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PubMed2002

Quality control of biotechnology-derived vaccines: technical and regulatory considerations.

Vaccines for human use have been produced for decades using classical manufacturing methods including culture of viruses and bacteria followed by various concentration-, inactivation-, detoxification-, conjugation production processes. Availability of techniques for molecular biology and for the complete chemical synthesis of genes provides prospects of genetic engineering of microorganisms so as to generate novel biotechnological/biological-derived vaccines. The potential large-scale availability of biotechnology-derived vaccines makes feasible their evaluation in the prevention and/or treatment of various infectious, chronic, degenerative and cancer human diseases. There are potential safety concerns that arise from the novel manufacturing processes and from the complex structural and biological characteristics of the products. These products have distinguishing characteristics to which consideration should be given in a well-defined quality control testing programme. The evaluation of their quality, safety, efficacy and stability necessitate complex analytical methods and appropriate physicochemical, biochemical and immunochemical methods for the analysis of the molecular entity. A flexible approach to the control of these novel products is being developed by regulatory authorities so that recommendations can be modified in the light of experience of research and development in vaccinology, production and use of biotechnology products and with the further development of new technologies.

Biotechnology↗
PubMed2001

Protein design based on folding models.

The basic rules governing the folding of small, single-domain proteins are being discovered. New algorithms that can predict the major features of the folding process give the opportunity to design and optimise protein folding in a rational way. Recent experimental works suggest that sequence-specific features should be integrated in folding models to improve their performance.

Algorithms↗
PubMed1999

Energy functions for protein design.

Recent successes in protein design have illustrated the promise of computational approaches. These methods rely on energy expressions to evaluate the quality of different amino acid sequences for target protein structures. The force fields optimized for design differ from those typically used in molecular mechanics and molecular dynamics calculations.

Chemical Phenomena↗
PubMed1999

Probing intermolecular backbone H-bonding in serine proteinase-protein inhibitor complexes.

BACKGROUND: Intermolecular backbone H-bonding (N-H.O=C) is a common occurrence at the interface of protein-protein complexes. For instance, the amide NH groups of most residues in the binding loop of eglin c, a potent serine proteinase inhibitor from the leech Hirudo medicinalis, are H-bonded to the carbonyl groups of residues in the target enzyme molecules such as chymotrypsin, elastase and subtilisins. We sought to understand the energetic significance of these highly conserved backbone-backbone H-bonds in the enzyme-inhibitor complexes. RESULTS: We synthesized an array of backbone-engineered ester analogs of eglin c using native chemical ligation to yield five inhibitor proteins each containing a single backbone ester bond from P3 to P2' (i.e. -CONH-to -COO-). The structure at the ligation site (P6-P5) is essentially unaltered as shown by a high-resolution analysis of the subtilisin-BPN'-eglin c complex. The free-energy changes (DeltaDeltaGNH-->O) associated with the binding of ester analogs at P3, P1 and P2' with bovine alpha-chymotrypsin, subtilisin Carlsberg and porcine pancreatic elastase range from 0-4.5 kcal/mol. Most markedly, the NH-->O substitution at P2 not only stabilizes the inhibitor but also enhances binding to the enzymes by as much as 500-fold. CONCLUSIONS: Backbone H-bond contributions are context dependent in the enzyme-eglin c complexes. The interplay of rigidity and adaptability of the binding loop of eglin c seems to play a prominent role in defining the binding action.

Amino Acid Sequence↗
PubMed2003

Dynamic simulation and metabolic re-design of a branched pathway using linlog kinetics.

This paper presents a new mathematical framework for modeling of in vivo dynamics and for metabolic re-design: the linlog approach. This approach is an extension of metabolic control analysis (MCA), valid for large changes of enzyme and metabolite levels. Furthermore, the presented framework combines MCA with kinetic modeling, thereby also combining the merits of both approaches. The linlog framework includes general expressions giving the steady-state fluxes and metabolite concentrations as a function of enzyme levels and extracellular concentrations, and a metabolic design equation that allows direct calculation of required enzyme levels for a desired steady state when control and response coefficients are available. Expressions giving control coefficients as a function of the enzyme levels are also derived. The validity of the linlog approximation in metabolic modeling is demonstrated by application of linlog kinetics to a branched pathway with moiety conservation, reversible reactions and allosteric interactions. Results show that the linlog approximation is able to describe the non-linear dynamics of this pathway very well for concentration changes up to a factor 20. Also the metabolic design equation was tested successfully.

Algorithms↗
PubMed2000

Phytoremediation of toxic elemental and organic pollutants.

Phytoremediation is the use of plants to extract, sequester, and/or detoxify pollutants. Phytoremediation is widely viewed as the ecologically responsible alternative to the environmentally destructive physical remediation methods currently practiced. Plants have many endogenous genetic, biochemical, and physiological properties that make them ideal agents for soil and water remediation. Significant progress has been made in recent years in developing native or genetically modified plants for the remediation of environmental contaminants. Because elements are immutable, phytoremediation strategies for radionuclide and heavy metal pollutants focus on hyperaccumulation above-ground. In contrast, organic pollutants can potentially be completely mineralized by plants.

Agriculture↗
PubMed2004

Tracing sequence diversity change of RNA-cleaving deoxyribozymes under increasing selection pressure during in vitro selection.

In vitro selection has been used extensively over the past 10 years to create functionally diverse DNA enzymes. The majority of in vitro selection experiments to date have focused on the outcome rather than the process itself, a process that remains to be fully elucidated. In vitro selection techniques rely on the probability that some DNA molecules in a random-sequence library will fold into an appropriate tertiary structure and catalyze a desired reaction. Thus, sufficient sequence diversity in the DNA pool (and hence more catalytic DNA sequences) is a prerequisite for the successful isolation of efficient deoxyribozymes. The catalytic sequence diversity established by in vitro selection is governed largely by the choice of selection pressures, one of which is the length of the reaction time. The objective of this study was to evaluate the sequence diversity change of a pool of RNA-cleaving deoxyribozymes as a function of the reaction time. Seventeen rounds of in vitro selection were performed, and the reaction time was progressively decreased from 5 h to 5 s. A representative population from each time class was subsequently cloned and sequenced. A decline in sequence diversity was observed with decreasing reaction time, and the relationship appears to be logarithmic. In contrast, a control selection performed with a constant reaction time during each round led to a linear and comparatively very slow decrease in sequence diversity. This study provides the first methodical examination of the change in catalytic sequence diversity that occurs through the course of a deoxyribozyme selection experiment. Moreover, it represents a first step toward fully understanding the intricate pathway that lies between the beginning and end of an in vitro selection experiment.

Base Sequence↗
PubMed2003

Modeling the transport of PCDD/F compounds in a contaminated river and the possible influence of restoration dredging on calculated fluxes.

River Kymijoki, the fourth largest river in Finland, has been heavily polluted by pulp mill effluents as well as by chemical industry. Loading has been reduced considerably, although remains of past emissions still exist in river sediments. The sediments are highly contaminated with polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated diphenyl ethers (PCDEs), and mercury originating from production of the chlorophenolic wood preservative (Ky-5) and other sources. The objective of this study was to simulate the transport of these PCDD/F compounds with a one-dimensional flow and transport model and to assess the impact of restoration dredging. Using the estimated trend in PCDD/F loading, downstream concentrations were calculated until 2020. If contaminated sediments are removed by dredging, the temporary increase of PCDD/F concentrations in downstream water and surface sediments will be within acceptable limits. Long-term predictions indicated only a minor decrease in surface sediment concentrations but a major decrease if the most contaminated sediments close to the emission source were removed. A more detailed assessment of the effects is suggested.

Benzofurans↗
PubMed2005

Transgenic plants in phytoremediation: recent advances and new possibilities.

Phytoremediation, the use of plants and their associated microbes to remedy contaminated soils, sediments, and groundwater, is emerging as a cost-effective and environmentally friendly technology. Due in large part to its aesthetic appeal, this technology has gained increasing attention over the past 10 years. Phytoremediation uses different plant processes and mechanisms normally involved in the accumulation, complexation, volatilization, and degradation of organic and inorganic pollutants. Certain plants, called hyperaccumulators, are good candidates in phytoremediation, particularly for the removal of heavy metals. Phytoremediation efficiency of plants can be substantially improved using genetic engineering technologies. Recent research results, including overexpression of genes whose protein products are involved in metal uptake, transport, and sequestration, or act as enzymes involved in the degradation of hazardous organics, have opened up new possibilities in phytoremediation. This paper provides a critical review of the recent progress made toward the development of transgenic plants with improved phytoremediation capabilities and their potential use in environmental cleanup.

Biodegradation, Environmental↗
PubMed2006

The contemporary anthropogenic chromium cycle.

Chromium is an essential engineering metal used in stainless and alloy steels, chemicals, and refractory products. Using material flow analysis, all major anthropogenic chromium flows are characterized for the year 2000, from mining through discard, on three spatial levels: fifty-four countries, nine world regions, and the planet. Included is the first detailed quantification of chromium in internationally traded finished products and diverse waste streams. Findings include (1) 78% of chromium flow entering final use is added as a net addition to stock on the global level; most countries are close to this figure; (2) the majority of mining occurs in Africa (2400 Gg Cr/yr) and the Commonwealth of Independent States (1090 Gg Cr/yr), while the major end-users are Asia, Europe, and North America at 1150, 1140, and 751 Gg Cr/yr, respectively; (3) waste flows of chromium are the greatest in Europe (420 Gg Cr/yr), Asia (370 Gg Cr/yr), and North America (290 Gg Cr/yr), but the composition of these waste flows varies greatly among the world regions; (4) releases of chromium by the global system, which total 2630 Gg Cr/yr, are nearly evenly divided among tailings, ferrochromium slag, downgraded scrap, and post-consumer losses; (5) many countries have a heavy foreign dependence on chromium in the all forms, as is demonstrated for the United States. The findings relating to in-use stock changes and finished product trade are relevant to industry, allowing for more accurate planning for future scrap availability. The quantification of releases due to discards and dissipation hold environmental and human health relevance, while the full life cycle international trade assessment addresses local scarcity.

Chromium↗
PubMed1999

Grafting of aliphatic and aromatic probes on bovine serum albumin: influence on its structural and physicochemical characteristics.

Bovine serum albumin was chosen as a model protein to study the effect of the functionalization of the epsilon-NH2 of lysine residues with different carbon chains on the physical properties of proteins. Thus, BSA has been acylated and sulfonylated by means of anhydrides and sulfonyl chlorides, respectively. The secondary structures of modified BSA, studied by far-UV CD, showed very slight changes except after sulfamidation. However, near-UV CD and intrinsic fluorescence spectra revealed important conformational perturbations for proteins bearing long carbon chains. Furthermore, the binding of an apolar probe (ANS) to BSA revealed an improvement of surface hydrophobicity after modification. Meanwhile, Scatchard plot results indicate that only 20% of the hexanoyl carbon chains lie at the surface of the proteins. Solvent conditions should influence the exposure of these chains and consequently the surface hydrophobicity of proteins.

Acylation↗
PubMed1990

Small rearrangements in structures of Fv and Fab fragments of antibody D1.3 on antigen binding.

The potential use of monoclonal antibodies in immunological, chemical and clinical applications has stimulated the protein engineering and expression of Fv fragments, which are heterodimers consisting of the light and heavy chain variable domains (VL and VH) of antibodies. Although Fv fragments exhibit antigen binding specificity and association constants similar to their parent antibodies or Fab moieties, similarity in their interactions with antigen at the level of three-dimensional structure has not been investigated. We have determined the high-resolution crystal structure of the genetically engineered FvD1.3 fragment of the anti-hen egg-white lysozyme (HEL) monoclonal antibody D1.3, and of its complex with HEL. On comparison with the crystallographically refined FabD1.3-HEL complex, we find that FvD1.3 and FabD1.3 make, with minor exceptions, very similar contacts with the antigen. Furthermore, a small but systematic rearrangement of the domains of FvD1.3 occurs on binding HEL, bringing the contacting residues closer to the antigen by a mean value of about 0.7 A for VH (aligning on VL) or of 0.5 A for VL (aligning on VH). This is indicative of an induced fit rather than a 'lock and key' fit to the antigen.

Antibodies, Monoclonal↗
PubMed2000

Molecular breeding of carotenoid biosynthetic pathways.

The burgeoning demand for complex, biologically active molecules for medicine, materials science, consumer products, and agrochemicals is driving efforts to engineer new biosynthetic pathways into microorganisms and plants. We have applied principles of breeding, including mixing genes and modifying catalytic functions by in vitro evolution, to create new metabolic pathways for biosynthesis of natural products in Escherichia coli. We expressed shuffled phytoene desaturases in the context of a carotenoid biosynthetic pathway assembled from different bacterial species and screened the resulting library for novel carotenoids. One desaturase chimera efficiently introduced six rather than four double bonds into phytoene, to favor production of the fully conjugated carotenoid, 3, 4,3',4'-tetradehydrolycopene. This new pathway was extended with a second library of shuffled lycopene cyclases to produce a variety of colored products. One of the new pathways generates the cyclic carotenoid torulene, for the first time, in E. coli. This combined approach of rational pathway assembly and molecular breeding may allow the discovery and production, in simple laboratory organisms, of new compounds that are essentially inaccessible from natural sources or by synthetic chemistry.

Carotenoids↗
PubMed2006

Imparting size, shape, and composition control of materials for nanomedicine.

This tutorial review presents an overview of strategies for the synthesis and fabrication of organic nanomaterials, specifically those with potential for use in medical applications. Examples include liposomes, micelles, polymer-drug conjugates and dendrimers. Methods of driving shape via"bottom-up" synthetic approaches and thermodynamics and kinetics are discussed. Furthermore, methods of driving shape via"top-down" physical and engineering techniques are also explored. Finally, a novel method (referred to as PRINT) used to produce nanoparticles that are shape-specific, can contain any cargo, and can be easily modified is examined along with its potential future role in nanomedicine.

Animals↗
PubMed1999

Organization of the biosynthetic gene cluster for the polyketide anthelmintic macrolide avermectin in Streptomyces avermitilis.

Analysis of the gene cluster from Streptomyces avermitilis that governs the biosynthesis of the polyketide anthelmintic avermectin revealed that it contains four large ORFs encoding giant multifunctional polypeptides of the avermectin polyketide synthase (AVES 1, AVES 2, AVES 3, and AVES 4). These clustered polyketide synthase genes responsible for avermectin biosynthesis together encode 12 homologous sets of enzyme activities (modules), each catalyzing a specific round of polyketide chain elongation. The clustered genes encoding polyketide synthase are organized as two sets of six modular repeats, aveA1-aveA2 and aveA3-aveA4, which are convergently transcribed. The total of 55 constituent active sites makes this the most complex multifunctional enzyme system identified to date. The sequenced DNA region contains 14 additional ORFs, some of which encode polypeptides governing other key steps in avermectin biosynthesis. Between the two sets of polyketide synthase genes lie two genes involved in postpolyketide modification, one of which encodes cynthochrome P450 hydroxylase that probably catalyzes furan ring formation at C6 to C8a. Immediately right of the large polyketide synthase genes is a set of genes involved in oleandrose biosynthesis and its transglycosylation to polyketide-derived aglycons. This cluster includes nine genes, but one is not functional in the biosynthesis of avermectin. On the left side of polyketide synthase genes, two ORFs encoding methyltransferase and nonpolyketide synthase ketoreductase involved in postpolyketide modification are located to the left of the polyketide synthase genes, and an adjacent gene encodes a regulatory function that may be involved in activation of the transcription of avermectin biosynthetic genes.

Anthelmintics↗