The long-term objective of this work is the development of general computational and theoretical techniques which, based on sophisticated information-processing, insights from basic physical sciences, biological regularities, and specific observations, can determine the mechanisms and behavior of the system, consistent with prior knowledge, and guide the experiments by testing and eliminating alternative hypotheses. As a short-term objective, proposed here is the investigation of the metabolism of small molecules (as opposed to macromolecules), carried out by enzyme-catalyzed bioreactions. The metabolism is not uncoupled from other biological phenomena; for example, the regulation of the expression of a gene determines the conditions under which the corresponding biochemical reaction is active. Conversely, a specific function at the bioreaction level, achieved by concerted action of several enzymes, can suggest patterns of gene expression. The work will contribute to better understanding of defects in human metabolism and how they can be diagnosed and treated. The extent to which different intermediates in the defective route will actually accumulate depends on the equilibrium constants of the bioreactions. This has implications in the development of diagnostic tests of the disease based on detection of intermediates, as well as the development of means for catabolizing or simply deactivating the intermediate. Thus, it would be very useful to have theoretical means of predicting the equilibria of bioreactions. A second important aspect that comes into play in both diagnosis and treatment is the influence of the metabolism that surrounds the defective pathway. It is important to know whether the surrounding metabolism can provide routes that bypass the defective step, or simply drain off the accumulating intermediates. The identification of pathways that can fulfill such functions is another thrust of the proposed research. The first specific question to be addressed is the determination of whether a given biochemical reaction or biotransformation is thermodynamically feasible. Since many biochemical reactions are reversible, even if they have not been observed to proceed in the reverse direction, the derivation of the thermodynamic reversibility and feasibility of a transformation is important in the identification of feasible pathways. One of the difficulties encountered in the thermodynamic analysis is that many biochemical compounds are resonance hybrids. To overcome this difficulty, a method will be developed incorporating into the estimation all possible formal electronic arrangements of a hybrid compound. The method will calculate Gibbs energies from the chemical structures of metabolites. In order to reason about metabolic functions and the pathways that can fulfill them, an algorithm is needed for construction of pathways that can accomplish a given metabolic function, i.e., the transformation of a given set of metabolic intermediates to target products. Computationally intensive portions of the algorithm will be enhanced by a Connection Machine -- a data-parallel computer with 16,000 processors, which will be used for preprocessing of the bioreaction database. The role of individual enzymes and intermediates for the metabolism can often be understood in terms of the pathways in which they participate and the metabolic functions these pathways fulfill. For example, if an enzyme occurs in all pathways then it is essential for the transformation, but if it can be bypassed through a small set of other enzymes it might not be essential. While the work includes the creation and integration of databases, the emphasis is placed on the development of techniques which use commonly available raw information from the database to draw significant qualitative conclusions.
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