Sergio Manzetti

Thiamin function, metabolism, uptake, and transport.

Vitamins are crucial components in the diet of animals and many other living organisms. One of these essential nutrients, thiamin, is known to be involved in several cell functions, including energy metabolism and the degradation of sugars and carbon skeletons. Other roles that are connected to this vitamin are neuronal communication, immune system activation, signaling and maintenance processes in cells and tissues, and cell-membrane dynamics. Because of the key functions of thiamin, uptake and transport through the body are crucial. Its uptake route is relatively complex, encompassing a variety of protein families, including the solute carrier anion transporters, the alkaline phosphatase transport system, and the human extraneuronal monoamine transporter family, some of which are multispecific proteins. There are two known structures of protein (subunits) involved in thiamin uptake in prokaryotes. Binding of thiamin to these proteins is strongly guided by electrostatic interactions. The lack of structural information about thiamin binding proteins for higher organisms remains a bottleneck for understanding the uptake process of thiamin in atomic detail. This review includes recent data on thiamin metabolism, related deficiencies and pathologies, and the latest findings on thiamin binding transporters.

Chemical properties, environmental fate, and degradation of seven classes of pollutants.

Industrialism has brought a long series of benefits for modern civilization. Concomitantly, reversible and irreversible changes have been inflicted upon the environment, affecting humans, animals, and whole ecosystems and leading to effects such as declining reproduction in modern human beings, developmental challenges on various species, and destroyed habitats and ecosystems across the globe. In this context, a vast repertoire of modern and older literature is reviewed for a series of pollutants and their status as of 2014. The compound classes covered in this review are polychlorinated biphenyls, halogenated hydrocarbons, estrogen analogues, phthalates, dioxins, perfluorinated compounds, and brominated flame retardants. These groups represent ubiquitous pollutants, of which some have circulated in the environment for more than 60 years. In this context, this review describes the chemical properties, the environmental fate, and the toxicological effects of these classes of pollutants on humans and animals, including an introductory section on the detoxification systems that are triggered in most species upon intoxication. This combined review of in vivo transformation, chemistry, toxicological properties, and structure-activity relationships of pollutants aids in the understanding of the fate, biomagnification, bioaccumulation, and transformation of these compounds, which is essential for toxicologists, environmental scientists, and environmental legislators. The review is concluded with an outlook.

Modeling of enzyme–substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10

The matrix metalloproteases (MMPs) and the ADAMs (A Disintegrin And Metalloprotease domain) are proteolytic enzyme families containing a catalytic zinc ion, that are implicated in a variety of normal and pathological processes involving tissue remodeling and cancer. Synthetic MMP inhibitors have been designed for applications in pathological situations. However, a greater understanding of substrate binding and the catalytic mechanism is required so that more effective and selective inhibitors may be developed for both experimental and clinical purposes. By modeling a natural substrate spanning P4-P4′ in complex with the catalytic domains, we aim to compare substrate-specificities between Stromelysin-1 (MMP-3), ADAM-9 and ADAM–10, with the aid of molecular dynamics simulations. Our results show that the substrate retains a favourable antiparallel beta-sheet conformation on the P-side in addition to the well-known orientation of the P′-region of the scissile bond, and that the primary substrate selectivity is dominated by the sidechains in the S1′ pocket and the S2/S3 region. ADAM-9 has a hydrophobic residue as the central determinant in the S1′ pocket, while ADAM-10 has an amphiphilic residue, which suggests a different primary specificity. The S2/S3 pocket is largely hydrophobic in all three enzymes. Inspired by our molecular dynamics calculations and supported by a large body of literature, we propose a novel, hypothetical, catalytic mechanism where the Zn-ion polarizes the oxygens from the catalytic glutamate to form a nucleophile, leading to a tetrahedral oxyanion anhydride transition state.

Wavefunction and reactivity study of benzo[a]pyrene diol epoxide and its enantiomeric forms

Abstract Benzo[a]pyrene is a known carcinogen, which derives from fossil fuel combustion, cigarette smoke, and generic biomass combustion including traffic emissions. This potent carcinogen has a well-known mechanism of action, leading to the formation of adducts with the DNA, primarily at guanosine positions. The reactivity and chemistry of this notorious compound are, however, dependent on the electronic configuration of the biologically activated metabolite, the benzo[a]pyrene diol epoxide. The activated metabolite exists mainly as four isomers, which have particular chemical reactivities toward guanosine sites on the DNA. These isomers exert also a different carcinogenicity compared to one another, which is a feature that is conventionally attributed to their geometry. However, the reactivity and properties of the isomers are not fully defined, and a determination of these properties by wavefunction behavior is required. This study reports the electronic properties of the benzo[a]pyrene diol epoxide enantiomers, along with a detailed analysis of the energy landscape, geometry, and electronic configuration of the epoxide ring. The results show that the epoxide ring, the core of the reactivity, bears different properties at the level of wavefunction for each isomer. Each of the isomers has a distinct profile on the epoxide ring, in terms of hydrogen bonds and in terms of the non-covalent interaction between the diol groups and the epoxide. These profiles generate differential reactivities of epoxide group, which can be attributed to its local bond lengths, the electron localization function, and polarized bonds. Most interestingly, the quantum chemical calculations showed also that the epoxide ring is inclined more perpendicularly toward the angular ring plane for the more carcinogenic isomers, a feature which suggests a potential geometrical relationship between the inclination of the epoxide group and its interaction with the guanosine group upon adduct formation. Our results introduce novel and crucial information, which assist in understanding the mechanism of toxic potential of this known molecule, and display the strength and level of detail of applying quantum chemical methods to reveal the reactivity, energy properties, and electronic properties of a mutagen.

Biochemical and physiological effects from exhaust emissions. A review of the relevant literature

Exhaust emissions are to date ranked among the most frequent causes of premature deaths worldwide. The combustion of fuels such as diesel, gasoline, and bio-blends provokes a series of pathophysiological responses in exposed subjects, which are associated with biochemical and immunological triggering. It is critical to understand these mechanisms, which are directly related to the levels of aerosol, liquid and gaseous components in fuel exhaust (e.g. nanoparticles, particulate matter, volatile compounds), so to cast attention on their toxicity and gradually minimize their use. This review reports findings in the recent literature concerning the biochemical and cellular pathways triggered during intoxication by exhaust emissions, and links these findings to pathophysiological responses such as inflammation and vasoconstriction. This study provides critical in vitro and in vivo data for the reduction of emissions in urban centers, with an emphasis on the prevention of exposure of groups such as children, the elderly, and other affected groups, and shows how the exposure to exhaust emissions induces mechanisms of pathogenesis related to cardiopulmonary pathologies and long-term diseases such as asthma, allergies, and cancer. This review summarizes the cellular and physiological responses of humans to exhaust emissions in a comprehensive fashion, and is important for legislative developments in fuel politics.

Alternant conjugated oligomers with tunable and narrow HOMO-LUMO gaps as sustainable nanowires†

Novel nanowire technologies encompass the use of metals and crystals with a high electric transport potential and superior charge-collection properties. However, nanowires built on metals such as cadmium, gallium-arsenide and similar alloys present serious environmental and health risks. The use of carbon is a far more environmentally friendly solution than heavy-metal based nanowires, and if arranged in a particular manner, it can provide excellent conductive properties that are applicable in nanowire technologies. Herein, we report an investigation into the particular carbon-based 4n/4n + 2 alternant resonance, which has the potential of becoming a key component for the design of novel and conductive nanomaterials, suitable for application in optoelectronics, nanoelectronics and microelectronics. A set of nine 4n/4n + 2 oligomers comprising in the range of 15–20 cyclic units (∼5 nm) were analyzed quantum mechanically. The results show that the number and type (4n or 4n + 2) of carbon-rings (cyclobutadiene, benzene and naphthalene) that constitute the oligomers, govern the HOMO–LUMO gaps with a statistical relevance of R2 = 0.919. Interestingly, we found that the sequence of the units played a central role in shaping the conductance of the 4n/4n + 2 oligomers, and that the sequencing of units in conductive carbon-based oligomers can be a potential future approach in tailoring the gaps of carbon-based conductive components for application in molecular electronics devices. An interesting relationship was also found between the symmetry and the homo- and heteromorphism of the LUMO elements with the HOMO–LUMO gaps, suggesting a pattern of continuity and wavefunction-symmetry across the LUMO orbitals of the 4n/4n + 2 systems to be a key-element determining the narrow gaps in the conductive carbon oligomers. In addition, population and electrostatic potential analysis showed that π-electron distribution over the oligomers is quite non-uniform. The electron delocalization behavior over the 4n and 4n + 2 rings was characterized by electron localization function, six-center bond order, and a striking linear relationship was found between the π-delocalization index of the C–C bonds and the HOMO–LUMO gaps (R2 = 0.988). The results presented herein introduce valuable approaches and data for the engineering of conductive materials to be applied in the field of nanoelectronics and microelectronics, and to relieve the development of nanowires from its dependence on expensive and rare metals.

Impact of sludge deposition on biodiversity

Sludge deposition in the environment is carried out in several countries. It encompasses the dispersion of treated or untreated sludge in forests, marsh lands, open waters as well as estuarine systems resulting in the gradual accumulation of toxins and persistent organic compounds in the environment. Studies on the life cycle of compounds from sludge deposition and the consequences of deposition are few. Most reports focus rather on treatment-methods and approaches, legislative aspects as well as analytical evaluations of the chemical profiles of sludge. This paper reviews recent as well as some older studies on sludge deposition in forests and other ecosystems. From the literature covered it can be concluded that sludge deposition induces two detrimental effects on the environment: (1) raising of the levels of persistent toxins in soil, vegetation and wild life and (2) slow and long-termed biodiversity-reduction through the fertilizing nutrient pollution operating on the vegetation. Since recent studies show that eutrophication of the environment is a major threat to global biodiversity supplying additional nutrients through sludge-based fertilization seems imprudent. Toxins that accumulate in the vegetation are transferred to feeding herbivores and their predators, resulting in a reduced long-term survival chance of exposed species. We briefly review current legislation for sludge deposition and suggest alternative routes to handling this difficult class of waste.

Molecular simulation of carbon nanotubes as sorptive materials: sorption effects towards retene, perylene and cholesterol to 100 degrees Celsius and above

Abstract New water purification technologies are being developed as the world’s water sources are increasingly being polluted and experience a dramatic consumption with the increasing world population. In this context, the emerging era of nanotechnology has introduced a series of innovations and materials with promising potential as sorptive materials for water decontamination. The application of nanomaterials for the purification of ground/surface water introduces nevertheless a series of important challenges, such as health and safety, cost, process-efficiency and chemical sorption properties. In this study, we consider the latter class and present a study of the sorptive properties of carbon nanotubes (CNTs) as potential water decontaminating materials. Molecular dynamics simulations are used and three molecular candidates of the water contaminants, cholesterol, perylene and retene were selected for interaction study with CNTs at different diameters. The results show that CNTs form densely packed clusters with retene, perylene and cholesterol, binding each strongly to their tubular surfaces, as well as in their hollow tubular spaces. Cholesterol and perylene bind more strongly than retene, accounting for the calculated binding energies in vacuo, however the planar geometries of polycyclics may in general favour binding to CNTs over semi-polar molecules and can require further studies. Our studies show furthermore that the CNTs retain the adsorbed molecules also at 100 degrees Celsius, and require therefore additional steps of separation for eventual recycling and reusing the nanomaterials for additional decontamination. This study is important in providing data for initiating studies and developments of water purification approaches based on using CNTs.

The accurate wavefunction of the active space of the rhenium dimer resolved using the ab initio Brueckner coupled-cluster method

Abstract Rhenium is a unique metal in the 5d-series of transition metals having the highest boiling point in the periodic table. It is also known to exist in poly-coordinated states with other rhenium atoms. Based on the existence of strikingly unusual states of elements in astrophysical bodies of nebulae, interstellar debris, exoplanets and other part of the universe, a set of ab initio calculations of the rhenium dimer has been conducted to provide detailed description of its molecular properties that are applicable to the astrochemical research. Ab initio calculations and NBO analysis revealed that rhenium forms quintuple bond in its diatomic state and that it displays preferred state of triplet configuration with high-lying electrons. Calculations also revealed that the two states of rhenium dimer vary in their bonding nature. The singlet spin space is composed of five single bonds, while the triplet state comprises four bonds and two additional lone pairs. Interestingly, while these two states vary in subdivision of electrons at the highest d-level, they share the same frequencies while having different zero-point energies. The calculations reveal intrinsic synergy between the atoms composed of natural bond orbitals, the bonding pattern and the thermochemical properties of Re2, all features being of significant importance to physical and chemical sciences.

Quantum chemical calculations of the active site of the solute-binding protein PsaA from Streptococcus pneumoniae explain electronic selectivity of metal binding

Streptococcus pneumoniae is the world’s foremost bacterial pathogen. Virulence in the host is dependent on manganese acquisition via the PsaBCA permease. Crystallographic studies of its solute-binding protein component, PsaA, have previously shown that the nature of the metal ion bound by the protein modulates the conformational changes associated with its function. Notably, manganese and cadmium ions can be bound in a reversible manner, facilitating transport via PsaA, whereas zinc binds in an essentially irreversible manner preventing release to the permease. All three ionic species show a similar coordination in the PsaA crystal structures. A set of quantum chemical calculations have here been performed in order to differentiate between the ions in terms of electronic configuration. Based on natural bond orbital (NBO) analysis, the results show that manganese and cadmium bind more strongly to the protein than zinc, in that their coordination to the enzyme involves more shared electrons. Manganese has the highest indirect indicator of bonding strength and provides an unpaired electron that induces the formation of three bonds to the enzyme active site. Cadmium binds more strongly than zinc, though more weakly than manganese, and forms only ionic bonds in its ligand framework. These calculations indicate a concrete differentiation of the bonding states of the three active sites; however, bonding energies which can give more accurate estimates have not been computed presently. The calculations further show that the ionic radii are critical for the bonding state between the enzyme and the metal and that the conformational motions responsible for the PsaA’s functional cycle may depend on the ion binding strongly to the enzyme. Our results add important information of the PsaA-metal ion binding architecture to the existing crystallography data and aid in understanding the function of this protein.