Tyrosine aminotransferase is involved in the oxidative stress response by metabolizing meta-tyrosine in Caenorhabditis elegans
Year: 2019
Type: article
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.
Source: Journal of Biological Chemistry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Funders: U.S. Department of Veterans Affairs, Cancer Prevention and Research Institute of Texas, Ludwig Institute for Cancer Research, National Institutes of Health, University of Texas Health Science Center at San Antonio, National Institute on Aging, NIH Office of the Director, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
Awards: G1143455775, Mays Cancer Center at UT Health SA, South Texas Medical Scientist Training Program (STX-MSTP), Regulation on of the AIRAP/aip-1 pathway by metabolic stress, G2889789141, High Throughput DNA Sequencer: Illumina HiSeq 3000 Sequencer, G3874765150, G399382401, Improving omega-3 fatty acid supplementation with microencapsulation, G4830487413, UTHSCSA Cancer Genome Sequencing and Computation Core, Effects of insulin-like signaling, aging, and ubiquinone on C. elegans muscle, G571033708, G574163375, G5827286289, G6081885499, G6750732523, Contribution of m-tyrosine to the adverse effects of oxidative stress, G9000075801, G9000324485, San Antonio Nathan Shock Center of Excellence in the Biology of Aging
OpenAlex ID: W2942680339