@article{3b5ac7b939814dff843a86619940f587,
title = "Tyrosine aminotransferase is involved in the oxidative stress response by metabolizing meta-tyrosine in Caenorhabditis elegans",
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.",
author = "Ipson, {Brett R.} and Green, {Rebecca A.} and Wilson, {John T.} and Watson, {Jacob N.} and Faull, {Kym F.} and Fisher, {Alfred L.}",
note = "Funding Information: The WT N2 C. elegans strain was obtained from the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health National Center for Research Resources, as were the following strains: OD95 (unc-119(ed3); ltIs37[pie-1p::mCherry::his-58 + unc-119(+)]; ltIs38[pie-1p::GFP::PH(PLC1Δ) + unc-119(+)]); CL2166 ((pAF15)gst-4p::GFP::NLS); and HT1593 (unc-119(ed3)). LG335 (skn-1(zu135)/nT1[qIs51]) was a gift from Nicholas Bishop and Leonard Guarente. tatn-1(qd182) was described previously and is a gift from Daniel Pagano and Dennis Kim (62). The ALF131 (bafIs131[tatn-1p::tatn-1 cDNA::GFP]) strain, which expresses a TATN-1::GFP fusion protein, has been described previously (62). Standard genetic crosses were performed to introduce transgenes into mutant backgrounds with PCR being used to confirm the presence of the desired mutations. Funding Information: Acknowledgments—Whole-genome sequencing and RNA-Seq data were generated in the Genome Sequencing Facility at the University of Texas Health Science Center at San Antonio, which is supported by NCI, National Institutes of Health (NIH), Grant P30 CA054174, NIH Shared Instrument Grant 1S10OD021805-01, and Cancer Prevention and Research Institute of Texas (CPRIT) Core Facility Award RP160732. Funding Information: This work was supported by funds from the South Texas Veterans Affairs Healthcare System; National Institutes of Health Grant AG053034 (to B. R. I.); NIA, National Institutes of Health, Grant AG044768 (to A. L. F.); NIEHS, National Institutes of Health, Grant ES017761 (to A. L. F.); and NINDS, National Institutes of Health, Grant NS102782 (to A. L. F.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: 3Supported by funds from NIA, National Institutes of Health, Grant AG013319. To whom correspondence should be addressed: Division of Geriatrics, Gerontology, and Palliative Medicine, Dept. of Internal Medi-cine, University of Nebraska Medical Center, 986155 Nebraska Medical Center, Omaha, NE 68198-6155. Tel.: 402-559-9600; Fax: 402-559-3877; E-mail: alfred.fisher@unmc.edu. Funding Information: 1Supported in part by funds from National Institutes of Health T32 Training Grant GM113896. Publisher Copyright: {\textcopyright} 2019 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.",
year = "2019",
month = jun,
day = "14",
doi = "10.1074/jbc.RA118.004426",
language = "English (US)",
volume = "294",
pages = "9536--9554",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "24",
}