Glucose‑6‑phosphate dehydrogenase (G6PD) is a cytoplasmic enzyme found in human erythrocytes that provides reduced NADPH for cell metabolism. Glutathione produced by the G6PD pathway can reduce the degree of harm caused by reactive oxygen species such as oxygen‑containing free radicals, peroxides and lipid peroxides. Investigation of G6PD has long focused on hemolysis, jaundice and other diseases caused by defects in its function. However, increased mRNA expression levels of G6PD are predictive of adverse clinical outcomes in cancer patients, including increased drug resistance, migration or proliferation of tumor cells. Mutations in the G6PD gene affect protein expression and activity, and alters the balance of redox states, leading to disease. However, the association between G6PD and tumors is incompletely understood. The aim of the present review was to summarize the current body of knowledge on the role of G6PD in tumor progression and the possible regulatory mechanisms involved. It is hypothesized that G6PD will prove to be of value as a target of cancer treatment in the near future.

Thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH are key members of the Trx system that is involved in redox regulation and antioxidant defense. In recent years, several researchers have provided information about the roles of the Trx system in cancer development and progression. These reports indicated that many tumor cells express high levels of Trx and TrxR, which can be responsible for drug resistance in tumorigenesis. Inhibition of the Trx system may thus contribute to cancer therapy and improving chemotherapeutic agents. There are now a number of effective natural and synthetic inhibitors with chemotherapy applications possessing antitumor activity ranging from oxidative stress induction to apoptosis. In this article, we first described the features and functions of the Trx system and then reviewed briefly its correlations with cancer. Finally, we summarized the present knowledge about the Trx/TrxR inhibitors as anticancer drugs.

NAD(P)H-dependent oxidoreductases catalyze the reduction or oxidation of a substrate coupled to the oxidation or reduction, respectively, of a nicotinamide adenine dinucleotide cofactor NAD(P)H or NAD(P)+. NAD(P)H-dependent oxidoreductases catalyze a large variety of reactions and play a pivotal role in many central metabolic pathways. Due to the high activity, regiospecificity and stereospecificity with which they catalyze redox reactions, they have been used as key components in a wide range of applications, including substrate utilization, the synthesis of chemicals, biodegradation and detoxification. There is great interest in tailoring NAD(P)H-dependent oxidoreductases to make them more suitable for particular applications. Here, we review the main properties and classes of NAD(P)H-dependent oxidoreductases, the types of reactions they catalyze, some of the main protein engineering techniques used to modify their properties and some interesting examples of their modification and application.

Pyridine nucleotides are abundant soluble coenzymes and they undergo reversible oxidation and reduction in several biological electron-transfer reactions. They are comprised of two mononucleotides, adenosine monophosphate and nicotinamide mononucleotide, and are present as oxidized and reduced nicotinamide adenine dinucleotides in their unphosphorylated (NAD(+) and NADH) and phosphorylated (NADP(+) and NADPH) forms. In the past, pyridine nucleotides were considered to be primarily electron-shuttling agents involved in supporting the activity of enzymes that catalyze oxidation-reduction reactions. However, it has recently been demonstrated that pyridine nucleotides and the balance between the oxidized and reduced forms play a wide variety of pivotal roles in cellular functions as important interfaces, beyond their coenzymatic activity. These include maintenance of redox status, cell survival and death, ion channel regulation, and cell signaling under normal and pathological conditions. Furthermore, targeting pyridine nucleotides could potentially provide therapeutically useful avenues for treating cardiovascular diseases. This review series will highlight the functional significance of pyridine nucleotides and underscore their physiological role in cardiovascular function and their clinical relevance to cardiovascular medicine.

Proton-translocating transhydrogenase is found in the inner membranes of animal mitochondria, and in the cytoplasmic membranes of many bacteria. It catalyses hydride transfer from NADH to NADP(+) coupled to inward proton translocation. Evidence is reviewed suggesting the enzyme operates by a \"binding-change\" mechanism. Experiments with Escherichia coli transhydrogenase indicate the enzyme is driven between \"open\" and \"occluded\" states by protonation and deprotonation reactions associated with proton translocation. In the open states NADP(+)/NADPH can rapidly associate with, or dissociate from, the enzyme, and hydride transfer is prevented. In the occluded states bound NADP(+)/NADPH cannot dissociate, and hydride transfer is allowed. Crystal structures of a complex of the nucleotide-binding components of Rhodospirillum rubrum transhydrogenase show how hydride transfer is enabled and disabled at appropriate steps in catalysis, and how release of NADP(+)/NADPH is restricted in the occluded state. Thermodynamic and kinetic studies indicate that the equilibrium constant for hydride transfer on the enzyme is elevated as a consequence of the tight binding of NADPH relative to NADP(+). The protonation site in the translocation pathway must face the outside if NADP(+) is bound, the inside if NADPH is bound. Chemical shift changes detected by NMR may show where alterations in protein conformation resulting from NADP(+) reduction are initiated. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).

Oxidant stress plays an important role in the pathogenesis of atherosclerosis. In the late 1980s, biological studies demonstrated that oxygen-free radicals oxidize low-density lipoprotein-cholesterol, resulting in the creation of foam cells and inciting the cascade of biological events that ultimately result in the formation of atherosclerosis. In vitro studies showed the ability of antioxidant vitamins to scavenge free radicals and block the oxidation of low-density lipoprotein. This data was supported in vivo by early observational studies suggesting the benefit of antioxidants, particularly vitamin E, in the prevention of coronary artery disease. On the basis of these studies, the use of antioxidant supplements by the general population increased substantially and became a multibillion dollar industry. Despite strong biological evidence and promising observational data, more rigorous scientific evaluation did not support a causational relationship between vitamin supplements and lowering coronary artery disease risk. Several prospective, double-blind, placebo-controlled trials showed no benefit and possibly harmful effects. Therapies such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and statins, which are known to have benefit in preventing and treating atherosclerosis by reducing blood pressure and cholesterol, also have a \"pleiotropic\" effect in reducing the formation of reactive oxygen species (ROS). Advances in molecular biology and the study of ROS led to a better understanding of the mechanisms that govern their production and role in atherogenesis. This progress identified unforeseen pathways by which these drugs favorably alter the balance in ROS production, and have raised possibilities for future targeted therapies in the prevention of atherosclerosis.

Paraquat, a cationic herbicide, produces degenerative lesions in the lung and in the nervous system after systemic administration to man and animals. Many cases of acute poisoning and death have been reported over the past few decades. Although a definitive mechanism of toxicity of paraquat has not been delineated, a cyclic single electron reduction/oxidation is a critical mechanistic event. The redox cycling of paraquat has two potentially important consequences relevant to the development of toxicity: the generation of the superoxide anion, which can lead to the formation of more toxic reactive oxygen species which are highly reactive to cellular macromolecules; and the oxidation of reducing equivalents (e.g., NADPH, reduced glutathione), which results in the disruption of important NADPH-requiring biochemical processes necessary for normal cell function. Nitric oxide is an important signaling molecule that reacts with superoxide derived from the paraquat redox cycle, to form the potent oxidant peroxynitrite, which causes serious cell damage. Although nitric oxide has been involved in the mechanism of paraquat-mediated toxicity, the role of nitric oxide has been controversial as both protective and harmful effects have been described. The present review summarizes recent findings in the field and describes new knowledge on the role of nitric oxide in the paraquat-mediated toxicity.

Worldwide, over 1 million cases of colorectal cancer (CRC) were reported in 2002, with a 50% mortality rate, making CRC the second most common cancer in adults. Certain racial/ethnic populations continue to experience a disproportionate burden of CRC. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been associated with a lower risk of CRC. The authors performed both a meta-analysis (29 studies; 11,936 cases, 18,714 controls) and a pooled analysis (14 studies; 5,068 cases, 7,876 controls) of the C677T MTHFR polymorphism and CRC, with stratification by racial/ethnic population and behavioral risk factors. There were few studies on different racial/ethnic populations. The overall meta-analysis odds ratio for CRC for persons with the TT genotype was 0.83 (95% confidence interval (CI): 0.77, 0.90). An inverse association was observed in whites (odds ratio = 0.83, 95% CI: 0.74, 0.94) and Asians (odds ratio = 0.80, 95% CI: 0.67, 0.96) but not in Latinos or blacks. Similar results were observed for Asians, Latinos, and blacks in the pooled analysis. The inverse association between the MTHFR 677TT polymorphism and CRC was not significantly modified by smoking status or body mass index; however, it was present in regular alcohol users only. The MTHFR 677TT polymorphism seems to be associated with a reduced risk of CRC, but this may not hold true for all populations.

Malate dehydrogenases (MDHs) are specific class of ubiquitous and multimeric oxidative decarboxylases with well conserved amino acid sequences in structurally important regions and with similar overall structural topology. They mostly use malate or oxaloacetate as substrates to generate pyruvate and utilize preferentially NADP or NAD as cofactor. Among species and even within an organism they differ in their subcellular localization and specificity for the cofactor. Comparison across microbial, plant and animal kingdoms show that MDHs were able to adopt tissue-, species- or environmental-specific functions while still keeping main structural features. Although basic principles of MDH regulation are similar to other enzymes and include oligomerization, cofactor binding, divalent cation availability, some of MDH enzymes are regulated also at different levels involving control of hysteresis, protein-protein interaction and gene expression. In this review we concentrate on those aspects of MDH function and regulation in animals that are specifically associated with cell differentiation and proliferation, ontogenic development, hormonal control, and partly with diseases. Accenting these aspects of MDHs provides emerging and new views on their regulatory function in complex eukaryotic metazoan organisms that goes beyond their classical role in basic metabolism.

The recent discovery of two defects (ribose-5-phosphate isomerase deficiency and transaldolase deficiency) in the reversible part of the pentose phosphate pathway (PPP) has stimulated interest in this pathway. In this review we describe the functions of the PPP, its relation to other pathways of carbohydrate metabolism and an overview of the metabolic defects in the reversible part of the PPP.