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.

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

“…Moreover, serum L-tyrosine level has also emerged as a novel marker that links diabetes and cardiovascular disease (CVD) susceptibility [406]. Interestingly, L-tyrosine influences developmental decisions and longevity in Caenorhabditis elegans [407,408] and potentiates the detrimental effects of oxidative stress either by decreasing glutathione and stimulating lipid and protein oxidation in rat cerebral cortex [409] or by increasing the thiobarbituric acid reactive species levels in the hippocampus and the carbonyl levels in the cerebellum, hippocampus, and striatum [410]. Moreover, chronic administration of Ltyrosine increased DNA damage frequency and damage index in the hippocampus, striatum, cerebral cortex, and blood [411,412].…”

Assessment of serum phenylalanine and tyrosine isomers in patients with ST‐segment elevation vs non‐ST‐segment elevation myocardial infarction

“…According to previous studies, 13‐18 Phe can be enzymatically transformed into physiological p‐Tyr. Additionally, p‐Tyr can also be nonenzymatically produced by reactions involving hydroxyl radicals during oxidative stress.…”

“…These Tyr isomers differ, depending on the location of the hydroxyl group on the benzyl ring (Figure 1). 13‐18 …”

“…However, the enzymatically produced p‐Tyr is more plentiful than the free radical‐derived p‐Tyr. Therefore, p‐Tyr is viewed as the physiological isoform 13‐18 . Furthermore, in humans, m‐ and o‐Tyr amino acids cannot be formed enzymatically; instead, they are produced as a result of the reaction between the hydroxyl free radical and the benzyl ring of Phe.…”

“…Furthermore, in humans, m‐ and o‐Tyr amino acids cannot be formed enzymatically; instead, they are produced as a result of the reaction between the hydroxyl free radical and the benzyl ring of Phe. Therefore, m‐Tyr and o‐Tyr are viewed as free radical markers, 13‐18 which may play a role in chronic inflammation during the initiation and progression of ACS 16,17,19 . This study aimed to compare patients with STEMI and NSTEMI, and the serum levels of Phe and Tyr isomers at the aortic root and distal to the culprit lesion in both patient groups.…”