Regulation of Inositol Biosynthesis: Balancing Health and Pathophysiology.

Inositol is the precursor for all inositol compounds and is essential for viability of eukaryotic cells. Numerous cellular processes and signaling functions are dependent on inositol compounds, and perturbation of their synthesis leads to a wide range of human diseases. Although considerable research has been directed at understanding the function of inositol compounds, especially phosphoinositides and inositol phosphates, a focus on regulatory and homeostatic mechanisms controlling inositol biosynthesis has been largely neglected. Consequently, little is known about how synthesis of inositol is regulated in human cells. Identifying physiological regulators of inositol synthesis and elucidating the molecular mechanisms that regulate inositol synthesis will contribute fundamental insight into cellular processes that are mediated by inositol compounds and will provide a foundation to understand numerous disease processes that result from perturbation of inositol homeostasis. In addition, elucidating the mechanisms of action of inositol-depleting drugs may suggest new strategies for the design of second-generation pharmaceuticals to treat psychiatric disorders and other illnesses.

Amorphizing MnIn2S4 Atomic Layers Create an Asymmetrical InO1S5 Polarization Plane for Photocatalytic Ammonia Synthesis and CO2 Reduction.

Building a polarization center is an effective avenue to boost charge separation and molecular activation in photocatalysis. However, a limited number of polarization centers are usually created. Here, a polarization plane based on two-dimensional (2D) atomic layers is designed to maximize the surface polarization centers. The Mn in a 2D crystal lattice is etched from the MnIn2S4 atomic layers to build a consecutive symmetry-breaking structure of isolated InO1S5 sites. More charges aggregate around O, making the isolated InO1S5 sites highly polarized. Due to the formation of the InO1S5 polarization plane, an enormous polarized electric field is formed perpendicular to the 2D atomic layers and the carrier lifetime can be prolonged from 93.2 ps in MnIn2S4 to 1130 ps in amorphous MnxIn2Sy. Meantime, the formed large charge density gradient favors coupling and activation of small molecules. Benefiting from these features, a good NH3 photosynthesis performance (515.8 µmol g-1 h-1) can be realized over amorphous MnxIn2Sy, roughly 2.5 and 48.9 times higher than those of MnIn2S4 atomic layers and bulk MnIn2S4, respectively. The apparent quantum yields reach 5.4 and 3.3% at 380 and 400 nm, respectively. Meanwhile, a greatly improved CO2 reduction activity is also achieved over MnxIn2Sy. This strategy provides an accessible pathway for designing an asymmetrical polarization plane to motivate photocatalysis optimization.

Recruitment of an Activated Gene to the Yeast Nuclear Pore Complex Requires Sumoylation.

In addition to their role in regulating transport across the nuclear envelope, increasing evidence suggests nuclear pore complexes (NPCs) function in regulating gene expression. For example, the induction of certain genes (e.g., yeast INO1) is accompanied by their movement from the nuclear interior to NPCs. As sumoylation has been linked to the regulation of chromatin spatial organization and transcriptional activity, we investigated the role of sumoylation in the expression and NPC recruitment of the INO1 gene. We observed that induction of INO1 is accompanied by both increased and decreased sumoylation of proteins associated with specific regions along the INO1 locus. Furthermore, we show that the E3 ligase Siz2/Nfi1 is required for targeting the INO1 locus to the NPC where it interacts with the SUMO isopeptidase Ulp1. Our data suggest that this interaction is required for both the association of INO1 with the NPC and for its normal expression. These results imply that sumoylation is a key regulator of INO1 targeting to the NPC, and a cycle of sumoylation and NPC-associated desumoylation events contribute to the regulation of INO1 expression.

Myo-inositol-1-phosphate synthase (Ino-1) functions as a protection mechanism in Corynebacterium glutamicum under oxidative stress.

Reactive oxygen species (ROS) generated in aerobic metabolism and oxidative stress lead to macromolecules damage, such as to proteins, lipids, and DNA, which can be eliminated by the redox buffer mycothiol (AcCys-GlcN-Ins, MSH). Myo-inositol-phosphate synthase (Ino-1) catalyzes the first committed step in the synthesis of MSH, thus playing a critical role in the growth of the organism. Although Ino-1s have been systematically studied in eukaryotes, their physiological and biochemical functions remain largely unknown in bacteria. In this study, we report that Ino-1 plays an important role in oxidative stress resistance in the gram-positive Actinobacteria Corynebacterium glutamicum. Deletion of the ino-1 gene resulted in a decrease in cell viability, an increase in ROS production, and the aggravation of protein carbonylation levels under various stress conditions. The physiological roles of Ino-1 in the resistance to oxidative stresses were corroborated by the absence of MSH in the Δino-1 mutant. In addition, we found that the homologous expression of Ino-1 in C. glutamicum yielded a functionally active protein, while when expressed in Escherichia coliBL21(DE3), it lacked measurable activity. An examination of the molecular mass (Mr) suggested that Ino-1 expressed in E. coliBL21(DE3) was not folded in a catalytically competent conformation. Together, the results unequivocally showed that Ino-1 was important for the mediation of oxidative resistance by C. glutamicum.

Overexpression of PkINO1 improves ethanol resistance of Pichia kudriavzevii N77-4 isolated from the Korean traditional fermentation starter nuruk.

The yeast Pichia kudriavzevii N77-4 was isolated from the Korean traditional fermentation starter nuruk. In this study, fermentation performance and stress resistance ability of N77-4 was analyzed. N77-4 displayed superior thermotolerance (up to 44°C) in addition to enhanced acetic acid resistance compared to Saccharomyces cerevisiae. Moreover, N77-4 produced 7.4 g/L of ethanol with an overall production yield of 0.37 g/g glucose in 20 g/L glucose medium. However, in 250 g/L glucose medium the growth of N77-4 slowed down when the concentration of ethanol reached 14 g/L or more and ethanol production yield also decreased to 0.30 g/g glucose. An ethanol sensitivity test indicated that N77-4 was sensitive to the presence of 1% ethanol, which was not the case for S. cerevisiae. Furthermore, N77-4 displayed a severe growth defect in the presence of 6% ethanol. Because inositol biosynthesis is critical for ethanol resistance, expression levels of the PkINO1 encoding a key enzyme for inositol biosynthesis was analyzed under ethanol stress conditions. We found that ethanol stress clearly repressed PkINO1 expression in a dose-dependent manner and overexpression of PkINO1 improved the growth of N77-4 by 19% in the presence of 6% ethanol. Furthermore, inositol supplementation also enhanced the growth by 13% under 6% ethanol condition. These findings indicate that preventing downregulation in PkINO1 expression caused by ethanol stress improves ethanol resistance and enhances the utility of P. kudriavzevii N77-4 in brewing and fermentation biotechnology.

Tipping the scales: Lessons from simple model systems on inositol imbalance in neurological disorders.

Inositol and inositol-containing compounds have signalling and regulatory roles in many cellular processes, suggesting that inositol imbalance may lead to wide-ranging changes in cellular functions. Indeed, changes in inositol-dependent signalling have been implicated in various diseases and cellular functions such as autophagy, and these changes have often been proposed as therapeutic targets. However, few studies have highlighted the links between inositol depletion and the downstream effects on inositol phosphates and phosphoinositides in disease states. For this research, many advances have employed simple model systems that include the social amoeba D. discoideum and the yeast S. cerevisiae, since these models enable a range of experimental approaches that are not possible in mammalian models. In this review, we discuss recent findings initiated in simple model systems and translated to higher model organisms where the effect of altered inositol, inositol phosphate and phosphoinositide levels impact on bipolar disorder, Alzheimer disease, epilepsy and autophagy.