Brain Metabolite, Myo-inositol, Inhibits Catalase Activity: A Mechanism of the Distortion of the Antioxidant Defense System in Alzheimer's disease.

A strong correlation between brain metabolite accumulation and oxidative stress has been observed in Alzheimer's disease (AD) patients. There are two central hypotheses for this correlation: (i) coaccumulation of toxic amyloid-ß and Myo-inositol (MI), a significant brain metabolite, during presymptomatic stages of AD, and (ii) enhanced expression of MI transporter in brain cells during oxidative stress-induced volume changes in the brain. Identifying specific interactive effects of MI with cellular antioxidant enzymes would represent an essential step in understanding the oxidative stress-induced AD pathogenicity. This study demonstrated that MI inhibits catalase, an essential antioxidant enzyme primarily inefficient in AD, by decreasing its k cat (turnover number) and increasing K m (Michaelis-Menten constant) values. This inhibition of catalase by MI under in vivo studies increased cellular H2O2 levels, leading to decreased cell viability. Furthermore, MI induces distortion of the active heme center with an overall loss of structure and stability of catalase. MI also alters distances of the vital active site and substrate channel residues of catalase. The present study provides evidence for the involvement of MI in the inactivation of the antioxidant defense system during oxidative stress-induced pathogenesis of AD. Regulation of MI levels, during early presymptomatic stages of AD, might serve as a potential early-on therapeutic strategy for this disease.

The gut metabolite, trimethylamine N-oxide inhibits protein folding by affecting cis-trans isomerization and induces cell cycle arrest.

Trimethylamine N-Oxide (TMAO) is an important metabolite, which is derived from choline, betaine, and carnitine in various organisms. In humans, it is synthesized through gut microbiota and is abundantly found in serum and cerebrospinal fluid (CSF). Although TMAO is a stress protectant especially in urea-rich organisms, it is an atherogenic agent in humans and is associated with various diseases. Studies have also unveiled its exceptional role in protein folding and restoration of mutant protein functions. However, most of these data were obtained from studies carried on fast-folding proteins. In the present study, we have investigated the effect of TMAO on the folding behavior of a well-characterized protein with slow folding kinetics, carbonic anhydrase (CA). We discovered that TMAO inhibits the folding of this protein via its effect on proline cis-trans isomerization. Furthermore, TMAO is capable of inducing cell cycle arrest. This study highlights the potential role of TMAO in developing proteopathies and associated diseases.

Disturbed homocysteine metabolism is associated with cancer.

Hyperhomocysteinemia/Homocysteinuria is characterized by an increased level of toxic homocysteine in the plasma. The plasma concentration of homocysteine is 5-15 µmol/L in healthy individuals, while in hyperhomocysteinemic patients, it can be as high as 500 µmol/L. While increased homocysteine levels can cause symptoms such as osteoporosis and eye lens dislocation, high homocysteine levels are most closely associated with cardiovascular complications. Recent advances have shown that increased plasma Hcy is also a fundamental cause of neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, and dementia), diabetes, Down syndrome, and megaloblastic anemia, among others. In recent years, increased plasma homocysteine has also been shown to be closely related to cancer. In this review, we discuss the relation between elevated plasma Hcy levels and cancer, and we conclude that disturbed homocysteine metabolism is associated with cancer. Future clinical perspectives are also discussed.