Metabolic manipulation

D. V. Cokkinos, Can metabolic manipulation reverse myocardial dysfunction Editorial Eur Heart J 22, 2138-2139(2001). 

The interrelationships described above provide a basis for evaluating the possibility that chemotherapeutic or metabolic manipulation can be used to produce drastic alterations in ceU functions. We have shown that one mechanism of cell death, which we have called Type 1 or the Suicide mechanism, is mediated by activation of poly(ADP-ribose) polymerase and the consequent depletion of cellular energy metabolites (1,2). This enzyme is activated by DNA strand breaks to cleave NAD at the glycosylic bond between the nicotinamide and adenosine diphosphoribose moieties (3). The latter are joined by the same enzyme into linear or branched chain polymers of ADP-ribose (3). Poly(ADP-ribose) polymerase activity and utilization of its substrate, NAD, are proportional to the number and duration of DNA strand breaks (4, 5). As shown in Fig. 2, DNA damage can sufficiently... 

Metabolic manipulation. In an attempt to achieve by metabolic means what the geneticists had achieved by mutation, Davies et al. (1990) carried out cultivation of C. curvatalA. curvatum under low O2 conditions. It was argued that of all the parameters that could affect fatty acid composition (cf. Ratledge, 1982), the rate of supply of O2 into the fermenter was likely to be most influential for the promotion of saturated fatty acids. All the desaturase reactions (see Figure 9.5) are 02-dependent and therefore if O2 were made rate-limiting, cells may then have a diminished ability to convert stearic acid to oleic acid and beyond. 

Several approaches for metabolic manipulation can be used to reprogram microbial metabolic pathways to produce valuable metabolites. Firstly, the metabolic pathway for a specific metabolite can be set up by using reference books and online databases. Secondly, the theoretical yield of the metabolite or the reaction fluxes in the cell can be determined by analyzing and modeling the metabolic pathway. Finally, the yield of the desired metabolite can be maximized by altering the reaction fluxes using metabolic engineering. 

Metabolic manipulation can be achieved either by over-expression or knockout of key enzymes to increase or decrease the accumulation of particular end-products, or to divert existing pathways to create new products. However, the rational engineering of alkaloid... 

Butanol is naturally produced by a number of microorganisms from the Clostridia genus. The metabohsm of these organisms is regulated by their genetic information, and a number of metabolic manipulations have already been examined, mostly in order to improve butanol tolerance. 

Life forms are based on coded chemicals that, in the right environment, can reproduce themselves and make other chemicals needed to break down and utilize food. Within an organism, these biochemical reactions constitute nonnal metabolism. Biotechnology is the manipulation of these biochemical reactions at either the cellular or the molecular level. 

The World Wide Web has transformed the way in which we obtain and analyze published information on proteins. What only a few years ago would take days or weeks and require the use of expensive computer workstations can now be achieved in a few minutes or hours using personal computers, both PCs and Macintosh, connected to the internet. The Web contains hundreds of sites of Interest to molecular biologists, many of which are listed in Pedro s BioMolecular Research Tools (http // www.fmi.ch/biology/research tools.html). Many sites provide free access to databases that make it very easy to obtain information on structurally related proteins, the amino acid sequences of homologous proteins, relevant literature references, medical information and metabolic pathways. This development has opened up new opportunities for even non-specialists to view and manipulate a structure of interest or to carry out amino-acid sequence comparisons, and one can now rapidly obtain an overview of a particular area of molecular biology. We shall here describe some Web sites that are of interest from a structural point of view. Updated links to these sites can be found in the Introduction to Protein Structure Web site (http // WWW.ProteinStructure.com/). 

The refractory nature of some pollutants, notably, persistent polyhalogenated compounds, has raised problems of bioremediation of contaminated sites (e.g., sediments and dumping sites). There has been interest in the identification, or the production by genetic manipulation, of strains of microorganisms that can metabolically degrade recalcitrant molecules. For example, there are bacterial strains that can reductively dechlorinate PCBs under anaerobic conditions. 

It is important that chemical engineers master an understanding of metabolic engineering, which uses genetically modified or selected organisms to manipulate the biochemical pathways in a cell to produce a new product, to eliminate unwanted reactions, or to increase the yield of a desired product. Mathematical models have the potential to enable major advances in metabolic control. An excellent example of industrial application of metabolic engineering is the DuPont process for the conversion of com sugar into 1,3-propanediol,... 

Transgenic E. coli accumulate comparatively low levels of carotenoids " compared to microbial algae, yeasts, and bacteria. Many efforts ° have focused on increasing accumulation by manipulation of factors affecting metabolic flux and metabolite accnmnlation (listed and discnssed in Sections 5.3.1.1 and 5.3.1.3 A) and have been reviewed." - " In bacterial systems, approaches to control can be categorized as either infrastructural (plasmids, enzymes, strains) or ultrastructural (media and feeding, enviromnent, precursor pools, substrate flux). 

Plant use is less biotechnologically advanced and fundamentally more complex. The first generation of plant metabolic engineering met with mixed success and produced unanticipated results — problems that are not necessarily restricted to manipulation of carotenogenesis. The reason is that predictive metabolic engineering relies on the establishment of both needed tools and an information infrastructure... 

Bioavailability is defined as the portion or fraction of a chemical that is available for biological action and is influenced by several factors including the molecular size and charge of a molecule, structural features of membranes, first pass metabolism, and therefore, bio availability can be influenced by the molecular structure of a chemical. This situation presents an opportunity for molecular designers to manipulate a chemical s structure to decrease bioavailability and consequently hazard. If the availability of a molecule can be decreased, the amount of chemical at the site of action is decreased which leads to decreased toxicity. 

Chemical manipulation of phenolic allelochemical production in plants has two potential values 1) for study of the role of phenolic allelochemicals in plant interactions with other organisms and 2) to alter such interactions for agricultural purposes. The first of these uses has already been accomplished on a limited scale (21, 22, 50, 51, 84, 86), however, there is no published evidence of the latter. This does not mean that herbicide and growth regulator-influences on plant secondary metabolism do not affect agricultural ecosystems by changing allelochemic compositions of plants. It is likely that this is the case, but it... 

During the past decade, numerous articles reviewing the effects of aging on pharmacokinetic processes (i.e., absorption, distribution, metabolism, and elimination) have been published [115 124h]. An outline of the observations made in these reports is supplied in Table 5. The absorption process is the only process that will be covered in depth in this chapter, as this is the process that can most easily be manipulated through formulation techniques. 

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