Search PubMed⌕ Search

Biomedical subjects

D A Fell

Publications and source records attributed to D A Fell.

At least 55 records · Page 3Linked to original sources
PubMed1990

Metabolic control analysis of mammalian serine metabolism.

(1) Mammalian serine metabolism is discussed in relation to its synthesis and utilization in proliferating cells, particularly during the nonmalignant proliferation of lymphocytes. (2) An analysis of the control of serine biosynthesis de novo under conditions of high pathway flux has been carried out using metabolic control theory. (3) The important and novel conclusions are that control of pathway flux is localized exclusively at the final step of this biosynthetic pathway, phosphoserine phosphatase. This conclusion challenges the frequently stated maxim that control of biosynthetic pathways is always directed at the first pathway enzyme in a sequence. In the case of phosphoserine phosphatase, the enzyme is inhibited uncompetitively by its product serine, and this feedback control mechanism has the most significant controlling influence on overall pathway flux. Thus, the serine biosynthesis pathway, under these conditions, is controlled by product demand (serine utilization) and not by substrate supply (glycolytic provision of 3-phosphoglycerate), despite the high rate of glycolysis associated with cell proliferation. (4) The control structure of the pathway is not immutable. As has been observed with other pathways analyzed by metabolic control theory, the key points of control in the pathway can shift according to physiological circumstances. At low pathway flux, the control of serine biosynthesis is shared between all the component enzymes of the pathway, and the responsiveness of flux shifts from product demand to substrate supply. (5) Serine utilization has been studied in mitogenically-stimulated human peripheral lymphocytes. Cell proliferation and serine utilization for nucleic acid synthesis have been shown to be responsive to serine concentrations in the normal plasma range. (6) It is concluded that the maintenance of normal plasma serine concentrations is an important factor in the rate of lymphocyte proliferation and hence the effectiveness with which the body can mount an immune response to an antigenic challenge, such as in infection.

Animals↗
PubMed1990

Metabolic control analysis by computer: progress and prospects.

In metabolic control analysis, the set of rules called the matrix method simplifies writing the matrix equation that relates the control coefficients to elasticities of enzymes, and a subset of the velocities and substrate concentrations in a metabolic system. However, since the process of writing and solving these equations can be clearly defined, a computer program is being produced that will write the equations for the control coefficients given only the reactions of the metabolic system. In this way, the results of metabolic control analysis can be made available to all those who can use them, even if they do not know the theory in detail. The computational strategies underlying such a program, and the similarities to a biochemical simulation program developed previously are described.

Algorithms↗
PubMed1989

The matrix method of metabolic control analysis: its validity for complex pathway structures.

The sensitivities of the variables of a metabolic system (such as fluxes and concentrations) to variations in enzyme concentration are expressed in metabolic control analysis as control coefficients. The matrix method is a system of writing matrix equations that generate expressions for the control coefficients in terms of the characteristics of the components (principally the enzymes). Previously, the matrix method has been considered in terms of simple pathway structures; here we justify its applicability to complex pathways, such as those with multiple branches. It is shown that this requires modification of the branch point relationship to take account of changes of flux along the limbs of the branch and of stoichiometric factors. The method of deriving the flux control coefficients with respect to different fluxes in the system is extended to cope with these circumstances.

Animals↗
PubMed1988

Control analysis of mammalian serine biosynthesis. Feedback inhibition on the final step.

The flux of serine biosynthesis in the liver of the normal rabbit, and of the rat on a low protein diet, is most sensitive to the activity of phosphoserine phosphatase (flux control coefficient up to 0.97), the last of the three enzymes in the pathway after it branches from glycolysis. The concentration of the pathway product, serine, has a strong controlling influence on the flux (response coefficient up to -0.64) through feedback inhibition at this step. The pathway is therefore controlled primarily by the demand for serine rather than the supply of the pathway precursor, 3-phosphoglycerate. Under conditions where there is a lower biosynthetic flux, the flux control coefficients of the first two enzymes of the pathway are increased, and are probably dominant in the rat on a normal diet. In rabbit liver, when ethanol is used to inhibit serine biosynthesis, control can be distributed between the three enzymes, even though the reactions catalysed by the first two remain close to equilibrium. Apart from their intrinsic value in aiding the understanding of the regulation of mammalian serine metabolism, our findings illustrate the danger of assuming that there are invariant design principles in the regulation of metabolic pathways, such as feedback control on the first step after a branch.

Animals↗
PubMed1987

Metabolic control and its analysis. Extensions to the theory and matrix method.

The matrix algebra procedure for determining the flux control coefficients of enzymes in metabolic pathways has been extended to allow determination of the concentration control coefficients. Although it is shown that the procedure is essentially unchanged in most cases, the presence of moiety-conserved cycles in a pathway places additional limitations on the form of the equations that can be used in the matrix formulation for concentration control coefficients. In the case of branched pathways, a new coefficient has been defined, the branch distribution control coefficient, which can be obtained via the matrix procedure. Thus a single matrix equation permits calculation or algebraic evaluation of the control coefficients for flux, concentration and distribution of flux at branches, so that the complete response of a pathway to alteration of enzyme content, or to modulation by an effector, can be determined. The relationships have been determined between flux control coefficients in isolated sections of metabolic pathways and the coefficients for the same enzymes when part of a larger metabolic system. It is shown that the control analysis of the isolated system provides useful information towards determining the control properties of the extended system.

Enzymes↗
PubMed1986

Fat synthesis in adipose tissue. An examination of stoichiometric constraints.

The requirement for net balance of synthesis, degradation and transport for all intermediates in the pathways from glucose to fat imposes constraints on the balance of fluxes between different pathways. Linear programming has been used to examine the interactions between these constraints on metabolism in adipocytes and the requirement for efficiency in the conversion of glucose into fat. The circumstances under which excessive ATP synthesis would accompany this conversion have been investigated.

Adipose Tissue↗
PubMed1985

Metabolic control and its analysis. Additional relationships between elasticities and control coefficients.

Existing theorems from the analysis of metabolic control have been taken and embedded in a simple matrix algebra procedure for calculating the flux control coefficients of enzymes (formerly known as sensitivities) in a metabolic pathway from their kinetic properties (their elasticities). New theorems governing the flux control coefficients of branched pathways and substrate cycles have been derived to allow the procedure to be applied to complex pathway configurations. Modifications to the elasticity terms used in the equations have been theoretically justified so that the method remains valid for pathways with conserved metabolites (for example, the adenine nucleotide pool or the intermediates of a catalytic cycle such as the tricarboxylic acid cycle) or with pools of metabolites kept very near to equilibrium by very rapid reactions. The matrix equations generated using these theorems and relationships may be solved algebraically or numerically. Algebraic solutions have been used to determine the factors responsible for the degree of amplification of flux control coefficients by substrate cycles and to show that it is possible to derive expressions for the elasticities of a group of enzymes.

Biological Transport↗
PubMed1982

Subunit interactions and catalytic activity of triose phosphate isomerase.

Rabbit and chicken triose phosphate isomerase were labelled with iodo-(1-14C)-acetamide. The efficiencies of renaturation after denaturation in guanidinium chloride were similar to those of the unlabelled enzymes. The enzymes were immobilised to Sepharose 4B and after guanidinium treatment only immobilised monomers remained on the gel. Hybridisation studies demonstrated that the dimeric form could be reformed on the denatured gels with recovery of the original specific activity. Under similar conditions formation of rabbit-chicken dimers were observed. However, competition studies demonstrated a preferential formation of the homogeneous dimers.

Animals↗
PubMed1980

Surgical versus nonsurgical management of metastatic melanoma of the brain.

A retrospective analysis of 80 patients with cerebral metastases from melanoma revealed that 42 patients in whom the metastases were excised experienced a median survival of 5 months, in comparison with a 6-week median survival for 38 patients who were not operated upon. The same survival figures applied when comparing only patients with known Stage 4 disease at the time of diagnosis of the brain metastasis. The surgical mortality rate was 9.5% for the entire series and 5.4% for the 37 patients treated surgically since 1960.

Adolescent↗
PubMed1979

The breakdown of 2,3-bis(phospho)-D-glycerate by Fe(III)-haemoglobin.

Fe(III)-haemoglobin is shown to catalyse the hydrolysis of 2,3-bis(phospho)-D-glycerate to Pi and 3-phosphoglycerate, although the rate is slow, even when the protein is present at concentrations in the millimolar range. The rate of hydrolysis is proportional to the subtrate concentration up to at least 10 mM, so if the process is enzymic, the Km must be high.

Diphosphoglyceric Acids↗