The rationalization of high enzyme concentration in metabolic pathways such as glycolysis

Betts, Graham F.; Srivastava, D. K.

doi:10.1016/s0022-5193(05)80359-5

Cited by 25 publications

(17 citation statements)

References 17 publications

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“…Additionally, accumulation of intermediates would undesirably slow the response of pathway flux to abrupt changes in energetic demand. Analytical calculations for a simple unbranched pathway (A.S. and M.A.S., unpublished data) and numerical results for a simple model pathway that was parameterized to resemble glycolysis (49) indicate that up-regulation of the equilibrium and downstream nonequilibrium enzymes achieves increased flux without the previous disadvantages. In metabolic engineering, it has also been found that large increases in some enzyme activities intended to ‡ ‡ If, as seems likely, the glycolytic pathway represents the typical situation, most enzymes are excess-activity enzymes, and these are usually also the most abundantly expressed enzymes in each pathway (19,47).…”

Section: Discussionmentioning

confidence: 99%

Evolution of enzymes in a series is driven by dissimilar functional demands

Salvador

Savageau

2006

Proc. Natl. Acad. Sci. U.S.A.

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That distinct enzyme activities in an unbranched metabolic pathway are evolutionarily tuned to a single functional requirement is a pervasive assumption. Here we test this assumption by examining the activities of two consecutively acting enzymes in human erythrocytes with an approach to quantitative evolutionary design that avoids the above-mentioned assumption. We previously found that avoidance of NADPH depletion during the pulses of oxidative load to which erythrocytes are normally exposed is the main functional requirement mediating selection for high glucose-6-phosphate dehydrogenase activity. In the present study, we find that, in contrast, the maintenance of oxidized glutathione at low concentrations is the main functional requirement mediating selection for high glutathione reductase activity. The results in this case show that, contrary to the assumption of a single functional requirement, natural selection for the normal activities of the distinct enzymes in the pathway is mediated by different requirements. On the other hand, the results agree with the more general principles that underlie our approach. Namely, that (i) the values of biochemical parameters evolve so as to fulfill the various performance requirements that are relevant to achieve high fitness, and (ii) these performance requirements can be inferred from quantitative systems theory considerations, informed by knowledge of specific aspects of the biochemistry, physiology, genetics, and ecology of the organism.human erythrocytes ͉ oxidative stress ͉ safety factors ͉ quantitative evolutionary design ͉ systems biology A lthough numerous mutations can drastically change the values of biochemical parameters such as enzyme activities, these values are often narrowly distributed in natural populations. This outcome owes largely to the interplay between constraints imposed by physicochemical laws and natural selection for good performance of the organism's biochemical circuits. The strength of natural selection in shaping the design of living organisms at the molecular level (1) is just beginning to be appreciated. In humans, natural selection is strong enough to almost prevent fixation of mutations that decrease fitness by Ͼ0.002%. Furthermore, Ͼ70% of the amino acid-changing mutations are selected against (2, 3). In the many organisms that have larger effective populations, even smaller fitness differentials can drive natural selection. Understanding the quantitative design for biochemical parameters that has been achieved through natural selection (i.e., the qualitative and quantitative functional requirements that mediate their evolutionary tuning) is a goal of systems biology with far-reaching implications. Such understanding would provide valuable insight regarding physiological as well as evolutionary adaptation (4, 5) and guidance for metabolic engineering (6). However, this type of understanding for parameters such as enzyme activities remains limited.The assumption that the distinct enzyme activities in a metabolic pathway are evolutio...

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Section: Discussionmentioning

confidence: 99%

Evolution of enzymes in a series is driven by dissimilar functional demands

Salvador

Savageau

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…There are, however, a number of exceptions to this rule (cf. Betts and Srivastava, 1991), notably in the case of ribulose bisphosphate carboxylase (EC 4.1.1.39) (Farquhar, 1979). Consider a simple enzymic reaction with the catalytic mechanism shown in Scheme 1 (Section 2.2).…”

Section: Methodsmentioning

confidence: 99%

“…Accordingly, the relaxation time constants of the glycolytic enzymes in human erythrocytes cover at least a range of four orders of magnitude, let alone the enzymes so fast as to be near equilibrium, for which the time constants are very low and difficult to measure or calculate. This separation of time constants is accompanied by the fact that the fast enzymes are so efficient that they can catalyze rates much higher than maximum pathway flux (e.g., 100-fold in glycolysis in muscle, see Betts and Srivastava, 1991). A biochemical reaction is usually said to be fast if '[ is less than 1 s.…”

Section: Time Constants Of Metabolic Processesmentioning

confidence: 99%

The Regulation of Cellular Systems

Heinrich¹,

Schuster²

1996

930

991

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“…Explanations for apparently superfluous enzyme activities based on criteria other than capacity for sustained flux are implicit in ref. 23 and have been proposed (24), but they have never been substantiated by detailed analysis of a well characterized biochemical network.…”

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confidence: 99%

Quantitative evolutionary design of glucose 6-phosphate dehydrogenase expression in human erythrocytes

Salvador

Savageau

2003

Proc. Natl. Acad. Sci. U.S.A.

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Why do the activities of some enzymes greatly exceed the flux capacity of the embedding pathways? This is a puzzling open problem in quantitative evolutionary design. In this work we investigate reasons for high expression of a thoroughly characterized enzyme: glucose 6-phosphate dehydrogenase (G6PD) in human erythrocytes. G6PD catalyses the first step of the pathway that supplies NADPH for antioxidant defense mechanisms. Normal G6PD activity far exceeds the capacity of human erythrocytes for a steady NADPH supply, which is limited upstream of G6PD. However, the distribution of erythrocyte G6PD activity in human populations reveals a selective pressure for maintaining high activity. To clarify the nature of this selective pressure, we studied how G6PD activity and other parameters in a model of the NADPH redox cycle affect metabolic performance. Our analysis indicates that normal G6PD activity is sufficient but not superfluous to avoid NADPH depletion and ensure timely adaptation of the NADPH supply during pulses of oxidative load such as those that occur during adherence of erythrocytes to phagocytes. These results suggest that large excess capacities found in some biochemical and physiological systems, rather than representing large safety factors, may reflect a close match of system design to unscrutinized performance requirements. Understanding quantitative evolutionary design thus calls for careful consideration of the various performance specifications that biological components͞processes must meet in order for the organism to be fit. The biochemical systems framework used in this paper is generally applicable for such a detailed examination of the quantitative evolutionary design of gene expression levels in other systems. U nderstanding the quantitative relationship of biological capacities to each other and to the peak natural loads on them, the problem of quantitative evolutionary design (1), is a key issue in integrative biology (2-5). Natural selection against both poor performance and misallocation of resources to superfluous ''infrastructure'' could be thought to promote a close match between capacities of components operating in series and between these capacities and the peak natural loads. Nevertheless, research at both the molecular (6-9) and the organ (2, 10) levels has shown that ratios between the highest capacities in a series and the lowest ones, as well as between capacities and their loads, are often quite high. In particular, ratios between catalytic capacities (i.e., activities, V max ) of some enzymes, which we will call ''excess-activity enzymes,'' and the flux capacity of the embedding pathways may exceed 1,000 (11). These ratios remain unexplained.It has been argued (7) that these high activities are necessary to ensure sufficient net flux in reactions that operate near equilibrium. There are two problems with this argument. First, one must still provide an evolutionary explanation for why the step in question must be near equilibrium. Second, any enzyme whose activity greatly exce...

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The rationalization of high enzyme concentration in metabolic pathways such as glycolysis

Cited by 25 publications

References 17 publications

Evolution of enzymes in a series is driven by dissimilar functional demands

Evolution of enzymes in a series is driven by dissimilar functional demands

The Regulation of Cellular Systems

Quantitative evolutionary design of glucose 6-phosphate dehydrogenase expression in human erythrocytes

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