VDACs: An Outlook on Biochemical Regulation and Function in Animal and Plant Systems

The voltage-dependent anion channels (VDACs) are the most abundant proteins present on the outer mitochondrial membrane. They serve a myriad of functions ranging from energy and metabolite exchange to highly debatable roles in apoptosis. Their role in molecular transport puts them on the center stage as communicators between cytoplasmic and mitochondrial signaling events. Beyond their general role as interchangeable pores, members of this family may exhibit specific functions. Even after nearly five decades of their discovery, their role in plant systems is still a new and rapidly emerging field. The information on biochemical regulation of VDACs is limited. Various interacting proteins and post-translational modifications (PTMs) modulate VDAC functions, amongst these, phosphorylation is quite noticeable. In this review, we have tried to give a glimpse of the recent advancements in the biochemical/interactional regulation of plant VDACs. We also cover a critical analysis on the importance of PTMs in the functional regulation of VDACs. Besides, the review also encompasses numerous studies which can identify VDACs as a connecting link between Ca2+ and reactive oxygen species signaling in special reference to the plant systems.

The effective graph reveals redundancy, canalization, and control pathways in biochemical regulation and signaling

The ability to map causal interactions underlying genetic control and cellular signaling has led to increasingly accurate models of the complex biochemical networks that regulate cellular function. These network models provide deep insights into the organization, dynamics, and function of biochemical systems: for example, by revealing genetic control pathways involved in disease. However, the traditional representation of biochemical networks as binary interaction graphs fails to accurately represent an important dynamical feature of these multivariate systems: some pathways propagate control signals much more effectively than do others. Such heterogeneity of interactions reflects canalization—the system is robust to dynamical interventions in redundant pathways but responsive to interventions in effective pathways. Here, we introduce the effective graph, a weighted graph that captures the nonlinear logical redundancy present in biochemical network regulation, signaling, and control. Using 78 experimentally validated models derived from systems biology, we demonstrate that 1) redundant pathways are prevalent in biological models of biochemical regulation, 2) the effective graph provides a probabilistic but precise characterization of multivariate dynamics in a causal graph form, and 3) the effective graph provides an accurate explanation of how dynamical perturbation and control signals, such as those induced by cancer drug therapies, propagate in biochemical pathways. Overall, our results indicate that the effective graph provides an enriched description of the structure and dynamics of networked multivariate causal interactions. We demonstrate that it improves explainability, prediction, and control of complex dynamical systems in general and biochemical regulation in particular.

Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling

Methylglyoxal (MG) is a reactive glycation metabolite and potentially induces dicarbonyl stress. The production of MG in cells is increased along with an increase in carbohydrate metabolism. The efficiency of the glyoxalase system, consisting of glyoxalase 1 (GlxI) and glyoxalase 2 (GlxII), is crucial for turning the accumulated MG into nontoxic metabolites. Converting MG-glutathione hemithioacetal to S-d-lactoylglutathione by GlxI is the rate-determining step of the enzyme system. In this study, we found lactic acid accumulated during insulin stimulation in cells, however, cellular MG and S-d-lactoylglutathione also increased due to the massive flux of glycolytic intermediates. The insulin-induced accumulation of MG and S-d-lactoylglutathione were efficiently removed by the treatment of metformin, possibly via affecting the glyoxalase system. With the application of isotopic 13C3-MG, the flux of MG from extracellular and intracellular origins was dissected. While insulin induced an influx of extracellular MG, metformin inhibited the trafficking of MG across the plasma membrane. Therefore, metformin could maintain the extracellular MG by means of reducing the secretion of MG rather than facilitating the scavenging. In addition, metformin may affect the glyoxalase system by controlling the cellular redox state through replenishing reduced glutathione. Overall, alternative biochemical regulation of the glyoxalase system mediated by insulin signaling or molecules like biguanides may control cellular MG homeostasis.

Unconventional biochemical regulation of the oxidative pentose phosphate pathway in the model cyanobacterium Synechocystis sp. PCC 6803

Metabolite production from carbon dioxide using sugar catabolism in cyanobacteria has been in the spotlight recently. Synechocystis sp. PCC 6803 (Synechocystis 6803) is the most studied cyanobacterium for metabolite production. Previous in vivo analyses revealed that the oxidative pentose phosphate (OPP) pathway is at the core of sugar catabolism in Synechocystis 6803. However, the biochemical regulation of the OPP pathway enzymes in Synechocystis 6803 remains unknown. Therefore, we characterized a key enzyme of the OPP pathway, glucose-6-phosphate dehydrogenase (G6PDH), and related enzymes from Synechocystis 6803. Synechocystis 6803 G6PDH was inhibited by citrate in the oxidative tricarboxylic acid (TCA) cycle. Citrate has not been reported as an inhibitor of G6PDH before. Similarly, 6-phosphogluconate dehydrogenase, the other enzyme from Synechocystis 6803 that catalyzes the NADPH-generating reaction in the OPP pathway, was inhibited by citrate. To understand the physiological significance of this inhibition, we characterized succinic semialdehyde dehydrogenase (SSADH) from Synechocystis 6803 (SySSADH), which catalyzes one of the NAD(P)H generating reactions in the oxidative TCA cycle. Similar to isocitrate dehydrogenase from Synechocystis 6803, SySSADH specifically catalyzed the NADPH-generating reaction and was not inhibited by citrate. The activity of SySSADH was lower than that of other bacterial SSADHs. Previous and this studies revealed that unlike the OPP pathway, the oxidative TCA cycle is a pathway with low efficiency in NADPH generation in Synechocystis 6803. It has, thus, been suggested that to avoid NADPH overproduction, the OPP pathway dehydrogenase activity is repressed when the flow of the oxidative TCA cycle increases in Synechocystis 6803.

Significance and Transformation of 3-Alkyl-2-Methoxypyrazines Through Grapes to Wine: Olfactory Properties, Metabolism, Biochemical Regulation, and the HP–MP Cycle

3-Alkyl-2-methoxypyrazines (MPs) contribute to the herbaceous flavor characteristics of wine and are generally considered associated with poor-quality wine. To control the MPs in grapes and wine, an accurate understanding of MP metabolism is needed. This review covers factors affecting people in the perception of MPs. Also, the history of O-methyltransferases is revisited, and the present review discusses the MP biosynthesis, degradation, and biochemical regulation. We propose the existence of a cycle between MPs and 3-alkyl-2-hydropyrazines (HPs), which proceeds via O-(de)methylation steps. This cycle governs the MP contents of wines, which make the cycle the key participant in MP regulation by genes, environmental stimuli, and microbes. In conclusion, a comprehensive metabolic pathway on which the HP–MP cycle is centered is proposed after gaining insight into their metabolism and regulation. Some directions for future studies on MPs are also proposed in this paper.