechanisms of tryptophan and tyrosine hydroxylase.

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