Biomedical subjects

S Schuster

Publications and source records attributed to S Schuster.

At least 55 records · Page 3Linked to original sources

PubMed1998

Control analysis of metabolic systems involving quasi-equilibrium reactions.

Reactions for which the rates are extremely sensitive to changes in the concentrations of variable metabolite concentrations contribute little to the control of biochemical reaction networks. Yet they do interfere with the calculation of the system's behaviour, both in terms of numerical integration of the rate equations and in terms of the analysis of metabolic control. We here present a way to solve this problem systematically for systems with time hierarchies. We identify the fast reactions and fast metabolites, group them apart from the other ("slow") reactions and metabolites, and then apply the appropriate quasi-equilibrium condition for the fast subsystem. This then makes it possible to eliminate the fast reactions and their elasticity coefficients from the calculations, allowing the calculation of the control coefficients of the slow reactions in terms of the elasticity coefficients of the slow reactions. As expected, the elasticity coefficients of the fast reactions drop out of the calculations, and they are irrelevant for control at the time resolution of the steady state of the slow reactions. The analysis, when applied iteratively, is expected to be particularly valuable for the control analysis of living cells, where a time hierarchy exists, the fastest being at the level of enzyme kinetics and the slowest at gene expression.

Cells↗

PubMed1998

Impact of early risk stratification on the length of hospitalization in patients with acute Q-wave myocardial infarction. 'The 60-minutes myocardial infarction project'.

UNLABELLED: An assessment of individual risk factors may identify a subgroup of postinfarction patients at low risk, i.e. patients appropriate for early discharge. Using a large unselected population of the national registry, 'The 60-Minutes Myocardial Infarction Project', we (1) attempted to provide a retrospective analysis of clinical factors and in-hospital mortality in a population living on the 6th hospital day following admission to define a low-risk patient group with a residual in-hospital mortality of less than 1% eligible for early discharge, and (2) to analyze the current impact of risk stratification based on these clinical factors on the length of hospitalization. The study group consisted of 12,045 survivors on the 6th day after admission out of 14,980 patients of the registry with proven Q-wave myocardial infarction. Risk modeling was performed with multiple logistic regression. RESULTS: A total of 873 patients (7.3%) died after day 6 in hospital. The most important prognostic factors were cardiopulmonary resuscitation prior to admission (odds ratio, OR: 7.2, confidence interval, CI: 5.11-10.22), thrombolysis complicated by severe bleedings (OR: 6.2, CI: 1.2-31. 2) and age >70 years (OR 4.7, CI 3.51-6.39). The other more significant independent predictors of increased mortality were end-stage renal disease, age between 56 and 70 years, systolic blood pressure <95 mm Hg on admission, history of trauma </=2 months, cancer and left-bundle-branch block. Summarizing these nine groups of patients with the strongest association to in-hospital mortality, we defined a high-risk group comprising 79% of the AMI patients with a residual in-hospital mortality of 8.8%. On the other hand, by excluding these nine high-risk patient groups, a low-risk group of 21% of all AMI patients seems to be appropriate for early discharge (residual in-hospital mortality = 1.07%). However, in the current practice, there was no difference regarding the median length of hospital stay between the two risk groups. The low-risk patients were hospitalized 20 days compared to 22 days in the high-risk patients. CONCLUSION: Using a simple logistic regression model, which considers clinical factors of the early hospital phase, one fifth of the infarction patients can be stratified to be at low risk, and might be eligible for early hospital discharge. Currently, an individual risk stratification has no impact on the length of hospital stay in Germany.

Aged↗

PubMed1998

Mitochondria as an important factor in the maintenance of constant amplitudes of cytosolic calcium oscillations.

Theoretical models of intracellular calcium oscillations have hitherto focused on the endoplasmic reticulum (ER) as an internal calcium store. These models reproduced the large variability in oscillation frequency observed experimentally. In the present contribution, we extend our earlier model [Marhl et al., Biophys. Chem., 63 (1997) 221] by including, in addition to the ER, mitochondria as calcium stores. Simple plausible rate laws are used for the calcium uptake into, and release from, the mitochondria. It is demonstrated with the help of this extended model that mitochondria are likely to act in favour of frequency encoding by enabling the maintenance of fairly constant amplitudes over wide ranges of frequency.

Calcium Signaling↗

PubMed1997

Influence of the global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO-1) trial on the use of thrombolytics in Germany. ALKK Study Group. Arbeitsgemeinschaft der Leitenden Kardiologischen Krankenhausärtze.

Our results show significant and independent influence of the GUSTO-1 trial on the use of recombinant tissue plasminogen activator in acute myocardial infarction in Germany. This influence started soon after the publication of the trial and was not restricted to subgroups who benefitted most from recombinant tissue plasminogen activator.

Aged↗

PubMed1997

Modeling the interrelations between the calcium oscillations and ER membrane potential oscillations.

A refined electrochemical model accounting for intracellular calcium oscillations and their interrelations with oscillations of the potential difference across the membrane of the endoplasmic reticulum (ER) or other intracellular calcium stores is established. The ATP dependent uptake of Ca2+ from the cytosol into the ER, the Ca2+ release from the ER through channels following a calcium-induced calcium release mechanism, and a potential-dependent Ca2+ leak flux out of the ER are included in the model and described by plausible rate laws. The binding of calcium to specific proteins such as calmodulin is taken into account. The quasi-electroneutrality condition allows us to express the transmembrane potential in terms of the concentrations of cytosolic calcium and free binding sites on proteins, which are the two independent variables of the model. We include monovalent ions in the model, because they make up a considerable portion in the balance of electroneutrality. As the permeability of the endoplasmic membrane for these ions is much higher than that for calcium ions, we assume the former to be in Nernst equilibrium. A stability analysis of the steady-state solutions (which are unique or multiple depending on parameter values) is carried out and the Hopf bifurcation leading from stable steady states to self-sustained oscillations is analysed with the help of appropriate mathematical techniques. The oscillations obtained by numerical integration exhibit the typical spike-like shape found in experiments and reasonable values of frequency and amplitude. The model describes the process of switching between stationary and pulsatile regimes as well as changes in oscillation frequency upon parameter changes. It turns out that calcium oscillations can arise without a permanent influx of calcium into the cell, when a calcium-buffering system such as calmodulin is included.

Animals↗

PubMed1997

[Direct dilatation and emergency bypass operation of main branch occlusion in acute anterior wall infarct and cardiogenic shock].

Occlusion of the left main coronary artery (LMCA) is the cause of myocardial infarction in about 0.04%. Those patients who do not die during the acute phase often do have a dominant right coronary artery with extensive collaterals to the left coronary artery. Because this is a very rare situation there are only some cases reports dealing with the management of these patients. A 60 years old woman was admitted to our hospital with the signs of an acute Q-wave anterior myocardial infarction. Within a few minutes after the arrival she developed a cardiogenic shock. Coronary angiography was performed immediately. The left main coronary artery was occluded and a big right coronary artery showed a significant stenosis. There were many collaterals from the right coronary artery supplying the left coronary artery. After information of the cardiac surgeons, primary angioplasty of the LMCA was performed in order to achieve hemodynamic stabilisation and to relieve symptoms. Reperfusion of the left anterior descendent coronary artery (LAD) could be achieved within 30 minutes. This led to hemodynamic stabilisation of the patient. But a significant residual stenosis of the LMCA remained and the circumflex artery was still occluded. In the meanwhile cardiac surgery was able to be performed and so the patient was transferred to surgery without further dilatation or stent implantation. Four venous grafts (LAD, first diagonal branch, circumflex artery and right coronary artery) were inserted. After 4 weeks the patient was in a good shape and could be discharged at home. Primary angioplasty seems to be an effective treatment in patients with acute myocardial infarction and an occlusion of the LMCA. But coronary bypass surgery is nearly almost necessary during the following period in order to achieve complete revascularisation and to improve survival.

Angioplasty, Balloon, Coronary↗

PubMed1997

Regulatory O2 tensions for the synthesis of fermentation products in Escherichia coli and relation to aerobic respiration.

In an oxystat, the synthesis of the fermentation products formate, acetate, ethanol, lactate, and succinate of Escherichia coli was studied as a function of the O2 tension (pO2) in the medium. The pO2 values that gave rise to half-maximal synthesis of the products (pO0. 5) were 0.2-0.4 mbar for ethanol, acetate, and succinate, and 1 mbar for formate. The pO0.5 for the expression of the adhE gene encoding alcohol dehydrogenase was approximately 0.8 mbar. Thus, the pO2 for the onset of fermentation was distinctly lower than that for anaerobic respiration (pO0.5 </= 5 mbar), which was determined earlier. An essential role for quinol oxidase bd in microaerobic growth was demonstrated. A mutant deficient for quinol oxidase bd produced lactate as a fermentation product during growth at microoxic conditions (approximately 10 mbar O2), in contrast to the wild-type or a quinol-oxidase-bo-deficient strain. In the presence of nitrate, the amount of lactate was largely decreased. Therefore, under microoxic conditions, the pO2 appears to be too high for (mixed acid) fermentation to function and too low for aerobic respiration by quinol oxidase bo.

Acetates↗

PubMed1997

[Early treatment of acute myocardial infarct: implementation of therapy guidelines in routine clinical practice, MITRA pilot phase].

The prognostic value of thrombolytics, aspirin, beta-blockers and ACE-inhibitors has been well documented in large clinical trials, but the application of these drugs in clinical practice is not known. MITRA is a multicenter study of 54 hospitals in a defined region in southwest Germany. The aim is to document actual clinical practice (pilot phase) and to establish an individually optimised prognostic therapy for acute myocardial infarction, considering only the absolute contraindications for each drug. In the pilot phase, 1303 consecutive patients with acute transmural myocardial infarction were enrolled. The median age was 66 years, the prehospital time was 2.7 hours. 47% had an anterior infarction. In the subgroup of patients without absolute contraindications, only 53.4% were treated with thrombolytics, 87.6% with aspirin, 37.1% with beta-blocker, and 17.4% with ACE-inhibitor. Out of these, patients were classified as "optimally treated" if they received thrombolysis, aspirin as well as beta-blocker. Patients were also included if any of these medications was withheld in the presence of absolute contraindications. Treatment was defined suboptimal, if the patients did not receive any of these three medications despite the absence of absolute contraindications. Only 29% (n = 383) received an optimal post-infarction therapy and 71% (n = 775) a suboptimal treatment. The univariate analysis revealed 10 variables influencing optimal therapy. In this subgroup patients were younger, they more often had clear ECG-findings or left bundle branch block, an anterior infarction, acute cardiac failure, AV-block, bradycardia, recent trauma or surgery (less then 2 weeks) and a severe chronic obstructive lung disease. The prehospital time was more often available. Early mortality after 2 days was 5.0% versus 9.3% in the suboptimal treated patients (OR: 0.5, CI: 0.30-0.86) the total inhospital mortality was 10.9% in the optimal versus 17.7% in the suboptimal group (OR: 0.6, CI: 0.38-0.84). In a multivariate analysis the parameter "optimal treatment" was found to be an independent predictor of the early (OR = 0.4; CI: 0.20-0.69) and the inhospital mortality (OR = 0.4; CI: 0.25-0.64). The following in-hospital events occurred: stroke 2.8%, reinfarction 12.9%, cardiac failure 21.5%, cardiogenic shock 10.4% and in-hospital mortality 18.1% (2-days mortality 9.5%). Pharmacological therapy for acute myocardial infarction is inconsistent with the recommendations suggested in recent clinical trials and needs to be individually optimised. Optimal treatment is an independent predictor of early and inhospital mortality.

Adrenergic beta-Antagonists↗

PubMed1997

[Balloon dilatation in acute myocardial infarct in routine clinical practice: results of the register of the Working Society of Leading Cardiologic Hospital Physicians in 4,625 patients].

Balloon angioplasty as the treatment of first choice in the setting of an acute myocardial infarction (AMI) is gaining widespread acceptance because of favourable results from specialised centres concerning high patency rates and low mortality. This study reports the results of angioplasty for AMI at large community hospitals during 1992-1995. 4625 procedures were performed at 68 centres of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK). The age of the patients was 60.8 +/- 11.3 years, with 75.1% men. The infarct related artery was the left anterior descendent in 43%, the right coronary artery in 37%, the circumflex artery in 16%, a bypass graft in 2.3% and the left main stem in 1.4% of patients. The success rate (residual stenosis < 50%) of the intervention was 86%. There was a wide range of procedures per centre, with a median of 40 AMI angioplasties per year and centre. The amount of angioplasties for AMI in relation to all angioplasties performed during this period rose from 5.2% in 1992 to 5.9% in 1995 (p = 0.01). Local complications at the puncture site occurred in 3.2%, with the need for a surgical intervention in 1.1% of patients. In 273 (5.9%) of the patients a second angioplasty was performed during the hospital stay. Aortocoronary bypass surgery was performed in 3% of the patients. Hospital mortality was 9.5% (438/4625 patients). The mortality rate remained constant during the years investigated (1992: 10.6%; 1993: 8.6%; 1994: 9.7%; 1995: 9.8%; p = ns). Higher mortality was observed in older patients, patients with multiple vessel disease, the left anterior descending artery or a bypass graft as infarct related artery as well as in patients with failed reperfusion (residual stenoses > 50%). Hospitals with a case load of more than 40 angioplasties for AMI per year showed a lower mortality as compared to the others. In clinical practice at large community hospitals results of angioplasty for AMI concerning mortality, complications and technical success rate are comparable to those of highly specialised centres. The absolute numbers of angioplasties for AMI increased constantly over the years.

Aged↗

PubMed1997

Intravascular ultrasound in patients with acute pulmonary embolism after treatment with intravenous urokinase and high-dose heparin.

OBJECTIVE: To compare the diagnostic value of intravascular ultrasound (IVUS) with angiography in patients with pulmonary embolism. DESIGN: Open, prospective clinical study. SETTING: Two university hospitals. PATIENTS: Angiography and IVUS were used in 11 patients (5 men) (mean (SD) age 50 (18) years) with acute pulmonary embolism. INTERVENTIONS: At a mean (SD) of 6 (4) hours after thrombolytic therapy with urokinase and full-dose heparin, all patients underwent pulmonary artery angiography. Then 3.5 F mechanical, 20 or 30 MHz IVUS catheters were advanced into the pulmonary circulation. MAIN OUTCOME MEASURES: The pulmonary circulation was studied by both methods to detect the presence of thrombus, and a modified Miller score (assessing perfusion defects only and not velocity of flow) was used to quantify the angiographic images. RESULTS: The modified Miller score was mean (SD) 7.4 (2.3) points. 168 pulmonary artery segments (diameter range 2-14 mm) were studied by angiography and IVUS. On angiography, seven segments showed complete obstruction and 49 partial obstruction; 112 were normal. Two distinct types of thrombus formation were found by IVUS. Type A thrombus only partly adhered to the wall but otherwise was mobile and type B predominantly adhered to the wall. IVUS confirmed all seven angiographically complete obstructions but missed three (6%) of the 49 partial occlusions. Forty (87%) of the remaining 46 segments had type A thrombus and six (13%) type B. IVUS indicated a thrombus in 38 (34%) of the 112 angiographically normal segments; 20 (53%) showed a type A pattern and 18 (47%) a type B pattern (P < 0.001). CONCLUSION: IVUS was more sensitive than angiography in detecting thrombus but the clinical impact of this finding is not clear as yet.

Acute Disease↗

PubMed1997

Processing of artificial visual feedback in the walking fruit fly Drosophila melanogaster.

A computerized 360 degrees panorama allowed us to suppress most of the locomotion-induced visual feedback of a freely walking fly without neutralizing its mechanosensory system ('virtual open-loop' conditions). This novel paradigm achieves control over the fly's visual input by continuously evaluating its actual position and orientation. In experiments with natural visual feedback (closed-loop conditions), the optomotor turning induced by horizontal pattern motion in freely walking Drosophila melanogaster increased with the contrast and brightness of the stimulus. Conspicuously striped patterns were followed with variable speed but often without significant overall slippage. Using standard open-loop conditions in stationary walking flies and virtual open-loop or closed-loop conditions in freely walking flies, we compared horizontal turning induced by either horizontal or vertical motion of appropriately oriented rhombic figures. We found (i) that horizontal displacements and the horizontal-motion illusion induced by vertical displacements of the oblique edges of the rhombic figures elicited equivalent open-loop turning responses; (ii) that locomotion-induced visual feedback from the vertical edges of the rhombic figures in a stationary horizontal position diminished the closed-loop turning elicited by vertical displacements to only one-fifth of the response to horizontal displacements; and (iii) that virtual open-loop responses of mobile flies and open-loop responses of immobilized flies were equivalent in spite of delays of up to 0.1 s in the generation of the virtual stimulus. Horizontal compensatory turning upon vertical displacements of oblique edges is quantitatively consistent with the direction-selective summation of signals from an array of elementary motion detectors for the horizontal stimulus components within their narrow receptive fields. A compensation of the aperture-induced ambiguity can be excluded under these conditions. However, locomotion-induced visual feedback greatly diminished the horizontal-motion illusion in a freely walking fly. The illusion was used to assay the quality of open-loop simulation in the new paradigm.

Animals↗

PubMed1997

Corneal endothelial hyaluronidase: a role in anterior chamber hyaluronic acid catabolism.

The possible role of the human corneal endothelium in the turnover of anterior chamber hyaluronic acid (HA) was investigated. Hyaluronidase, an endoglycosidase that degrades HA and other glycosaminoglycans, is thought to play a role in HA homeostasis. The presence of hyaluronidase in the corneal endothelium was demonstrated immunohistochemically in sections from normal adult human cornea. Additionally, by using a modified enzyme-linked immunosorbent assay-like assay, active hyaluronidase was detected in the supernatant from primary culture human corneal endothelial cells. The optimal activity for the corneal endothelial hyaluronidase was in the acid range (pH 4.0), similar to previously isolated lysosomal hyaluronidase. Further immunohistochemistry showed that the corneal endothelial cells also express CD44, the receptor for HA, which would allow endocytosis of HA. Human corneal endothelial hyaluronidase may play a role in normal anterior segment HA metabolism and in the degradation of highly concentrated HA used as a visco-elastic.

Adult↗

PubMed1996

Postinfarction stress testing and one year outcome of stable patients after myocardial infarction treated with thrombolytics.

OBJECTIVE: The purpose of our study was to evaluate the predictive power of early postinfarction stress testing in survivors of uncomplicated MI treated with thrombolytics. METHODS: The study population consisted of 102 consecutive, thrombolyzed survivors (56 +/- 11 years) of acute, transmural myocardial infarction with uncomplicated postinfarction course. All patients were clinically stable in the postinfarction period and underwent cycle ergometry, 99mTc perfusion scintigraphy and dobutamine stress-echocardiography within three weeks after the acute event. Coronary angiography was used to determine the extent of CAD, LV ejection fraction (LVEF), TIMI grade and residual stenosis of the infarct-related coronary artery. A follow up questionnaire was performed one year after hospital discharge to determine the relation to the occurrence of cardiac events (unstable angina, reinfarction, PTCA, bypass surgery and death). RESULTS: 30 patients developed 34 cardiac events. Four patients died. Two thirds of the 'cardiac events' in the year of follow-up were revascularization procedures mostly selected by evidence of ischemia on 99mTc perfusion scintigraphy and/or stress-echocardiography. These two methods were significantly associated with the development of new cardiac events (stress-echocardiography: p < 0.01; 99mTc perfusion scintigraphy: p < 0.006). Parameters of bicycle ergometry and variables of coronary angiography were not related to an increased risk of future cardiac events. The number of 'hard cardiac events'--death or nonfatal AMI--was too small (8%) in these patients who are able to exercise to make statistical comparisons. CONCLUSIONS: The study underlines the necessity of early noninvasive risk assessment to identify patients at a greater risk among survivors of uncomplicated AMI treated with thrombolytics who are clinically stable in the early postinfarction period. PTCA and coronary bypass surgery is performed in one third of these patients selected mostly by evidence of ischemia on 99mTc perfusion scintigraphy and/or stress-echocardiography. Results of bicycle ergometry are of limited value in these patients within the first year after acute myocardial infarction.

Coronary Angiography↗

PubMed1996

Control analysis in terms of generalized variables characterizing metabolic systems.

Metabolic Control Analysis had originally been devised to quantify the effects of changes in enzyme concentrations on steady-state fluxes and metabolite concentrations. In many situations, fluxes and concentrations are not the only relevant variables. A formalism is presented by which the control of generalized variables characterizing biochemical systems can be described. The concepts of "state variables" and "response variables" are introduced. Formulae linking generalized control coefficients to generalized elasticities are established. From these, unified summation and connectivity theorems are derived. These formulae result in some of the well-known equations of Metabolic Control Analysis as special cases when the variables are specified to concentrations or fluxes. It is shown that if the response variables only depend on the state variables or the reaction rates or both, control coefficients do not depend on the special choice of the perturbation parameters. This is no longer the case if the response variables do depend on the parameters directly. The formalism provides framework for dealing with proton-motive force, energy charge and many other variables as special cases. We illustrate the analysis by specifying it to the control analysis of concentration ratios, free-energy differences, transition times, and growth rate.

Animals↗

PubMed1996

Intraindividual comparison of three stress tests during the early postinfarction period in stable patients with thrombolysis.

The intention of the study was to intraindividually compare the ischemic yield of three stress tests early after acute myocardial infarction. At a large community hospital 107 stable patients who survived acute transmural myocardial infarction after thrombolytic therapy followed by an individual optimized medical treatment, were prospectively investigated by three noninvasive stress tests. All patients received bicycle ergometry, 99mTc perfusion scintigraphy and stress-echocardiography within three weeks after the acute event. Each patient underwent diagnostic cardiac catheterization for determination of angiographic data. 99mTc perfusion scintigraphy had the highest rate of positive test results (61%), as compared to bicycle ergometry (32%), stress echocardiography (34%) and stress induced angina in any of the stress tests performed (40%). In 79% of the patients studied, at least one of four ischemic parameters was positive. The combination of bicycle ergometry, stress induced angina and 99mTc perfusion scintigraphy detected myocardial ischemia in 78% of the patients studied. Concordance of at least three positive parameters was seen in only 27%. Intraindividual comparison between positive and negative test results was inconclusive. Only stress-echocardiography versus stress-induced angina showed a moderate agreement (kappa = 0.44). Stress-induced angina was the only ischemic parameter which corresponded to the grade of the residual stenosis of the infarct related coronary artery (p < 0.01) and reduced left ventricular function (p < 0.005). These findings show, that concordance of three common stress tests in detecting myocardial ischemia anywhere in patients after acute transmural myocardial infarction and thrombolytic therapy is poor. Stress-echocardiography and stress inducible angina show a moderate agreement. Follow-up studies of these patients are currently performed to clarify prognostic significance and therapeutic consequences of positive test results in these patients.

Angina Pectoris↗

PubMed1996

How to recognize monofunctional units in a metabolic system.

In intracellular metabolic networks, it is often useful to discern subsystems (modules) of which the metabolites are only produced or consumed by reactions within that subsystem or by a limited number of fluxes crossing the borders of the subsystem. In many cases such subsystems function as units with respect to their effect on the remainder of the system. In this paper we show that the co-response of two metabolic variables outside that subsystem to a perturbation of a subsystem reaction does not depend on which subsystem reaction is perturbed if three conditions are fulfilled: (1) the reactions outside the subsystem are not affected directly by metabolites belonging to the subsystem; (2) there are no conservation relations linking the subsystem to the rest; and (3) the subsystem is linked to the remainder of the system only via one degree of freedom in fluxes. We propose the name "monofunctional units" for subsystems fulfilling these three criteria. Identification of such units greatly simplifies metabolic control analysis. Only one reaction per unit needs to be perturbed to analyse control in the system. Difficulties, such as the inaccessibility of some reactions to experimental perturbation, may be circumvented by perturbing another reaction within the unit that leads to the same co-response coefficients. The analysis can also serve to identify unsuspected regulatory interactions in the metabolic network. The differences in the behaviour between metabolic units and other types of subsystems are illustrated by numerical examples.

Animals↗

PubMed1995

Composite control of cell function: metabolic pathways behaving as single control units.

This paper shows that under some conditions the control exerted by a part of a metabolic network (a pathway) on a flux or concentration in any other part can be described through a single (overall) control coefficient. This has the following implications: (i) the relative contributions of a pathway enzyme to the regulation of the pathway (output) flux and of any flux or concentration outside are identical; therefore, the control analysis of the pathway 'in isolation' allows one to determine the control exerted by any pathway enzyme on the rest of the cell by estimation of the control efficient of just one, arbitrarily chosen enzyme; (ii) the relative control of any two metabolic variables outside the pathway (measured as the ratio of the control coefficients over these two variables outside) is the same for all pathway enzymes. These properties allow one to substitute effectively a pathway by a single (super)reaction and make it possible to consider such a pathway as a metabolic unit within the cellular enzyme network.

Cells↗

PubMed1995

Defining control coefficients in non-ideal metabolic pathways.

The extent to which an enzyme controls a flux has been defined as the effect on that flux of a small modulation of the activity of that enzyme divided by the magnitude of the modulation. We here show that in pathways with metabolic channelling or high enzyme concentrations and conserved moieties involving both enzymic and non-enzymic species, this definition is ambiguous; the magnitude of the corresponding flux control coefficient depends on how the enzyme activity is modulated. This is illustrated with two models of biochemically relevant pathways, one in which dynamic metabolite channelling plays a role, and one with a moiety-conserved cycle. To avoid such ambiguity, we view biochemical pathways in a more detailed manner, i.e., as a network of elemental steps. We define 'elemental control coefficients' in terms of the effect on a flux of an equal modulation of the forward and reverse rate constant of any such elemental step (which may correspond to transitions between enzyme states). This elemental control coefficient is independent of the method of modulation. We show how metabolic control analysis can proceed when formulated in terms of the elemental control coefficients and how the traditional control coefficients are related to these elemental control coefficients. An 'impact' control coefficient is defined which quantifies the effect of an activation of all elemental processes in which an enzyme is involved. It equals the sum of the corresponding elemental control coefficients. In ideal metabolic pathways this impact control coefficient reduces to the traditional flux control coefficient. Differences between the traditional control coefficients are indicative of non-ideality of a metabolic pathway, i.e. of channelling or high enzyme concentrations.

Journal Article↗