Abstract
A previous report showed that the consumption of glutathione through oxidative stress activates the glutathione synthetic pathway, which is accompanied by production of ophthalmic acid from 2-aminobutyric acid (2-AB). We conducted a comprehensive quantification of serum metabolites using gas chromatography-mass spectrometry in patients with atrial septal defect to find clues for understanding myocardial metabolic regulation, and demonstrated that circulating 2-AB levels reflect hemodynamic changes. However, the metabolism and pathophysiological role of 2-AB remains unclear. We revealed that 2-AB is generated by an amino group transfer reaction to 2-oxobutyric acid, a byproduct of cysteine biosynthesis from cystathionine. Because cysteine is a rate-limiting substrate for glutathione synthesis, we hypothesized that 2-AB reflects glutathione compensation against oxidative stress. A murine cardiomyopathy model induced by doxorubicin supported our hypothesis, i.e., increased reactive oxygen species are accompanied by 2-AB accumulation and compensatory maintenance of myocardial glutathione levels. Intriguingly, we also found that 2-AB increases intracellular glutathione levels by activating AMPK and exerts protective effects against oxidative stress. Finally, we demonstrated that oral administration of 2-AB efficiently raises both circulating and myocardial glutathione levels and protects against doxorubicin-induced cardiomyopathy in mice. This is the first study to demonstrate that 2-AB modulates glutathione homeostasis in the myocardium.
Highlights
A previous report showed that the consumption of glutathione through oxidative stress activates the glutathione synthetic pathway, which is accompanied by production of ophthalmic acid from 2-aminobutyric acid (2-AB)
We found that circulating 2-aminobutyric acid (2-AB) levels alter depending on hemodynamic status in patients with atrial septal defect (ASD)
Soga et al reported that the activation of GSH biosynthetic pathway simultaneously initiates the production of ophthalmic acid, a GSH analog, from 2-aminobutyric acid (2-AB) and that ophthalmic acid is a potential biomarker for hepatic GSH depletion following oxidative stress[12]
Summary
Circulating 2-AB levels alter depending on hemodynamic status. Metabolome analysis in patients with ASD revealed that circulating 2-AB was significantly decreased 1 month after transcatheter closure of ASD among 85 metabolites (Supplementary Table 1). AOA treatment had no effect on the incorporation of 2-OBA, 2-AB production was significantly suppressed (Fig. 2e) These results suggest that 2-AB is an AST-mediated byproduct in the cysteine biosynthesis pathway. We found that oxidative stress caused by H2O2 administration increased the 2-AB levels in both cardiomyocytes and culture medium (Fig. 3a,b), depending on AST activity (Supplementary Figure 1). The levels of 2-AB in both plasma and hearts were increased after the administration of DOX (Fig. 3e,f). 2-AB increases intracellular GSH levels and exerts protective effects against oxidative stress. 2-AB increases intracellular GSH levels by altering metabolism and AMPK activation as well as exerting cardioprotective effects against oxidative stress. Whereas 2-OBA requires esterification for cellular uptake, 2-AB is incorporated directly into cells, followed by an increase in intracellular GSH levels. The current findings suggest the potential of 2-AB modulation as a novel therapeutic strategy for targeting dysregulation in cellular GSH homeostasis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
