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Biomedical subjects

A Cornish-Bowden

Publications and source records attributed to A Cornish-Bowden.

At least 19 recordsLinked to original sources
PubMed1992

Response coefficients of interconvertible enzyme cascades towards effectors that act on one or both modifier enzymes.

Explicit expressions have been derived for the response coefficients for the effect of activator and inhibitor concentrations on the fraction in the active state of the target enzyme of a monocyclic interconvertible enzyme cascade. These allow one to assess the adequacy of such a cascade for producing a highly sensitive response to an effector. Numerical studies indicate that this type of system can readily generate response coefficients of about seven, even without requiring both modification reactions to be modulated simultaneously, and without requiring all of the parameters that characterize the system to have their optimum values. Thus, a monocyclic cascade can constitute a highly effective on/off switching device in a linear pathway.

Catalysis↗
PubMed1991

Quantitative assessment of regulation in metabolic systems.

We show how metabolic regulation as commonly understood in biochemistry can be described in terms of metabolic control analysis. The steady-state values of the variables of metabolic systems (fluxes and concentrations) are determined by a set of parameters. Some of these parameters are concentrations that are set by the environment of the system; they can act as external regulators by communicating changes in the environment to the metabolic system. How effectively a system is regulated depends both on the degree to which the activity of the regulatory enzyme with which a regulator interacts directly can be altered by the regulator (its regulability) and on the ability of the regulatory enzyme to transmit the changes to the rest of the system (its regulatory capacity). The regulatory response of a system also depends on its internal organisation around key variable metabolites that act as internal regulators. The regulatory performance of the system can be judged in terms of how sensitivity the fluxes respond to the external stimulus and to what degree homeostasis in the concentrations of the internal regulators is maintained. We show how, on the level of both external and internal regulation, regulability can be quantified in terms of an elasticity coefficient and regulatory capacity in terms of a control coefficient. Metabolic regulation can therefore be described in terms of metabolic control analysis. The combined response relationship of control analysis relates regulability and regulatory capacity and allows quantification of the regulatory importance of the various interactions of regulators with enzymes in the system. On this basis we propose a quantitative terminology and analysis of metabolic regulation that shows what we should measure experimentally and how we should interpret the results. Analysis and numerical simulation of a simple model system serves to demonstrate our treatment.

Animals↗
PubMed1991

Failure of channelling to maintain low concentrations of metabolic intermediates.

Computer modelling has been used to investigate the effect of direct transfer of metabolites between consecutive enzymes (channelling) on the free concentrations of the channelled metabolites. When a channelled intermediate cannot participate in any other reactions, any increase in channelling tends to increase its free concentration, albeit very slightly, unless the increase in net flux brought about by the channel is compensated for by a simultaneous decrease in the activity of the route through the free intermediate, in which case channelling has no effect at all on the free steady-state concentration of the channelled intermediate. If the free intermediate is capable of participating in side reactions, channelling can decrease these side reactions, but only slightly unless virtually all of the final product results from flux through the channel and the rate constants for the direct pathway are virtually zero. In general, channelling appears not to provide a useful mechanism for maintaining intermediate concentrations at low levels.

Computer Simulation↗
PubMed1991

Hexokinase and 'glucokinase' in liver metabolism.

Rat liver contains four hexokinase isoenzymes, one of which, despite often being called 'glucokinase', is no more specific for glucose than the others. However, it does differ from them in displaying a sigmoid kinetic response to glucose, requiring much higher glucose concentrations for activity, and being insensitive to physiological concentrations of glucose 6-phosphate.

Animals↗
PubMed1991

MetaModel: a program for modelling and control analysis of metabolic pathways on the IBM PC and compatibles.

MetaModel is a user-friendly program for calculating steady-state fluxes and metabolite concentrations of metabolic systems on the IBM PC and compatible computers. For any steady state that is obtained, one can then calculate a matrix of elasticity coefficients at that steady state, or a matrix of control and response coefficients. It thus offers a simple way to calculate the control structure of a pathway: it provides not only an educational tool that allows the student to verify empirically the classic summation relationships of metabolic control analysis but also a research tool for addressing 'what if?' questions about the behaviour of metabolic systems. Results can not only be printed or stored in a file, but can also be written to a special file that can be read by popular spreadsheet programs, thereby giving access to rapid, flexible and powerful methods for subsequent analysis and plotting of these results.

Algorithms↗
PubMed1990

Very large response coefficients in interconvertible enzyme cascades.

Explicit expressions have been derived for the response coefficients for the effect of activator and inhibitor concentrations on the fraction in the active state of the target enzyme of a monocyclic interconvertible enzyme cascade. These allow one to assess the adequacy of such a cascade for producing a highly sensitive response to an effector. Numerical studies indicate that this type of system can readily generate response coefficients of about 7, even without requiring both modification reactions to be modulated simultaneously, and without requiring all of the parameters that characterize the system to have their optimum values.

Biotransformation↗
PubMed1989

Metabolic control therapy and biochemical systems theory: different objectives, different assumptions, different results.

The claim by Savageau et al. (1987 a, b, Math. Biosci. 86, 127-145, 147-167) that the theory of metabolic control associated with Kacser & Burns (1973, Symp. Soc. Exp. Biol. 27, 65-104) and with Heinrich & Rapoport (1974, Eur. J. Biochem. 42, 89-102) is no more than a special case of the biochemical systems theory of Savageau and colleagues is examined. It is shown to be based on a misconception of the objectives and assumptions of metabolic control theory. In particular, the control and elasticity coefficients that play a central role in metabolic control theory are not constants and cannot be treated as constants. Consequently they cannot in general be equated with the kinetic orders that appear in biochemical systems theory, though they do correspond at the point where the two theories are tangential to one another.

Animals↗
PubMed1989

Characteristics necessary for an interconvertible enzyme cascade to generate a highly sensitive response to an effector.

A monocyclic interconvertible enzyme cascade, in which active and inactive states of an enzyme are interconverted by two opposing enzyme-catalysed reactions, does not necessarily produce a greater degree of sensitivity to an effector than one could expect from direct interaction between effector and target reaction. On the contrary, a cascade in which an effector acts on one of the enzymes catalysing the interconversion reactions by altering the apparent value of its specificity constant will always generate a less sensitive response than direct interaction would give. Nonetheless, even if both interconversion reactions obey Michaelis-Menten kinetics with the ordinary types of inhibition and activation, one can easily generate an enormous sensitivity in which a 0.5% change in concentration can increase the proportion of target enzyme in the active state from 10% to 90%: this corresponds approximately to a Hill coefficient of 800. To maximize the sensitivity, the following conditions must be satisfied: (1) both modifier enzymes must act under conditions of near saturation; (2) the effector must act on both of them in opposite directions; (3) it must alter the apparent values of their catalytic constants; (4) the enzyme subject to inhibition by the effector must respond at much lower effector concentrations than the enzyme subject to activation. As the last of these conditions appears to be counter-intuitive, it suggests that feeble activation of modifier enzymes in real systems may have passed unnoticed, or been dismissed as physiologically insignificant, although in reality crucial to the effective response of the system.

Animals↗
PubMed1988

Significance of the purine-pyrimidine motif present in most gene groups.

The probability of the sequence YRY(Ni)YRY occurring most frequently with the same i value in seven out of nine gene classes is reassessed and found to be about 1.3 X 10(-8), more than 4000 times greater than the value calculated by Arquès & Michel (1987), but still much too small for chance to be a reasonable explanation for the observation. Even if the sequence YRYNNNNNNYRY were very frequent in the most primitive genes, it would not have survived in a recognizable form to the present day if it were selectively neutral. However, if it is selectively favoured one would expect it to exist regardless of whether it was present in primitive genes.

Animals↗
PubMed1987

Kinetics of hexokinase D ('glucokinase') with inosine triphosphate as phosphate donor. Loss of kinetic co-operativity with respect to glucose.

When ATP, the normal phosphate donor for hexokinase D ('glucokinase'), is replaced by ITP, the positive co-operativity with respect to glucose disappears. This may be rationalized in relation to kinetic models for hexokinase D co-operativity, which assume that with the normal substrates the chemical reaction and subsequent release of products occur so rapidly that binding of substrates cannot approach equilibrium and is therefore not constrained by the thermodynamic requirement that the Hill coefficient for substrate binding cannot exceed the number of binding sites. ITP is a much poorer substrate than ATP, however: its Km value at high glucose concentrations is 24 times the value for ATP, whereas the value of the limiting rate V is decreased about 8-fold. Consequently it is no longer possible for the ternary complex to be converted into products rapidly enough to generate kinetic co-operativity. The negative co-operativity with respect to glucose observed in 2H2O with ATP as phosphate donor also disappears when ITP is used instead of ATP.

Animals↗
PubMed1987

Dominance is not inevitable.

In a diploid organism, a mutant gene that results in elimination of an enzyme activity in the homozygote is almost universally found to be recessive, so that the heterozygote phenotype is virtually indistinguishable from the wild type. It has been argued (H. Kacser & J. A. Burns, Genetics 97, 639-666 (1981)) that there is no need to look to evolution for an explanation of this phenomenon, as it is an inevitable consequence of the low control coefficients for metabolic flux possessed by nearly all enzymes. However, it is possible to envisage pathways in which every enzyme is more than half-saturated, so that moderate changes in the concentration of any enzyme result in substantial changes in metabolic flux. Such behaviour can occur, for example, if the limiting rates of the enzymes decrease as one proceeds along the pathway and the precursor concentration is large compared with the Michaelis constants of all the enzymes. Consequently one does require an explanation in terms of natural selection of why such pathways are apparently not observed in nature.

Computer Simulation↗