Our results lead to the discovery

Our results lead to the discovery and characterization of VvAAT2, a gene potentially involved in acetate accumulation in grape berries discovered through amino-acid feeding experiments. Incubation with exogenous amino acids has also been a key in the discovery of new genes affecting fruit aromas [13,15]. Our work provides tools to augment and modify the aroma and chemical composition of fruits and other agricultural produce by increasing the levels of amino acids in the plant tissues. Indeed, petunia (Petunia × hybrida) flowers incubated with exogenous L-Phe displayed increased levels of benzaldehyde and 2-phenylethanal accompanied by an overall increase in flower aroma perception [57]. The enhancing of L-Phe levels using metabolic engineering methodologies has also been reported [[57], [58], [59]], resulting in significant increases in numerous volatile and non-volatile L-Phe-derived compounds, such as benzaldehyde, 2-phenylethanal, benzyl alcohol, 2-phenylethanol, benzyl acetate, enhancing flower aroma. These works demonstrate the potential to modify the chemical composition of plants to improve fragrance [55] and to study gene function [13,58]. In conclusion, although grape berries do not normally accumulate volatile esters, they undoubtedly possess a concealed biosynthetic potential to convert exogenous amino acids into volatile compounds.
Author contributions
Conflict of interest
Acknowledgment We would like to thank two anonymous reviewers for their very constructive comments. This study was partially funded by the Chief Scientist of the Ministry of Agriculture of Israel (project no. 20-14-0004). This is contribution number 12018 of the Agricultural Research Organization, The Volcani Center, Rishon LeZion, Israel.
Introduction Dysregulated amino Deoxycholic acid metabolism is an emerging hallmark of cancer (Hanahan and Weinberg, 2011, Pavlova and Thompson, 2016). Tumor cells take up amino acids from the extracellular environment as a carbon and nitrogen source for protein and nucleotide synthesis (DeBerardinis et al., 2008). Uptake of amino acids from the tumor microenvironment also contributes to one-carbon metabolism and redox maintenance (Altman et al., 2016, Yang and Vousden, 2016). Macropinocytosis, a recently described opportunistic pathway of amino acid uptake (Commisso et al., 2013, Pavlova and Thompson, 2016), provides one mechanism for coupling cancer cell proliferation with amino acid availability. However, tumor cells may also regulate amino acid uptake by modulating the level or activity of specific amino acid transporters (Bhutia et al., 2015). Currently, the underlying molecular mechanisms of amino acid transporter regulation in cancer are not well understood. The cystine-glutamate antiporter xCT encoded by the SLC7A11 gene, is highly expressed in multiple human cancer types, including triple-negative breast cancer and glioblastoma (GBM) (Chung et al., 2005, Takeuchi et al., 2013, Timmerman et al., 2013). xCT is a 12-pass transmembrane protein, which together with its binding partner CD98 (SLC3A2) forms the amino acid transporter system xc–. The primary function of system xc− is to take up cystine, the oxidized dimeric form of cysteine, in exchange for glutamate, contributing to tumor growth (Bassi et al., 2001, Lewerenz et al., 2012). In nutrient depleted conditions, cystine uptake is critical for glutathione synthesis to buffer reactive oxygen species (ROS), whereas, in nutrient replete conditions, glutamate can contribute to many anabolic reactions (Commisso et al., 2013, Conrad and Sato, 2012, DeBerardinis et al., 2008, Kim et al., 2001). Thus, post-translational mechanisms of xCT regulation may be important for enabling tumor cells to rapidly respond to changing environmental conditions. In triple-negative breast cancer, extracellular glutamate inhibits xCT through a paracrine mechanism, inducing hypoxia inducible factor (HIF) to drive tumor growth (Briggs et al., 2016), suggesting that xCT may be highly responsive to extracellular amino acids. Suppression of xCT activity results in intracellular cysteine depletion, which directly inhibits HIF prolyl hydroxylases, thereby inducing HIF to promote tumor growth (Briggs et al., 2016). We hypothesized that cell-autonomous signaling mechanisms could provide an additional route of xCT regulation.