Ceruloplasmin and myeloperoxidase in complex affect the enzymatic properties of each other

Ceruloplasmin (CP), the multicopper oxidase of plasma, interacts with myeloperoxidase (MPO), an enzyme of leukocytes, and inhibits its peroxidase and chlorinating activity. Studies on the enzymatic properties shows that CP behaves as a competitive inhibitor impeding the binding of aromatic substrates to the active centre of MPO. The contact between CP and MPO probably entails conformational changes close to the p-phenylenediamine binding site in CP, which explains the observed activation by MPO of the substrate's oxidation. CP subjected to partial proteolysis was virtually unable to inhibit activity of MPO. The possible protein–protein interface is comprised of the area near active site of MPO and the loop linking domains 5 and 6 in CP. One of the outcomes of this study is the finding of a new link between antioxidant properties of CP and its susceptibility to proteolysis.     

Voltage-gated sodium channels

Epilepsy is a brain disorder characterized by seizures and convulsions. The basis of epilepsy is an increase in neuronal excitability that, in some cases, may be caused by functional defects in neuronal voltage gated sodium channels, Nav1.1 and Nav1.2. The effects of antiepileptic drugs (AEDs) as effective therapies for epilepsy have been characterized by extensive research. Most of the classic AEDs targeting Nav share a common mechanism of action by stabilizing the channel’s fast-inactivated state. In contrast, novel AEDs, such as lacosamide, stabilize the slow-inactivated state in neuronal Nav1.1 and Nav1.7 isoforms. This paper reviews the different mechanisms by which this stabilization occurs to determine new methods for treatment.     

Ceruloplasmin: Macromolecular Assemblies with Iron-Containing Acute Phase Proteins

Copper-containing ferroxidase ceruloplasmin (Cp) forms binary and ternary complexes with cationic proteins lactoferrin (Lf) and myeloperoxidase (Mpo) during inflammation. We present an X-ray crystal structure of a 2Cp-Mpo complex at 4.7 Å resolution. This structure allows one to identify major protein–protein interaction areas and provides an explanation for a competitive inhibition of Mpo by Cp and for the activation of p-phenylenediamine oxidation by Mpo. Small angle X-ray scattering was employed to construct low-resolution models of the Cp-Lf complex and, for the first time, of the ternary 2Cp-2Lf-Mpo complex in solution. The SAXS-based model of Cp-Lf supports the predicted 1∶1 stoichiometry of the complex and demonstrates that both lobes of Lf contact domains 1 and 6 of Cp. The 2Cp-2Lf-Mpo SAXS model reveals the absence of interaction between Mpo and Lf in the ternary complex, so Cp can serve as a mediator of protein interactions in complex architecture. Mpo protects antioxidant properties of Cp by isolating its sensitive loop from proteases. The latter is important for incorporation of Fe³⁺ into Lf, which activates ferroxidase activity of Cp and precludes oxidation of Cp substrates. Our models provide the structural basis for possible regulatory role of these complexes in preventing iron-induced oxidative damage.     

Biodeterioration of Mayan buildings at uxmal and tulum,Mexico

Uxmal and Tulum are two important Mayan sites in the Yucatan peninsula. The buildings are mainly composed of limestone and grey/black discoloration is seen on exposed walls and copious greenish biofilms on inner walls. The principal microorganisms detected on interior walls at both Uxmal and Tulum were cyanobacteria; heterotrophic bacteria and filamentous fungi were also present. A dark‐pigmented mitosporic fungus and Bacillus cereus, both isolated from Uxmal, were shown to be acidogenic in laboratory cultures. Cyanobacteria belonging to rock‐degrading genera Synechocystis and Gloeocapsa were identified at both sites. Surface analysis previously showed that calcium ions were present in the biofilms on buildings at Uxmal and Tulum, suggesting the deposition of biosolubilized stone. Apart from their potential to degrade the substrate, the coccoid cyanobacteria supply organic nutrients for bacteria and fungi, which can produce organic acids, further increasing stone degradation.     

New records of the chaetiferous leech-like annelid Paracanthobdella livanowi (Epshtein, 1966) (Annelida: Clitellata: Acanthobdellida) from Kamchatka, Russia

Acanthobdellidans are unique in their organisation and phylogenetic relationships due to having transitional characters that combine features of oligochaetous and achaetous annelids. Alongside the relatively well-studied Acanthobdella peledina Grube, 1851, there is another member of the group, Paracanthobdella livanowi (Epshtein, 1966), with five rows of chaetae and an anterior sucker. It appears that the anterior sucker is weakly developed in small juveniles but acquires a deep cavity in adults. Smaller individuals of P. livanowi can be distinguished from A. peledina, which does not possess an anterior sucker, by the varying breadth of their chaetae. The mid-body segment consists of two doubled annuli in juveniles and is quadri-annulate in large individuals. In Kamchatka freshwaters, hosts of P. livanowi mostly include Salvelinus spp. and more rarely Gasterosteus aculeatus, Oncorhynchus mykiss and O. kisutch. New information on the distribution and the biology of P. livanowi is presented.     

l-Leucine 5-hydroxylase of Nostoc punctiforme is a novel type of Fe(II)/α-ketoglutarate-dependent dioxygenase that is useful as a biocatalyst

l-Leucine 5-hydroxylase (LdoA) previously found in Nostoc punctiforme PCC 73102 is a novel type of Fe(II)/α-ketoglutarate-dependent dioxygenase. LdoA catalyzed regio- and stereoselective hydroxylation of l-leucine and l-norleucine into (2S,4S)-5-hydroxyleucine and (2S)-5-hydroxynorleucine, respectively. Moreover, LdoA catalyzed sulfoxidation of l-methionine and l-ethionine in the same manner as previously described l-isoleucine 4-hydroxylase. Therefore LdoA should be a promising biocatalyst for effective production of industrially useful amino acids.     

Physicochemical properties and antiproliferative activity of recombinant Yersinia pseudotuberculosis L-asparaginase

The physicochemical, catalytic, and antiproliferative activity of a recombinant L-asparaginase from Yersinia pseudotuberculosis (YpA) have been studied. The following results were obtained: the K _M value for L-asparagine is 17 ± 0.9 ??M, the optimal temperature is 60°C, pH is 8.0, pI is 5.4 ± 0.3, the L-glutaminase activity is no more than 5?C6% of the L-asparaginase activity, and the antiproliferative activity on the Fisher L5178y lymphadenosis cell line comprised T/C = 136% (p < 0.001) at a 15% recovery rate. The described characteristic allows one to regard YpA as an antitumor enzyme with biological features similar to the L-asparaginase of E. coli.     

Hypochlorous acid as a precursor of free radicals in living systems

Hypochlorous acid (HOCl) is produced in the human body by the family of mammalian heme peroxidases, mainly by myeloperoxidase, which is secreted by neutrophils and monocytes at sites of inflammation. This review discusses the reactions that occur between HOCl and the major classes of biologically important molecules (amino acids, proteins, nucleotides, nucleic acids, carbohydrates, lipids, and inorganic substances) to form free radicals. The generation of such free radical intermediates by HOCl and other reactive halogen species is accompanied by the development of halogenative stress, which causes a number of socially important diseases, such as cardiovascular, neurodegenerative, infectious, and other diseases usually associated with inflammatory response and characterized by the appearance of biomarkers of myeloperoxidase and halogenative stress. Investigations aimed at elucidating the mechanisms regulating the activity of enzyme systems that are responsible for the production of reactive halogen species are a crucial step in opening possibilities for control of the development of the body’s inflammatory response.     

The antitumor effect of magnetic nanodisks and DNA aptamer conjugates

Here we describe a method of forming large arrays (up to 10⁹ pieces) of free magnetic Ni-nanodisks 50 nm thick coated on both sides with layers of 5 nm thick Au. The antitumor effect of the magnetic nickel gold-coated nanodisks and DNA aptamer conjugates was evaluated in vivo and in vitro. Under the influence of rotating magnetic field, the studied nanodisks can cause the death of Ehrlich ascites carcinoma cells.     

Pathway-Based Genomics Prediction using Generalized Elastic Net

We present a novel regularization scheme called The Generalized Elastic Net (GELnet) that incorporates gene pathway information into feature selection. The proposed formulation is applicable to a wide variety of problems in which the interpretation of predictive features using known molecular interactions is desired. The method naturally steers solutions toward sets of mechanistically interlinked genes. Using experiments on synthetic data, we demonstrate that pathway-guided results maintain, and often improve, the accuracy of predictors even in cases where the full gene network is unknown. We apply the method to predict the drug response of breast cancer cell lines. GELnet is able to reveal genetic determinants of sensitivity and resistance for several compounds. In particular, for an EGFR/HER2 inhibitor, it finds a possible trans-differentiation resistance mechanism missed by the corresponding pathway agnostic approach.