Molybdenum-Copper Antagonism In Metalloenzymes And Anti-Copper Therapy.

The connection between 3d (Cu) and 4d (Mo) via the "Mo-S-Cu" unit is called Mo-Cu antagonism. Biology offers case studies of such interactions in metalloproteins such as Mo/Cu-CO Dehydrogenases (Mo/Cu-CODH), and Mo/Cu Orange Protein (Mo/Cu-ORP). The CODH significantly maintains the CO level in the atmosphere below the toxic level by converting it to non-toxic CO2 for respiring organisms. Several models were synthesized to understand the structure-function relationship of these native enzymes. However, this interaction was first observed in ruminants, and they convert molybdate (MoO4 2- ) into tetrathiomolybdate (MoS4 2- ; TTM), reacting with cellular Cu to yield biological unavailable Mo/S/Cu cluster, then developing Cu-deficiency diseases. These findings inspire the use of TTM as a Cu-sequester drug, especially for treating Cu-dependent human diseases such as Wilson diseases (WD) and cancer. It is well known that a balanced Cu homeostasis is essential for a wide range of biological processes, but negative consequence leads to cell toxicity. Therefore, this review aims to connect the Mo-Cu antagonism in metalloproteins and anti-copper therapy.

Selenium-More than Just a Fortuitous Sulfur Substitute in Redox Biology.

Living organisms use selenium mainly in the form of selenocysteine in the active site of oxidoreductases. Here, selenium's unique chemistry is believed to modulate the reaction mechanism and enhance the catalytic efficiency of specific enzymes in ways not achievable with a sulfur-containing cysteine. However, despite the fact that selenium/sulfur have different physicochemical properties, several selenoproteins have fully functional cysteine-containing homologues and some organisms do not use selenocysteine at all. In this review, selected selenocysteine-containing proteins will be discussed to showcase both situations: (i) selenium as an obligatory element for the protein's physiological function, and (ii) selenium presenting no clear advantage over sulfur (functional proteins with either selenium or sulfur). Selenium's physiological roles in antioxidant defence (to maintain cellular redox status/hinder oxidative stress), hormone metabolism, DNA synthesis, and repair (maintain genetic stability) will be also highlighted, as well as selenium's role in human health. Formate dehydrogenases, hydrogenases, glutathione peroxidases, thioredoxin reductases, and iodothyronine deiodinases will be herein featured.

Human erythrocytes exposure to juglone leads to an increase of superoxide anion production associated with cytochrome b5 reductase uncoupling.

Cytochrome b5 reductase is an enzyme with the ability to generate superoxide anion at the expenses of NADH consumption. Although this activity can be stimulated by cytochrome c and could participate in the bioenergetic failure accounting in apoptosis, very little is known about other molecules that may uncouple the function of the cytochrome b5 reductase. Naphthoquinones are redox active molecules with the ability to interact with electron transfer chains. In this work, we made an inhibitor screening against recombinant human cytochrome b5 reductase based on naphthoquinone properties. We found that 5-hydroxy-1,4-naphthoquinone (known as juglone), a natural naphthoquinone extracted from walnut trees and used historically in traditional medicine with ambiguous health and toxic outcomes, had the ability to uncouple the electron transfer from the reductase to cytochrome b5 and ferricyanide. Upon complex formation with cytochrome b5 reductase, juglone is able to act as an electron acceptor leading to a NADH consumption stimulation and an increase of superoxide anion production by the reductase. Our results suggest that cytochrome b5 reductase could contribute to the measured energetic failure in the erythrocyte apoptosis induced by juglone, that is concomitant with the reactive oxygen species produced by cytochrome b5 reductase.

Effects of molybdate and tungstate on expression levels and biochemical characteristics of formate dehydrogenases produced by Desulfovibrio alaskensis NCIMB 13491.

Formate dehydrogenases (FDHs) are enzymes that catalyze the formate oxidation to carbon dioxide and that contain either Mo or W in a mononuclear form in the active site. In the present work, the influence of Mo and W salts on the production of FDH by Desulfovibrio alaskensis NCIMB 13491 was studied. Two different FDHs, one containing W (W-FDH) and a second incorporating either Mo or W (Mo/W-FDH), were purified. Both enzymes were isolated from cells grown in a medium supplemented with 1 µM molybdate, whereas only the W-FDH was purified from cells cultured in medium supplemented with 10 µM tungstate. We demonstrated that the genes encoding the Mo/W-FDH are strongly downregulated by W and slightly upregulated by Mo. Metal effects on the expression level of the genes encoding the W-FDH were less significant. Furthermore, the expression levels of the genes encoding proteins involved in molybdate and tungstate transport are downregulated under the experimental conditions evaluated in this work. The molecular and biochemical properties of these enzymes and the selective incorporation of either Mo or W are discussed.

Relations between mercury, methyl-mercury and selenium in tissues of Octopus vulgaris from the Portuguese coast.

Mercury, methyl-mercury (MeHg) and selenium were determined in digestive gland and mantle of Octopus vulgaris, from three areas of the Portuguese coast. To our knowledge these are the first data on MeHg in cephalopods. Concentrations were higher in the digestive gland and percentage of MeHg in mantle. Enhanced Hg and MeHg levels were obtained in digestive gland of specimens from Olhão (3.1-7.4 and 2.0-5.0 microg g(-1), respectively). Differences between areas may be partially related to Hg availability. Relationships between concentrations in mantle and digestive gland pointed to proportional increases of Hg and MeHg in tissues of specimens from Matosinhos and Cascais, but relatively constant values in mantle of individuals from Olhão (higher contamination). Se:Hg molar ratio in digestive gland was 32 and 30 in octopus from Matosinhos and Cascais, respectively, and 5.4 from Olhão. The proximity to the unit suggests demethylation as response to elevated MeHg levels in digestive gland.

Activation of N2O reduction by the fully reduced micro4-sulfide bridged tetranuclear Cu Z cluster in nitrous oxide reductase.

The tetranuclear CuZ cluster catalyzes the two-electron reduction of N2O to N2 and H2O in the enzyme nitrous oxide reductase. This study shows that the fully reduced 4CuI form of the cluster correlates with the catalytic activity of the enzyme. This is the first demonstration that the S = 1/2 form of CuZ can be further reduced. Complementary DFT calculations support the experimental findings and demonstrate that N2O binding in a bent mu-1,3-bridging mode to the 4CuI form is most efficient due to strong back-bonding from two reduced copper atoms. This back-donation activates N2O for electrophilic attack by a proton.