Metabolism computer models

TABLE 18.1 Human Enzymes Involved in Drug Metabolism That Have Been Computationally Modeled to Date... 

In conclusion, it is likely that computational approaches for metabolism prediction will continue to be developed and integrated with other algorithms for pharmaceutical research and development, which may in turn ultimately aid in their more widespread use in both industry and academia. Such models may already be having some impact when integrated with bioanalytical approaches to narrow the search for possible metabolites that are experimentally observed. Software that can be updated by the user as new metabolism information becomes available would also be of further potential value. The held of metabolism prediction has therefore advanced rapidly over the past decade, and it will be important to maintain this momentum in the future as the hndings from crystal structures for many discrete metabolic enzymes are integrated with the diverse types of computational models already derived. 

Fluxes of iron from the plasma towards BM and other tissues can be quantified by ferrokinetic studies, using 59Fe and sophisticated computer models (Ricketts et ah, 1975 Ricketts and Cavill, 1978 Barosi et ah, 1978 Stefanelli et ah, 1980). Plasma iron turnover (PIT), erythroid iron turnover (EIT), non-erythroid iron turnover (NEIT), marrow iron turnover (MIT), and tissue iron turnover (TIT) could be calculated in many disorders of iron metabolism and in all kinds of anaemias. Iron is rapidly cleared from the plasma in iron deficiency and in haemolytic anaemias. If more iron is needed for erythropoiesis, more transferrin receptors (TfR) are expressed on erythroblasts, resulting in an increased flux of iron from intestinal mucosal cells towards the plasma. In haemolytic anaemias MPS, and subsequently hepatocytes, are overloaded. In hereditary haemochromatosis too much iron is absorbed by an intrinsic defect of gut mucosal cells. As this iron is not needed for erythropoiesis,... 

In order to estimate the flux through the SMM cycle and to explore its function, a computer model of methionine metabolism in mature Arabidopsis rosette leaves was developed based on data from radiotracer experiments and on metabolite contents. This model suggested that the cycle serves to stop accumulation of AdoMet, rather than to prevent depletion of free methionine, as proposed by Mudd and Datko.54 Because plants lack the AdoMet feedbacks on MTHFR and AdoMet synthetase that regulate AdoMet pool size in other eucaryotes, the SMM cycle may be the main mechanism whereby plants achieve short-term control of AdoMet level. MMT knockouts of maize and Arabidopsis recently became available, and these can now be used to further investigate the role of the SMM cycle, and to test the predictions of the model. 

COMPUTATIONAL MODELS OF METABOLISM STABILITY AND REGULATION IN METABOLIC... 

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