Tyrosine aminotransferase is involved in the oxidative stress response by metabolizing meta-tyrosine in Caenorhabditis elegans

Brett R. Ipson, Rebecca A. Green, John T. Wilson, Jacob N. Watson, Kym F. Faull, Alfred L Fisher

Research output: Contribution to journalArticle

Abstract

Under oxidative stress conditions, hydroxyl radicals can oxidize the phenyl ring of phenylalanine, producing the abnormal tyrosine isomer meta-tyrosine (m-tyrosine). m-Tyrosine levels are commonly used as a biomarker of oxidative stress, and its accumulation has recently been reported to adversely affect cells, suggesting a direct role for m-tyrosine in oxidative stress effects. We found that the Caenorhabditis elegans ortholog of tyrosine aminotransferase (TATN-1)-the first enzyme involved in the metabolic degradation of tyrosine-is up-regulated in response to oxidative stress and directly activated by the oxidative stress-responsive transcription factor SKN-1. Worms deficient in tyrosine aminotransferase activity displayed increased sensitivity to multiple sources of oxidative stress. Biochemical assays revealed that m-tyrosine is a substrate for TATN-1-mediated deamination, suggesting that TATN-1 also metabolizes m-tyrosine. Consistent with a toxic effect of m-tyrosine and a protective function of TATN-1, tatn-1 mutant worms exhibited delayed development, marked reduction in fertility, and shortened lifespan when exposed to m-tyrosine. A forward genetic screen identified a mutation in the previously uncharacterized gene F01D4.5-homologous with human transcription factor 20 (TCF20) and retinoic acid-induced 1 (RAI1)-that suppresses the adverse phenotypes observed in m-tyrosine-treated tatn-1 mutant worms. RNA-Seq analysis of F01D4.5 mutant worms disclosed a significant reduction in the expression of specific isoforms of genes encoding ribosomal proteins, suggesting that alterations in protein synthesis or ribosome structure could diminish the adverse effects of m-tyrosine. Our findings uncover a critical role for tyrosine aminotransferase in the oxidative stress response via m-tyrosine metabolism.

Original languageEnglish (US)
Pages (from-to)9536-9554
Number of pages19
JournalJournal of Biological Chemistry
Volume294
Issue number24
DOIs
StatePublished - Jan 1 2019

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Tyrosine Transaminase
Oxidative stress
Caenorhabditis elegans
Oxidative Stress
Tyrosine
3-tyrosine
Deamination
Gene encoding
Ribosomal Proteins
Poisons
Biomarkers
Tretinoin
Phenylalanine
Ribosomes
Metabolism
Isomers
Hydroxyl Radical
Genes
Fertility
Assays

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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Tyrosine aminotransferase is involved in the oxidative stress response by metabolizing meta-tyrosine in Caenorhabditis elegans. / Ipson, Brett R.; Green, Rebecca A.; Wilson, John T.; Watson, Jacob N.; Faull, Kym F.; Fisher, Alfred L.

In: Journal of Biological Chemistry, Vol. 294, No. 24, 01.01.2019, p. 9536-9554.

Research output: Contribution to journalArticle

Ipson, Brett R. ; Green, Rebecca A. ; Wilson, John T. ; Watson, Jacob N. ; Faull, Kym F. ; Fisher, Alfred L. / Tyrosine aminotransferase is involved in the oxidative stress response by metabolizing meta-tyrosine in Caenorhabditis elegans. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 24. pp. 9536-9554.
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