The aromatic amino acid hydroxylases: Structures, catalysis, and regulation of phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase

Fitzpatrick, Paul F.

doi:10.1016/j.abb.2023.109518

Cited by 27 publications

(15 citation statements)

References 103 publications

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“…26 Previous studies have revealed that kyureninase, the key enzyme of tryptophan metabolism, is significantly overexpressed in psoriasis, contributing to the disease onset by affecting the proliferation of keratinocytes and the secretion of inflammatory cytokines. [27][28][29] Amino acid metabolism also influences the production of pro-inflammatory cytokines, such as IL-17 and TNFα, which are key drivers of inflammation in psoriasis. 30 Addiationally, amino acids can modulate the activity of immune cells, such as T cells and dendritic cells, which are implicated in the pathogenesis of psoriasis.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, arginine plays a crucial role in nitric oxide production and urea cycle regulation 26 . Previous studies have revealed that kyureninase, the key enzyme of tryptophan metabolism, is significantly overexpressed in psoriasis, contributing to the disease onset by affecting the proliferation of keratinocytes and the secretion of inflammatory cytokines 27–29 . Amino acid metabolism also influences the production of pro‐inflammatory cytokines, such as IL‐17 and TNF‐α, which are key drivers of inflammation in psoriasis 30 .…”

Section: Discussionmentioning

confidence: 99%

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Biological agent exerts therapeutic effects by reversing abnormalities in amino acid metabolic pathways in psoriasis

Miao,

Bai,

Shen

et al. 2024

Experimental Dermatology

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Psoriasis is a common chronic inflammatory skin disease with a complex pathogenesis involving immune system dysregulation and inflammation. Previous studies have indicated that metabolic abnormalities are closely related to the development and occurrence of psoriasis. However, the specific involvement of amino acid metabolism in the pathogenesis of psoriasis remains unclear. In this study, we conducted a comprehensive analysis of amino acid metabolism pathway changes in psoriasis patients using transcriptome data, genome‐wide association studies (GWASs) data, and single‐cell data. Our findings revealed 11 significant alterations in amino acid metabolism pathways within psoriatic lesions, with notable restorative changes observed after biological therapy. Branched‐chain amino acids, tyrosine and arginine metabolism have a causal relationship with the occurrence of psoriasis and may play a crucial role by promoting the proliferation and differentiation of the keratinocytes or immune‐related pathways. Activation of phenylalanine, tyrosine and tryptophan biosynthesis suggests a favourable prognosis of psoriasis after treatment. Additionally, we identified the abnormal metabolic pathways in specific cell types and key gene sets that contribute to amino acid metabolic disorders in psoriasis. Overall, our study enhances understanding of the role of metabolism in the pathogenesis of psoriasis and provides potential targets for developing new therapeutic strategies for the disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Biological agent exerts therapeutic effects by reversing abnormalities in amino acid metabolic pathways in psoriasis

Miao,

Bai,

Shen

et al. 2024

Experimental Dermatology

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“…Hydroxylation of free tyrosine by tyrosine hydroxylase forms 3,4-dihydroxy-phenylalanine (DOPA, 8 of Figure 24), which is the precursor of neurotransmitters dopamine, norepinephrine, and epinephrine. 348 Hydroxylation of tyrosine residues in proteins has been found in mussel proteins to increase adhesivity 349 and identified as a new histone maker associated with transcription. 350 Site-specific incorporation of DOPA into proteins has been established in both E. coli and mammalian cells.…”

Section: Tyrosine Hydroxylationmentioning

confidence: 99%

Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

Gan,

Fan

2024

Chem. Rev.

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Post-translational modifications (PTMs) endow proteins with new properties to respond to environmental changes or growth needs. With the development of advanced proteomics techniques, hundreds of distinct types of PTMs have been observed in a wide range of proteins from bacteria, archaea, and eukarya. To identify the roles of these PTMs, scientists have applied various approaches. However, high dynamics, low stoichiometry, and crosstalk between PTMs make it almost impossible to obtain homogeneously modified proteins for characterization of the site-specific effect of individual PTM on target proteins. To solve this problem, the genetic code expansion (GCE) strategy has been introduced into the field of PTM studies. Instead of modifying proteins after translation, GCE incorporates modified amino acids into proteins during translation, thus generating site-specifically modified proteins at target positions. In this review, we summarize the development of GCE systems for orthogonal translation for site-specific installation of PTMs.

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“…[1][2][3] TH is a nonheme iron-dependent enzyme that catalyzes the hydroxylation of L-Tyr to L-Dopa, using molecular oxygen as an additional substrate and tetrahydrobiopterin (BH 4 ) as a cofactor. 4 This is the rate-limiting step in the biosynthesis of catecholamines, such as dopamine, norepinephrine and epinephrine, 5 where the essential role of the cofactor explains the association of variants in genes involved in the synthesis of BH 4 with deficient catecholamine synthesis. 6 To date, more than 59 disease-causing variants have been identified in the TH gene (chromosome 11p15.5, Gene ID: 7054) and its promoter region, and are deposited in the PND database (http://www.biopku.org/home/ pnddb.asp).…”

Section: Introductionmentioning

confidence: 99%

Tetrahydrobiopterin (BH₄) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock‐in mouse model

Jung‐KC,

Tristán‐Noguero,

Altankhuyag

et al. 2024

J of Inher Metab Disea

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Proteostatic regulation of tyrosine hydroxylase (TH), the rate‐limiting enzyme in dopamine biosynthesis, is crucial for maintaining proper brain neurotransmitter homeostasis. Variants of the TH gene are associated with tyrosine hydroxylase deficiency (THD), a rare disorder with a wide phenotypic spectrum and variable response to treatment, which affects protein stability and may lead to accelerated degradation, loss of TH function and catecholamine deficiency. In this study, we investigated the effects of the TH cofactor tetrahydrobiopterin (BH4) on the stability of TH in isolated protein and in DAn‐ differentiated from iPSCs from a human healthy subject, as well as from THD patients with the R233H variant in homozygosity (THDA) and R328W and T399M variants in heterozygosity (THDB). We report an increase in TH and dopamine levels, and an increase in the number of TH+ cells in control and THDA cells. To translate this in vitro effect, we treated with BH4 a knock‐in THD mouse model with Th variant corresponding to R233H in patients. Importantly, treatment with BH4 significantly improved motor function in these mice, as demonstrated by increased latency on the rotarod test and improved horizontal activity (catalepsy). In conclusion, our study demonstrates the stabilizing effects of BH4 on TH protein levels and function in THD neurons and mice, rescuing disease phenotypes and improving motor outcomes. These findings highlight the therapeutic potential of BH4 as a treatment option for THDA patients with specific variants and provide insights into the modulation of TH stability and its implications for THD management.

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The aromatic amino acid hydroxylases: Structures, catalysis, and regulation of phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase

Cited by 27 publications

References 103 publications

Biological agent exerts therapeutic effects by reversing abnormalities in amino acid metabolic pathways in psoriasis

Biological agent exerts therapeutic effects by reversing abnormalities in amino acid metabolic pathways in psoriasis

Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

Tetrahydrobiopterin (BH₄) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock‐in mouse model

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The aromatic amino acid hydroxylases: Structures, catalysis, and regulation of phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase

Cited by 27 publications

References 103 publications

Biological agent exerts therapeutic effects by reversing abnormalities in amino acid metabolic pathways in psoriasis

Biological agent exerts therapeutic effects by reversing abnormalities in amino acid metabolic pathways in psoriasis

Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

Tetrahydrobiopterin (BH4) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock‐in mouse model

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Tetrahydrobiopterin (BH₄) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock‐in mouse model