Tetrahydropterin-Dependent Amino Acid Hydroxylases

Abstract

Phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase constitute a small family of monooxygenases that utilize tetrahydropterins as substrates. When from eukaryotic sources, these enzymes are composed of a homologous catalytic domain to which are attached discrete N-terminal regulatory domains and short C-terminal tetramerization domains, whereas the bacterial enzymes lack the N-terminal and C-terminal domains. Each enzyme contains a single ferrous iron atom bound to two histidines and a glutamate. Recent mechanistic studies have begun to provide insights into the mechanisms of oxygen activation and hydroxylation. Although the hydroxylating intermediate in these enzymes has not been identified, the iron is likely to be involved. Reversible phosphorylation of serine residues in the regulatory domains affects the activities of all three enzymes. In addition, phenylalanine hydroxylase is allosterically regulated by its substrates, phenylalanine and tetrahydrobiopterin.

SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression

“…Tryptophan hydroxylase (TPH), the rate-limiting enzyme in the synthesis of the neurotransmitter serotonin (5-HT), 3 is widely discussed as a major candidate gene in many psychiatric disorders, especially depression and suicidal behavior. 4,5 Numerous studies about genetic variants or different expression levels of the TPH gene related to depression, schizophrenia, alcoholism, drug abuse, aggression and sucidality have been reported, but none of them have led to convincingly confirmed results up to now.…”

Analysis of the novel TPH2 gene in bipolar disorder and suicidality

“…4 5-HT is synthesized in two steps, with tryptophan hydroxylase (TPH) as the rate-limiting enzyme. 5 Thus far, two TPH genes have been identified. The TPH1 gene is located on chromosome 11p15 and has been the focus of a number of genetic studies of suicidality.…”

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

“…[256b] By feeding glucose and monoterpene secologanin, hydroxystrictosidine was produced via a pterin-dependent mono-oxidation pathway in S. cerevisiae. [257] From inherent tryptophan, serotonin was produced via the pterin-dependent oxidation governed by tryptophan hydroxylase (TPH) and aromatic L-amino acid decarboxylase. Then, secologanin was condensed with serotonin in order to produce hydrostrictosidine.…”