Metabolic pathways comparison

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/). 

Recent work in our laboratories has confirmed the existence of a similar pathway in the oxidation of vindoline in mammals (777). The availability of compounds such as 59 as analytical standards, along with published mass spectral and NMR spectral properties of this compound, served to facilitate identification of metabolites formed in mammalian liver microsome incubations. Two compounds are produced during incubations with mouse liver microsome preparations 17-deacetylvindoline, and the dihydrovindoline ether dimer 59. Both compounds were isolated and completely characterized by spectral comparison to authentic standards. This work emphasizes the prospective value of microbial and enzymatic transformation studies in predicting pathways of metabolism in mammalian systems. This work would also suggest the involvement of cytochrome P-450 enzyme system(s) in the oxidation process. Whether the first steps involve direct introduction of molecular oxygen at position 3 of vindoline or an initial abstraction of electrons, as in Scheme 15, remains unknown. The establishment of a metabolic pathway in mammals, identical to those found in Strep-tomycetes, with copper oxidases and peroxidases again confirms the prospective value of the microbial models of mammalian metabolism concept. 

Summarizing, the numerical value and the sign of AG° allow us to make comparisons of different reactions under identical conditions but AG values reveal the real energy change occurring in a metabolic pathway. AG° and AG values are expressed in units of kj/mol. 

L. Grislain, M. T. Mocquard, J. F. Dabe, M. Bertrand, W. Luijten, B. Marchand, G. Res-plandy, M. Devissaguet, Interspecies Comparison of the Metabolic Pathways of Perin-dopril, a New Angiotensin-Converting Enzyme (ACE) Inhibitor , Xenobiotica 1990, 20, 787 - 800. 

In comparison to glycolysis and a few other metabolic pathways, no systematic stndies on the equilibrium nature of individual reactions in some important biochemical processes have been carried ont (e.g. protein synthesis, signal transdnction pathways see Chapters 12, 20 and 21). 

A reaction in a metabolic pathway is likely to be nonequilibrium if the maximum catalytic activity of the enzyme that catalyses the reaction is low in comparison with those of other enzymes in the pathway. In consequence, the concentration of substrate of this reaction is likely to be high whereas that of the product is likely to be low, since the next enzyme in the sequence readily catalyses its removal. Because the concentration of this product is low, the rate of the reverse component of the reaction is very much less than the rate of the forward component. This situation characterises a non-equilibrium process. Conversely, a reaction is near-equiUbrium if the maximum catalytic activity of the enzyme is high in relation to those of other enzymes in the pathway in this case, the rates of the forward and the reverse components of the reaction are similar and both are much greater than the overall flux... 

The principal metabolic pathway to mercapturic acids is presumably similar in humans and rodents. Because no data on kinetics or metabolic activation in humans are available, no quantitative comparison can be made. 

Structural motifs become especially important in defining protein families and superfamilies. Improved classification and comparison systems for proteins lead inevitably to the elucidation of new functional relationships. Given the central role of proteins in living systems, these structural comparisons can help illuminate every aspect of biochemistry, from the evolution of individual proteins to the evolutionary history of complete metabolic pathways. 

White Phosphorus. The pharmacokinetics database is inadequate. No quantitative information was located regarding absorption, distribution, metabolism, or excretion following inhalation, dermal, and dermal burn exposure to white phosphorus. Definitive quantitative data on metabolic pathways following oral exposure to white phosphorus also are lacking. Data that were located on absorption, distribution, and excretion following oral exposure were helpful. They provided some time-related data, but provided no information regarding comparisons between various dose levels. 

There is evidence that quinone methides form as intermediates in the metabolic oxidation of catechol derivatives, a key step in a variety of biosynthetic processes such as melanization and sclerotization of animal cells. Tyrosinase from mushrooms catalyzes the oxidation of a-methyldopa methyl ester 54a. It has been proposed that this reaction observed in vitro is part of a metabolic pathway for the metabolism of 54a. This reaction proceeds by oxidation of ct-methyl dopa methyl ester 54a to give 54b, which cyclizes and is further oxidized to quinone methide 54c (Scheme 26).101 This quinone methide was identified by comparison to authentic 54c, which was prepared by chemical oxidation of 54a to 54c.102... 

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