Metabolism optimization

Thus, knowledge of cell physiology is an important prerequisite for further directed metabolic optimization and the investigation of associated cellular phenomena. 

In addition to phenytoin, carbamazepine, and lamotrigine, metabolically optimized analogs of these drugs, such as fosphenytoin and oxcarbazepine, show clinical promise. Other anticonvulsants that block sodium channels, among several mechanisms of action, include zonisamide, felbamate, topiramate, and valproate (Fig. 5). 

Jensen PR, Hammer K (1998) Artificial promoters for metabolic optimization. Biotechnol Bioeng 58 191-195... 

Returning now to the theme of combinatorial games, the problems mentioned are sufficient for introducing the essential idea of metabolic optimization, and looking at the pentose phosphate pathway in the fight of it. First I shall treat this pathway as the game defmed in Figure 5.2, but afterwards we shall see how the apparently arbitrary rules actually apply to the real biochemical situation. 

Efficiency of cellular metabolism Optimal biomass and products yields... 

Jensen PR, Hammer K (1998a) The sequence of spacers between the consensus sequences modulates the strength of prokaryotic promoters. Appl Environ Microbiol 64 82-87 Jensen PR, Hammer K (1998b) Artifidal promoters for metabolic optimization. Biotechnol Bioeng 58 191-195... 

B. Testa, G. Cruciani, Structure-metabolism relations and the challenge of predicting biotransformation, in Pharmacokinetic Optimization in Drug Research, B. Testa, H. van de Water-beemd, G. Folkers, R. Guy (Eds.), WHey-VCH, Weinheim, New York, 2001, pp. 65-84. 

Because of the differences in primary and secondaiy metabolism, a reactor may have a dual-stage fed-batch system. In other words, fed-batch operation optimizes growth with little or no product formation. When sufficient biomass has accumulated, a different fed-batch protocol comes into play. 

Compound optimization in early- and late-phase drug discovery is covered, emphasizing physicochemical properties, in vitro absorption, metabolism and in vivo animal pharmacokinetic methodologies. 

Metabolic pathways containing dioxygenases in wild-type strains are usually related to detoxification processes upon conversion of aromatic xenobiotics to phenols and catechols, which are more readily excreted. Within such pathways, the intermediate chiral cis-diol is rearomatized by a dihydrodiol-dehydrogenase. While this mild route to catechols is also exploited synthetically [221], the chirality is lost. In the context of asymmetric synthesis, such further biotransformations have to be prevented, which was initially realized by using mutant strains deficient in enzymes responsible for the rearomatization. Today, several dioxygenases with complementary substrate profiles are available, as outlined in Table 9.6. Considering the delicate architecture of these enzyme complexes, recombinant whole-cell-mediated biotransformations are the only option for such conversions. E. coli is preferably used as host and fermentation protocols have been optimized [222,223]. 

Talafous J, Sayre LM, Mieyal JJ, Klopman G. META. 2. A dictionary model of mammalian xenobiotic metabolism. J Chem Inf Comput Sci 1994 34 1326-33. Klopman G, Tu M, Talafous J. META. 3. A genetic algorithm for metabolic transform priorities optimization. J Chem Inf Comput Sci 1997 37 329-34. Langowski J, Long A. Computer systems for the prediction of xenobiotic metabolism. Adv Drug Del Rev 2002 54 407-15. 

Melendes-Hevia E, Waddell TG, Shelton ED Optimization of molecular design in the evolution of metabolism the glycogen molecule. BiochemJ 1993 295 477. 

Metabolic control analysis (MCA) assigns a flux control coefficient (FCC) to each step in the pathway and considers the sum of the coefficients. Competing pathway components may have negative FCCs. To measure FCCs, a variety of experimental techniques including radio isotopomers and pulse chase experiments are necessary in a tissue culture system. Perturbation of the system, for example, with over-expression of various genes can be applied iteratively to understand and optimize product accumulation. 

Generation of mutants is also a starting point in optimization experiments, and now is the time for metabolic engineering of the astaxanthin biosynthetic pathway. Researchers should be able to manage carbon fluxes within the cells and resolve competitions between enzymes such as phytoene desaturase and lycopene cyclase. 

The cultivation of this yeast strain on pectin medium showed optimal grow conditions. The behaviour of this strain was compared with that of four strains of Candida boidinii from the Culture Collection of Yeasts. The grow curves of all strains on pectin medium showed marked plateau suggesting the presence of two existing C-sources in the pectin medium, requiring two different metabolic paths (Fig. 1). 

The application of substrates isotopically labeled in specific positions makes it possible to follow the fate of individual atoms during the microbial degradation of xenobiotics. Under optimal conditions, both the kinetics of the degradation, and the formation of metabolites may be followed— ideally when samples of the labeled metabolites are available. Many of the classical studies on the microbial metabolism of carbohydrates, carboxylic acids, and amino acids used radioactive... 

Chemical analysis alone is insufficient in view of analytical uncertainties in the optimal methods for extraction. These must take into account both the free and associated analytes (Cajthaml and Sasek 2005), as well as metabolic products. 

Metabolic and enzyme engineering have received a lot of attention in academic institutions and are now being applied for the optimization of biocatalysts used in the production of a diverse range of products. Engineered microorganisms, even with non-native enzyme activities, are being used for novel products and process improvements for the production of precursors, intermediates and complete compounds, required in the pharmaceutical industry (Chartrain et ai, 2000). 

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