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Enzyme kinetics and metabolic control. A method to test and quantify the effect of enzymic properties on metabolic variables.

ABSTRACT: It is usual to study the sensitivity of metabolic variables to small (infinitesimal) changes in the magnitudes of individual parameters such as an enzyme concentration. Here, the effect that a simultaneous change in all the enzyme concentrations by the same factor alpha (Co-ordinate-Control Operation, CCO) has on the variables of time-dependent metabolic systems is investigated. This factor alpha can have any arbitrary large value. First, we assume, for each enzyme measured in isolation, the validity of the steady-state approximation and the proportionality between reaction rate and enzyme concentration. Under these assumptions, any time-invariant variable may behave like a metabolite concentration, i.e. S alpha = Sr (S-type), or like a flux, i.e. J alpha = alpha Jr (J-type). The subscripts r and alpha correspond to the values of the variable before and after the CCO respectively. Similarly, time-dependent variables may behave according to S alpha (t/alpha) = Sr (t) (S-type) or to J alpha (t/alpha) = alpha J r (t) (J-type). A method is given to test these relationships in experimental systems, and to quantify deviations from the predicted behaviour. A positive test for deviations proves the violation of some of the assumptions made. However, the breakdown of the assumptions in an enzyme-catalysed reaction, studied in isolation, may or may not affect significantly the behaviour of the system when the component reaction is embedded in the metabolic network.

SUBMITTER: Acerenza L

PROVIDER: S-EPMC1131644 | biostudies-other | 1990 Aug

REPOSITORIES: biostudies-other

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Project description:BackgroundMouse studies have recently compared the age-onset patterns of cancer between different genotypes. Genes associated with earlier onset are tentatively assigned a causal role in carcinogenesis. These standard analyses ignore the great amount of information about kinetics contained in age-onset curves. We present a method for analyzing kinetics that measures quantitatively the causal role of candidate genes in cancer progression. We use our method to demonstrate a clear association between somatic mutation rates of different DNA mismatch repair (MMR) genotypes and the kinetics of cancer progression.MethodsMost experimental studies report age-onset curves as the fraction diagnosed with tumors at each age for each group. We use such data to estimate smoothed survival curves, then measure incidence rates at each age by the slope of the fitted curve divided by the fraction of mice that remain undiagnosed for tumors at that age. With the estimated incidence curves, we compare between different genotypes the median age of cancer onset and the acceleration of cancer, which is the rate of increase in incidence with age.ResultsThe direction of change in somatic mutation rate between MMR genotypes predicts the direction of change in the acceleration of cancer onset in all 7 cases (p approximately 0.008), with the same result for the association between mutation rate and the median age of onset.ConclusionMany animal experiments compare qualitatively the onset curves for different genotypes. If such experiments were designed to analyze kinetics, the research could move to the next stage in which the mechanistic consequences of particular genetic pathways are related to the dynamics of carcinogenesis. The data we analyzed here were not collected to test mechanistic and quantitative hypotheses about kinetics. Even so, a simple reanalysis revealed significant insights about how DNA repair genotypes affect separately the age of onset and the acceleration of cancer. Our method of comparing genotypes provides good statistical tests even with small samples for each genotype.

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Enzyme kinetics and metabolic control. A method to test and quantify the effect of enzymic properties on metabolic variables.

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