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2-Aminobutyric Acid Modulates Glutathione Homeostasis in the Myocardium

2-Aminobutyric Acid Modulates Glutathione Homeostasis in the Myocardium

Yasuhiro Irino, Ryuji Toh, Manabu Nagao, Takeshige Mori, Tomoyuki Honjo, Masakazu Shinohara, Shigeyasu Tsuda, Hideto Nakajima, Seimi Satomi-Kobayashi, Toshiro Shinke, Hidekazu Tanaka, Tatsuro Ishida, Okiko Miyata, etc.

Sci Rep. 2016 Nov 9;6:36749.

PMID: 27827456

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP600180	2-Oxobutyric acid		600-18-0	Price

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