Biochemistry (Moscow) (v.79, #13)

This review considers different methods for obtaining induced pluripotent stem (iPS) cells and their use in biochemical and biomedical research. Some viral and nonviral methods for obtaining iPS cells are described. Basic factors involved in reprogramming are considered. It is also demonstrated that the most suitable source of iPS cells are skin fibroblasts. Properties of iPS cells and embryonic stem cells are compared, and some advantages of iPS cells for biological and biomedical investigations are emphasized. The possibilities for application of iPS cells in the development of cell models of some neurodegenerative diseases, drug screening, and cell therapy are also considered.
Keywords: induced pluripotent stem cells; embryonic stem cells; reprogramming; differentiation; transcriptional factors; cell therapy; human diseases; neurodegeneration

Functions of noncoding sequences in mammalian genomes by L. I. Patrushev; T. F. Kovalenko (1442-1469).
Most of the mammalian genome consists of nucleotide sequences not coding for proteins. Exons of genes make up only 3% of the human genome, while the significance of most other sequences remains unknown. Recent genome studies with high-throughput methods demonstrate that the so-called noncoding part of the genome may perform important functions. This hypothesis is supported by three groups of experimental data: 1) approximately 10% of the sequences, most of which are located in noncoding parts of the genome, is evolutionarily conserved and thus can be of functional importance; 2) up to 99% of the mammalian genome is being transcribed forming short and long noncoding RNAs in addition to common mRNA; and 3) mutations in noncoding parts of the genome can be accompanied by progression of pathological states of the organism. In the light of these data, in the review we consider the functional role of numerous known sequences of noncoding parts of the genome including introns, DNA methylation regions, enhancers and locus control regions, insulators, S/MAR sequences, pseudogenes, and genes of noncoding RNAs, as well as transposons and simple repeats of centromeric and telomeric regions of chromosomes. The assumption is made that the intergenic noncoding sequences without definite/clear functions can be involved in spatial organization of genetic loci in interphase nuclei.
Keywords: noncoding sequences; pervasive transcription; transcription regulation; promoter; 5′-UTR, 3′-UTR; DNA methylation; CpG islands; intron; splicing; transcription enhancer; LCR; insulator; S/MAR; noncoding RNA; siRNA; miRNA; lncRNA; pseudogene; repeated sequences; MGE

Flagella of halophilic archaea: Differences in supramolecular organization by A. S. Syutkin; M. G. Pyatibratov; O. V. Fedorov (1470-1482).
Archaeal flagella are similar functionally to bacterial flagella, but structurally they are completely different. Helical archaeal flagellar filaments are formed of protein subunits called flagellins (archaellins). Notwithstanding progress in studies of archaeal flagella achieved in recent years, many problems in this area are still unsolved. In this review, we analyze the formation of these supramolecular structures by the example of flagellar filaments of halophilic archaea. Recent data on the structure of the flagellar filaments demonstrate that their supramolecular organization differs considerably in different haloarchaeal species.
Keywords: archaea; flagella; archaella; flagellin; supramolecular structure; halophilic

How membrane surface affects protein structure by V. E. Bychkova; L. V. Basova; V. A. Balobanov (1483-1514).
The immediate environment of the negatively charged membrane surface is characterized by decreased dielectric constant and pH value. These conditions can be modeled by water-alcohol mixtures at moderately low pH. Several globular proteins were investigated under these conditions, and their conformational behavior in the presence of phospholipid membranes was determined, as well as under conditions modeling the immediate environment of the membrane surface. These proteins underwent conformational transitions from the native to a molten globule-like state. Increased flexibility of the protein structure facilitated protein functioning. Our experimental data allow understanding forces that affect the structure of a protein functioning near the membrane surface (in other words, in the membrane field). Similar conformational states are widely reported in the literature. This indicates that the negatively charged membrane surface can serve as a moderately denaturing agent in the cell. We conclude that the effect of the membrane field on the protein structure must be taken into account.
Keywords: anionic phospholipid membranes; simple alcohols as a model; globular proteins; apo- and holomyoglobins; apo- and holocytochromes c ; cytochrome b 5 ; human α-lactalbumin; conformational changes; non-native protein states; membrane-protein interactions pathways; membrane field

Mechanisms of amyloid fibril formation by N. V. Dovidchenko; E. I. Leonova; O. V. Galzitskaya (1515-1527).
Amyloid and amyloid-like aggregates are elongated unbranched fibrils consisting of β-structures of separate monomers positioned perpendicular to the fibril axis and stacked strictly above each other. In their physicochemical properties, amyloid fibrils are reminiscent of synthetic polymers rather than usual proteins because they are stable to the action of denaturing agents and proteases. Their mechanical stability can be compared to a spider’s web, that in spite of its ability to stretch, is stronger than steel. It is not surprising that a large number of diseases are accompanied with amyloid fibril depositing in different organs. Pathologies provoked by depositing of incorrectly folded proteins include Alzheimer’s, Parkinson’s, and Huntington’s diseases. In addition, this group of diseases involves mucoviscidosis, some types of diabetes, and hereditary cataracts. Each type of amyloidosis is characterized by aggregation of a certain type of protein that is soluble in general, and thus leads to specific distortions of functions of the corresponding organs. Therefore, it is important to understand the process of transformation of “native” proteins to amyloid fibrils to clarify how these molecules acquire such strength and what key elements of this process determine the pathway of erroneous protein folding. This review presents our analysis of complied information on the mechanisms of formation and biochemical properties of amyloid fibrils.
Keywords: prion; stress granules; Alzheimer’s disease; oligomer particles; thioflavin T; aggregation kinetics

Acid-sensing ion channels and their modulators by D. I. Osmakov; Ya. A. Andreev; S. A. Kozlov (1528-1545).
According to a modern look acid-sensing ion channels (ASICs) are one of the most important receptors that perceive pH change in the body. ASICs represent proton-gated Na+-selective channels, which are expressed in neurons of the central and peripheral nervous system. These channels are attracting attention of researchers around the world, as they are involved in various physiological processes in the body. Drop of pH may occur in tissues in norm (e.g. the accumulation of lactic acid, the release of protons upon ATP hydrolysis) and pathology (inflammation, ischemic stroke, tissue damage and seizure). These processes are accompanied by unpleasant pain sensations, which may be short-lived or can lead to chronic inflammatory diseases. Modulators of ASIC channels activity are potential candidates for new effective analgesic and neuroprotection drugs. This review summarizes available information about structure, function, and physiological role of ASIC channels. In addition a description of all known ligands of these channels and their practical relevance is provided.
Keywords: acid-sensing ion channel; pain perception; ligand; low molecular weight modulator; peptide

Cation-chloride cotransporters: Regulation, physiological significance, and role in pathogenesis of arterial hypertension by S. N. Orlov; S. V. Koltsova; L. V. Kapilevich; N. O. Dulin; S. V. Gusakova (1546-1561).
This review summarizes the data on the functioning of carriers providing electroneutral symport of sodium, potassium, and chloride (Na+,K+,2Cl cotransport), potassium and chloride (K+,Cl cotransport), and sodium and chloride (K+,Cl cotransport) as well as molecular mechanisms of the regulation of these carriers and their physiological significance. We emphasized the involvement of chloride-coupled carriers in the regulation of cell volume and intracellular chloride concentration and novel data on the role of ubiquitous isoform of Na+,K+,2Cl cotransporter NKCC1 in regulation of vascular smooth muscle contraction and activity of GABAA receptors. Finally, we analyzed the data on activation of NKCC1 in patients with essential hypertension and its role in the long-term maintenance of elevated systemic blood pressure and myogenic response in microcirculatory beds.
Keywords: sodium; potassium; chloride; cotransport; smooth muscle; contraction; myogenic tone; sympathetic nervous system; hypertension

Over the last decade fundamentally new features have been revealed for the participation of glutathione and glutathione-dependent enzymes (glutathione transferase and glutaredoxin) in cell proliferation, apoptosis, protein folding, and cell signaling. Reduced glutathione (GSH) plays an important role in maintaining cellular redox status by participating in thiol-disulfide exchange, which regulates a number of cell functions including gene expression and the activity of individual enzymes and enzyme systems. Maintaining optimum GSH/GSSG ratio is essential to cell viability. Decrease in the ratio can serve as an indicator of damage to the cell redox status and of changes in redox-dependent gene regulation. Disturbance of intracellular GSH balance is observed in a number of pathologies including cancer. Consequences of inappropriate GSH/GSSG ratio include significant changes in the mechanism of cellular redox-dependent signaling controlled both nonenzymatically and enzymatically with the participation of isoforms of glutathione transferase and glutaredoxin. This review summarizes recent data on the role of glutathione, glutathione transferase, and glutaredoxin in the regulation of cellular redox-dependent processes.
Keywords: glutathione; glutathione transferase; glutaredoxin; redox regulation

Bacteria utilizing insoluble mineral forms of metal oxides as electron acceptors in respiratory processes are widespread in the nature. The electron transfer from a pool of reduced quinones in the cytoplasmic membrane across the periplasm to the bacterial outer membrane and then to an extracellular acceptor is a key step in bacterial dissimilatory metal reduction. Multiheme cytochromes c play a crucial role in the extracellular electron transfer. The bacterium Shewanella oneidensis MR-1 was used as a model organism to study the mechanism of extracellular electron transport. In this review, we discuss recent data on the composition, structures, and functions of multiheme cytochromes c and their functional complexes responsible for extracellular electron transport in Shewanella oneidensis.
Keywords: bacterial dissimilatory metal reduction; extracellular electron transfer; multiheme cytochrome c

Diversity of phosphorus reserves in microorganisms by T. V. Kulakovskaya; L. P. Lichko; L. P. Ryazanova (1602-1614).
Phosphorus compounds are indispensable components of the Earth’s biomass metabolized by all living organisms. Under excess of phosphorus compounds in the environment, microorganisms accumulate reserve phosphorus compounds that are used under phosphorus limitation. These compounds vary in their structure and also perform structural and regulatory functions in microbial cells. The most common phosphorus reserve in microorganism is inorganic polyphosphates, but in some archae and bacteria insoluble magnesium phosphate plays this role. Some yeasts produce phosphomannan as a phosphorus reserve. This review covers also other topics, i.e. accumulation of phosphorus reserves under nutrient limitation, phosphorus reserves in activated sludge, mycorrhiza, and the role of mineral phosphorus compounds in mammals.
Keywords: microorganism; phosphorus; inorganic polyphosphate; magnesium phosphate; phosphomannan; EBPR; limited growth; phosphorus reserve

Alternative oxidase: Distribution, induction, properties, structure, regulation, and functions by A. G. Rogov; E. I. Sukhanova; L. A. Uralskaya; D. A. Aliverdieva; R. A. Zvyagilskaya (1615-1634).
The respiratory chain in the majority of organisms with aerobic type metabolism features the concomitant existence of the phosphorylating cytochrome pathway and the cyanide- and antimycin A-insensitive oxidative route comprising a so-called alternative oxidase (AOX) as a terminal oxidase. In this review the history of AOX discovery is described. Considerable evidence is presented that AOX occurs widely in organisms at various levels of organization and is not confined to the plant kingdom. This enzyme has not been found only in Archaea, mammals, some yeasts and protists. Bioinformatics research revealed the sequences characteristic of AOX in representatives of various taxonomic groups. Based on multiple alignments of these sequences, a phylogenetic tree was constructed to infer their possible evolution. The ways of AOX activation, as well as regulatory interactions between AOX and the main respiratory chain are described. Data are summarized concerning the properties of AOX and the AOX-encoding genes whose expression is either constitutive or induced by various factors. Information is presented on the structure of AOX, its active center, and the ubiquinone-binding site. The principal functions of AOX are analyzed, including the cases of cell survival, optimization of respiratory metabolism, protection against excess of reactive oxygen species, and adaptation to variable nutrition sources and to biotic and abiotic stress factors. It is emphasized that different AOX functions complement each other in many instances and are not mutually exclusive. Examples are given to demonstrate that AOX is an important tool to overcome the adverse aftereffects of restricted activity of the main respiratory chain in cells and whole animals. This is the first comprehensive review on alternative oxidases of various organisms ranging from yeasts and protists to vascular plants.
Keywords: respiratory chain; alternative oxidase; distribution; induction; properties; biogenesis; genes; structure; regulation; functions

Human herpes simplex virus: Life cycle and development of inhibitors by M. K. Kukhanova; A. N. Korovina; S. N. Kochetkov (1635-1652).
WHO reports that 90% of human population is infected by different types of herpesviruses, which develop latency or cause oral and genital herpes, conjunctivitis, eczema herpeticum, and other diseases. Herpesvirus almost always accompanies HIV-infection and complicates AIDS treatment. Herpes simplex virus type 1 is one of the most wide spread viruses from the Herpesviridae family. HSV virion, genome structure, replication mechanisms, antiherpes drug development strategies, including design of prodrugs, and mutations causing ACV-resistance in clinical HSV isolates are discussed in this review.
Keywords: HSV; herpes simplex; life cycle; replication; drugs; mutations; resistance