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

Abstract

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-β 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 H 2 O 2 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 human milk component myo -inositol promotes neuronal connectivity

“…Beneficial effects of myo -inositol in depression and anxiety phenotypes have been reported ( 42 , 43 ). On the contrary, myo -inositol has been described to be accumulated in the brain of people with Down’s syndrome and patients diagnosed with Alzheimer’s disease including adults with Down’s syndrome, and may contribute to pathology ( 44 – 47 ). Studies to guide dietary recommendations to balance myo -inositol across life stages with consideration of disease conditions are therefore warranted.…”

TMEM2 is a bona fide hyaluronidase possessing intrinsic catalytic activity

“…The identity of the inhibitory substance(s) and its origin, whether it is a component(s) of culture media or a cell-derived factor, is currently unknown. Standard components of cell culture media, such as vitamins and sodium pyruvate, have been shown to inhibit the activity of various enzymes ( 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ). Inorganic anions in culture media, serum added to media, and lactate produced by cells could all reduce the effective concentration of calcium ( 35 ), a necessary factor for TMEM2 activity ( 11 ).…”

Exogenously Applied Cyclitols and Biosynthesized Silver Nanoparticles Affect the Soluble Carbohydrate Profiles of Wheat (Triticum aestivum L.) Seedling

“…Recently, MIN has been shown to be involved in the regulation of ROS biosynthesis and antioxidant enzyme activity in plants [47], animals [48] and humans [49]. In addition, it was shown that methyl derivatives of inositol, such as D-pinitol (3-O-methyl-D-chiroinositol (PIN)) and L-quebrachitol (2-O-methyl-L-inositol), also have free radical scavenging properties [50,51].…”