Mechanobiology

Tyrosine aminotransferase is involved in the oxidative stress response by metabolizing tyrosine in

AUTHORS

ABSTRACT

Under oxidative stress conditions, hydroxyl radicals can oxidize the phenyl ring of phenylalanine, producing the abnormal tyrosine isomer tyrosine (-tyrosine). 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 tyrosine in oxidative stress effects. We found that the 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 tyrosine is a substrate for TATN-1-mediated deamination, suggesting that TATN-1 also metabolizes tyrosine. Consistent with a toxic effect of -tyrosine and a protective function of TATN-1, mutant worms exhibited delayed development, marked reduction in fertility, and shortened lifespan when exposed to -tyrosine. A forward genetic screen identified a mutation in the previously uncharacterized gene -homologous with human transcription factor 20 (TCF20) and retinoic acid-induced 1 (RAI1)-that suppresses the adverse phenotypes observed in -tyrosine-treated mutant worms. RNA-Seq analysis of 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 -tyrosine. Our findings uncover a critical role for tyrosine aminotransferase in the oxidative stress response via tyrosine metabolism.