38 results on '"ENZYME DEFICIENCIES"'
Search Results
2. Pathophysiological Role of Purines and Pyrimidines in Neurodevelopment: Unveiling New Pharmacological Approaches to Congenital Brain Diseases
- Author
-
Marta Fumagalli, Davide Lecca, Maria P. Abbracchio, and Stefania Ceruti
- Subjects
neurodevelopmental disorders ,purine metabolism ,enzyme deficiencies ,adenosine ,purine salvage pathway ,P2X7 receptors ,Therapeutics. Pharmacology ,RM1-950 - Abstract
In recent years, a substantial body of evidence has emerged demonstrating that purine and pyrimidine synthesis and metabolism play major roles in controlling embryonic and fetal development and organogenesis. Dynamic and time-dependent changes in the expression of purine metabolizing enzymes (such as ectonucleotidases and adenosine deaminase) represent a key checkpoint for the correct sequential generation of the different signaling molecules, that in turn activate their specific membrane receptors. In neurodevelopment, Ca2+ release from radial glia mediated by P2Y1 purinergic receptors is fundamental to allow neuroblast migration along radial glia processes, and their correct positioning in the different layers of the developing neocortex. Moreover, ATP is involved in the development of synaptic transmission and contributes to the establishment of functional neuronal networks in the developing brain. Additionally, several purinergic receptors (spanning from adenosine to P2X and P2Y receptor subtypes) are differentially expressed by neural stem cells, depending on their maturation stage, and their activation tightly regulates cell proliferation and differentiation to either neurons or glial cells, as well as their correct colonization of the developing telencephalon. The purinergic control of neurodevelopment is not limited to prenatal life, but is maintained in postnatal life, when it plays fundamental roles in controlling oligodendrocyte maturation from precursors and their terminal differentiation to fully myelinating cells. Based on the above-mentioned and other literature evidence, it is now increasingly clear that any defect altering the tight regulation of purinergic transmission and of purine and pyrimidine metabolism during pre- and post-natal brain development may translate into functional deficits, which could be at the basis of severe pathologies characterized by mental retardation or other disturbances. This can occur either at the level of the recruitment and/or signaling of specific nucleotide or nucleoside receptors or through genetic alterations in key steps of the purine salvage pathway. In this review, we have provided a critical analysis of what is currently known on the pathophysiological role of purines and pyrimidines during brain development with the aim of unveiling new future strategies for pharmacological intervention in different neurodevelopmental disorders.
- Published
- 2017
- Full Text
- View/download PDF
3. Pathophysiological Role of Purines and Pyrimidines in Neurodevelopment: Unveiling New Pharmacological Approaches to Congenital Brain Diseases.
- Author
-
Fumagalli, Marta, Lecca, Davide, Abbracchio, Maria P., and Ceruti, Stefania
- Subjects
PURINES ,BRAIN diseases ,PYRIMIDINES - Abstract
In recent years, a substantial body of evidence has emerged demonstrating that purine and pyrimidine synthesis and metabolism play major roles in controlling embryonic and fetal development and organogenesis. Dynamic and time-dependent changes in the expression of purine metabolizing enzymes (such as ectonucleotidases and adenosine deaminase) represent a key checkpoint for the correct sequential generation of the different signaling molecules, that in turn activate their specific membrane receptors. In neurodevelopment, Ca
2+ release from radial glia mediated by P2Y1 purinergic receptors is fundamental to allow neuroblast migration along radial glia processes, and their correct positioning in the different layers of the developing neocortex. Moreover, ATP is involved in the development of synaptic transmission and contributes to the establishment of functional neuronal networks in the developing brain. Additionally, several purinergic receptors (spanning from adenosine to P2X and P2Y receptor subtypes) are differentially expressed by neural stem cells, depending on their maturation stage, and their activation tightly regulates cell proliferation and differentiation to either neurons or glial cells, as well as their correct colonization of the developing telencephalon. The purinergic control of neurodevelopment is not limited to prenatal life, but is maintained in postnatal life, when it plays fundamental roles in controlling oligodendrocyte maturation from precursors and their terminal differentiation to fully myelinating cells. Based on the above-mentioned and other literature evidence, it is now increasingly clear that any defect altering the tight regulation of purinergic transmission and of purine and pyrimidine metabolism during pre- and post-natal brain developmentmay translate into functional deficits, which could be at the basis of severe pathologies characterized by mental retardation or other disturbances. This can occur either at the level of the recruitment and/or signaling of specific nucleotide or nucleoside receptors or through genetic alterations in key steps of the purine salvage pathway. In this review, we have provided a critical analysis of what is currently known on the pathophysiological role of purines and pyrimidines during brain development with the aim of unveiling new future strategies for pharmacological intervention in different neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
4. Human disorders of peroxisome metabolism and biogenesis.
- Author
-
Waterham, Hans R., Ferdinandusse, Sacha, and Wanders, Ronald J.A.
- Subjects
- *
PEROXISOMES , *PEROXISOMAL disorders , *FATTY acid oxidation , *ENZYME deficiency , *PLASMALOGENS - Abstract
Peroxisomes are dynamic organelles that play an essential role in a variety of cellular catabolic and anabolic metabolic pathways, including fatty acid alpha- and beta-oxidation, and plasmalogen and bile acid synthesis. Defects in genes encoding peroxisomal proteins can result in a large variety of peroxisomal disorders either affecting specific metabolic pathways, i.e., the single peroxisomal enzyme deficiencies, or causing a generalized defect in function and assembly of peroxisomes, i.e., peroxisome biogenesis disorders. In this review, we discuss the clinical, biochemical, and genetic aspects of all human peroxisomal disorders currently known. This article is part of a Special Issue entitled: Peroxisomes edited by Ralf Erdmann. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
5. In silico study of peculiarities of metabolism of erythrocytes with glucosephosphate isomerase deficiency
- Author
-
O. I. Dotsenko
- Subjects
0301 basic medicine ,Premature aging ,Chemistry ,General Medicine ,Metabolism ,Isomerase ,Pentose phosphate pathway ,Glucose phosphate ,Flux balance analysis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Biochemistry ,stoichiometric modeling ,elementary flux modes ,control-effective flux ,system biology ,flux balance analysis method ,metabolic networks of erythrocytes ,enzyme deficiencies ,030220 oncology & carcinogenesis ,lcsh:Q ,Glycolysis ,lcsh:Science ,Flux (metabolism) - Abstract
Glucose phosphate isomerase (GPI) deficiency, the third most common cause of hereditary nonspherocytic hemolytic anemia, is associated with the mutation of the GPI gene. The results of the GPI deficiency are premature aging of erythrocytes, macrocytosis, reticulocytosis, minor splenomegaly, hyperbilirubinemia and hyperferritinemia, and hemolytic crisis under the influence of exogenous oxidants such as infections or drugs. Regarding the the lack of GPI correction drugs, the theoretical substantiation of supportive therapy based on system biology approaches that would allow the analysis of the relationships between numerical metabolic processes in a cell would be beneficial. The stoichiometric model of erythrocytes’ steady state metabolism, including the pathways of Embden-Meyerhof and pentose phosphate (PPP), purine metabolism cycles and glutathione synthesis, has been developed. To predict the redistribution of metabolic flows in erythrocytes under conditions of GPI deficiency, we used the flux balance analysis (FBA). In this approach, calculations of the elementary flux modes (EFMs) and the control-effective flux (CEF) have been performed. Using the CEF evaluation approach, effective profiles of enzymatic reactions depending on the degree of enzyme deficiency were obtained. It has been shown that these relationships can be the basis for future experimental studies. Analysis of the profiles of enzymatic reactions of metabolic networks suggests that erythrocytes are capable of metabolizing other substrates that contribute to overcoming the effects of energy stress in the case of enzymopathies. So, it is shown that erythrocytes can effectively use SAM and adenosine as alternative energy sources. It has been established that the GPI enzymopathy results in a decrease in the flow through the glycolysis and pentose phosphate pathway, resulting in a decrease in the content of such reducing agents as NADPH and GSH, ATP. The processes of the GSH synthesis from amino acids in the cell are shown to be suppressed. Decreased content of NADPH and GSH cause the premature aging of erythrocytes. The target therapeutic approaches that influence the behaviour of the metabolic network of erythrocytes are discussed.
- Published
- 2019
6. The generalized flux-minimization method and its application to metabolic networks affected by enzyme deficiencies
- Author
-
Holzhütter, Hermann-Georg
- Subjects
- *
ENZYMES , *ERYTHROCYTES , *CATALYSTS , *DRUGS - Abstract
Abstract: The flux-minimization method [Holzhütter, H.G., 2004. The principle of flux-minimization and its application to calculate stationary fluxes in metabolic networks. Eur. J. Biochem. 271, 2905–2922] has been proposed as an alternative to kinetic modeling to calculate stationary fluxes in metabolic networks. Here a generalization of this method is proposed that takes into account possible limitations of internal fluxes, e.g. due to enzyme defects or partial inhibition of enzyme activities by drugs. The generalized method consists in the minimization of an objective function which expresses the compromise that has to be made between minimization of internal fluxes on one hand and maintenance of the metabolic output required for various cellular functions on the other. Fulfillment of the latter condition is measured through a fitness function, which evaluates the relative deviation of the output fluxes from demanded target values. The method is applied to assess the metabolic consequences caused by a deficiency of enzymes involved in the metabolism of erythrocytes. The obtained results are in good agreement with those obtained on the basis of a comprehensive kinetic model. [Copyright &y& Elsevier]
- Published
- 2006
- Full Text
- View/download PDF
7. Adenine and adenosine salvage pathways in erythrocytes and the role of S-adenosylhomocysteine hydrolase.
- Author
-
Schuster, Stefan and Kenanov, Dimitar
- Subjects
- *
ADENINE , *ADENOSINES , *ERYTHROCYTES , *BLOOD cells , *NUCLEOSIDES , *NUCLEOTIDES , *HYDROLASES , *ENZYMES - Abstract
This article is devoted to the study of redundancy and yield of salvage pathways in human erythrocytes. These cells are not able to synthesize ATP de novo. However, the salvage (recycling) of certain nucleosides or bases to give nucleotide triphosphates is operative. As the salvage pathways use enzymes consuming ATP as well as enzymes producing ATP, it is not easy to see whether a net synthesis of ATP is possible. As for pathways using adenosine, a straightforward assumption is that these pathways start with adenosine kinase. However, a pathway bypassing this enzyme and using S-adenosylhomocysteine hydrolase instead was reported. So far, this route has not been analysed in detail. Using the concept of elementary flux modes, we investigate theoretically which salvage pathways exist in erythrocytes, which enzymes belong to each of these and what relative fluxes these enzymes carry. Here, we compute the net overall stoichiometry of ATP build-up from the recycled substrates and show that the network has considerable redundancy. For example, four different pathways of adenine salvage and 12 different pathways of adenosine salvage are obtained. They give different ATP/glucose yields, the highest being 3 : 10 for adenine salvage and 2 : 3 for adenosine salvage provided that adenosine is not used as an energy source. Implications for enzyme deficiencies are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
8. Effect of Enzyme Deficiencies on Oxidative Phosphorylation: From Isolated Mitochondria to Intact Tissues. Theoretical Studies.
- Author
-
Korzeniewski, Bernard
- Abstract
The present article briefly summarizes the theoretical studies made by the authors and co-workers on the effect of inborn enzyme deficiencies on oxidative phosphorylation in intact tissues and on the genesis of mitochondrial diseases. The dynamic computer model of oxidative phosphorylation developed previously allowed to extrapolate experimental data (especially: threshold curves describing the dependence of oxygen consumption and ATP turnover on activities/concentrations of particular oxidative phosphorylation enzymes) obtained for isolated muscle mitochondria in state 3 at saturating oxygen concentrations to more physiological conditions prevailing in intact tissues. In particular, theoretical studies demonstrated that the threshold value of the relative activity/concentration of a given mitochondrial complex, below which a significant decrease in the respiration rate takes place, increases with an increase in energy demand. This fact was proposed as a possible explanation of the tissue specificity of mitochondrial diseases. Additionally, a decreased oxygen concentration was shown to increase the threshold value (and flux control coefficient) for cytochrome oxidase. We subsequently developed a model called ‘binary mitochondria heteroplasmy’, in which there are only two subpopulations of mitochondria: one ‘wild-type’ and one containing only defected molecules of a given enzyme. In this model we show that a defect has a pronounced effect on oxidative phosphorylation, significantly increasing the threshold value. It was also proposed that a parallel activation in the ATP supply-demand system during an increased energy demand significantly lessens the effect of enzyme deficiencies on oxidative phosphorylation (decreases the threshold value). Finally, the necessity of substrate activation may lead to an instability in the system and to appearance of a second threshold, below which respiration suddenly drops to zero, which is equivalent to the energetic death of a cell. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
9. Trim37-deficient mice recapitulate several features of the multi-organ disorder Mulibrey nanism
- Author
-
Anu Jalanko, Susann Karlberg, Niklas Karlberg, Matti Jauhiainen, J. Kalervo Hiltunen, Kirsi Sainio, Anna-Elina Lehesjoki, Riikka H. Hämäläinen, Teija T. Toivonen, Natalia Kulesskaya, Marita Lipsanen-Nyman, Vootele Voikar, Kaisa Kettunen, Jorma Toppari, Elina Ikonen, Hannu Jalanko, Maarit Hölttä-Vuori, Riitta Karikoski, Vasily D. Antonenkov, Institute for Molecular Medicine Finland, Neuroscience Center, Research Programme for Molecular Neurology, Research Programs Unit, Heikki Rauvala Research Group, Medicum, Department of Anatomy, Lipid Trafficking Lab, Department of Biochemistry and Developmental Biology, Clinicum, Children's Hospital, Endokrinologian yksikkö, Lastentautien yksikkö, Anna-Elina Lehesjoki / Principal Investigator, and HUS Children and Adolescents
- Subjects
0301 basic medicine ,Mulibrey nanism ,medicine.medical_specialty ,COILED-COIL PROTEIN ,QH301-705.5 ,Cardiomyopathy ,Science ,LUTEINIZING-HORMONE ,BIOGENESIS ,Congenic ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,FINGER PROTEIN TRIM37 ,0302 clinical medicine ,MOUSE MODELS ,Internal medicine ,Fatty liver ,medicine ,Biology (General) ,WILMS-TUMOR ,Testosterone ,ENZYME DEFICIENCIES ,Growth failure ,LIPID HOMEOSTASIS ,ta1184 ,3112 Neurosciences ,medicine.disease ,3. Good health ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Infertility ,3121 General medicine, internal medicine and other clinical medicine ,Tumorigenesis ,RAT ,3111 Biomedicine ,General Agricultural and Biological Sciences ,Carcinogenesis ,Luteinizing hormone ,PEROXISOMES ,030217 neurology & neurosurgery ,Germ cell ,Hormone ,Research Article - Abstract
Mulibrey nanism (MUL) is a rare autosomal recessive multi-organ disorder characterized by severe prenatal-onset growth failure, infertility, cardiopathy, risk for tumors, fatty liver, and type 2 diabetes. MUL is caused by loss-of-function mutations in TRIM37, which encodes an E3 ubiquitin ligase belonging to the tripartite motif (TRIM) protein family and having both peroxisomal and nuclear localization. We describe a congenic Trim37 knock-out mouse (Trim37−/−) model for MUL. Trim37−/− mice were viable and had normal weight development until approximately 12 months of age, after which they started to manifest increasing problems in wellbeing and weight loss. Assessment of skeletal parameters with computer tomography revealed significantly smaller skull size, but no difference in the lengths of long bones in Trim37−/− mice as compared with wild-type. Both male and female Trim37−/− mice were infertile, the gonads showing germ cell aplasia, hilus and Leydig cell hyperplasia and accumulation of lipids in and around Leydig cells. Male Trim37−/− mice had elevated levels of follicle-stimulating and luteinizing hormones, but maintained normal levels of testosterone. Six-month-old Trim37−/− mice had elevated fasting blood glucose and low fasting serum insulin levels. At 1.5 years Trim37−/− mice showed non-compaction cardiomyopathy, hepatomegaly, fatty liver and various tumors. The amount and morphology of liver peroxisomes seemed normal in Trim37−/− mice. The most consistently seen phenotypes in Trim37−/− mice were infertility and the associated hormonal findings, whereas there was more variability in the other phenotypes observed. Trim37−/− mice recapitulate several features of the human MUL disease and thus provide a good model to study disease pathogenesis related to TRIM37 deficiency, including infertility, non-alcoholic fatty liver disease, cardiomyopathy and tumorigenesis., Summary: A congenic Trim37-deficient mouse model recapitulates several features of the human disorder Mulibrey nanism, and thus provides a good model to study disease pathogenesis related to TRIM37 deficiency.
- Published
- 2016
10. Rhabdomyolysis: Review of the literature
- Author
-
A. J. van der Kooi, M. de Visser, Gabor E. Linthorst, Ronald J.A. Wanders, and Rodi Zutt
- Subjects
myalgia ,Weakness ,Pediatrics ,medicine.medical_specialty ,CLINICAL APPROACH ,METABOLIC MYOPATHIES ,Exercise intolerance ,CYTOMEGALOVIRUS-INFECTION ,Rhabdomyolysis ,ACUTE PEDIATRIC RHABDOMYOLYSIS ,medicine ,CREATINE-PHOSPHOKINASE ,Animals ,Humans ,Intensive care medicine ,Genetics (clinical) ,Acute tubular necrosis ,ENZYME DEFICIENCIES ,biology ,business.industry ,Myoglobinuria ,EXERTIONAL RHABDOMYOLYSIS ,medicine.disease ,MALIGNANT HYPERTHERMIA ,Neurology ,Pediatrics, Perinatology and Child Health ,biology.protein ,Exertional rhabdomyolysis ,BETA-OXIDATION DEFECT ,Creatine kinase ,Neurology (clinical) ,medicine.symptom ,business ,ACUTE-RENAL-FAILURE - Abstract
Rhabdomyolysis is a serious and potentially life threatening condition. Although consensus criteria for rhabdomyolysis is lacking, a reasonable definition is elevation of serum creatine kinase activity of at least 10 times the upper limit of normal followed by a rapid decrease of the sCK level to (near) normal values. The clinical presentation can vary widely, classical features are myalgia, weakness and pigmenturia. However, this classic triad is seen in less than 10% of patients. Acute renal failure due to acute tubular necrosis as a result of mechanical obstruction by myoglobin is the most common complication, in particular if sCK is >16.000 IU/l, which may be as high as 100,000 IU/1. Mortality rate is approximately 10% and significantly higher in patients with acute renal failure. Timely recognition of rhabdomyolysis is key for treatment. In the acute phase, treatment should be aimed at preserving renal function, resolving compartment syndrome, restoring metabolic derangements, and volume replacement. Most patients experience only one episode of rhabdomyolysis, mostly by substance abuse, medication, trauma or epileptic seizures. In case of recurrent rhabdomyolysis, a history of exercise intolerance or a positive family history for neuromuscular disorders, further investigations are needed to identify the underlying, often genetic, disorder. We propose a diagnostic algorithm for use in clinical practice. (C) 2014 Elsevier B.V. All rights reserved.
- Published
- 2014
11. Rhabdomyolysis
- Subjects
MALIGNANT HYPERTHERMIA ,ENZYME DEFICIENCIES ,ACUTE PEDIATRIC RHABDOMYOLYSIS ,Myoglobinuria ,CLINICAL APPROACH ,EXERTIONAL RHABDOMYOLYSIS ,CREATINE-PHOSPHOKINASE ,BETA-OXIDATION DEFECT ,METABOLIC MYOPATHIES ,CYTOMEGALOVIRUS-INFECTION ,Rhabdomyolysis ,ACUTE-RENAL-FAILURE - Abstract
Rhabdomyolysis is a serious and potentially life threatening condition. Although consensus criteria for rhabdomyolysis is lacking, a reasonable definition is elevation of serum creatine kinase activity of at least 10 times the upper limit of normal followed by a rapid decrease of the sCK level to (near) normal values. The clinical presentation can vary widely, classical features are myalgia, weakness and pigmenturia. However, this classic triad is seen in less than 10% of patients. Acute renal failure due to acute tubular necrosis as a result of mechanical obstruction by myoglobin is the most common complication, in particular if sCK is >16.000 IU/l, which may be as high as 100,000 IU/1. Mortality rate is approximately 10% and significantly higher in patients with acute renal failure. Timely recognition of rhabdomyolysis is key for treatment. In the acute phase, treatment should be aimed at preserving renal function, resolving compartment syndrome, restoring metabolic derangements, and volume replacement. Most patients experience only one episode of rhabdomyolysis, mostly by substance abuse, medication, trauma or epileptic seizures. In case of recurrent rhabdomyolysis, a history of exercise intolerance or a positive family history for neuromuscular disorders, further investigations are needed to identify the underlying, often genetic, disorder. We propose a diagnostic algorithm for use in clinical practice. (C) 2014 Elsevier B.V. All rights reserved.
- Published
- 2014
12. Erythrozytäre Pyruvatkinase-Defizienz bei Somali- und Abessinierkatzen
- Author
-
Fumi, Christine
- Subjects
anaemia ,reticulocytes ,cats ,hereditary diseases ,enzyme deficiencies ,clinical aspects ,cat diseases ,deficiency ,pyruvate kinase ,jaundice ,hyperbilirubinaemia - Abstract
Die PK-Defizienz stellt beim Menschen eine der häufigsten hereditären hämolytischen Anämien dar, die durch eine Enzymopathie verursacht wird, und führt auch beim Hund zu einer stark regenerativen, chronischen hämolytischen Anämie. Im Jahre 1992 wurde der erste Fall einer PK-Defizienz bei einem Abessinierkater in den USA und 2002 in Deutschland diagnostiziert. Seither wurde die Erkrankung neben weiteren Abessiniern auch bei Somalis und wenigen Domestic Shorthair Katzen festgestellt. Bisher liegen kaum Daten über die Verbreitung, den Verlauf der Erkrankung und labordiagnostische Veränderungen bei Katzen mit PK-Defizienz vor. Ziel dieser Arbeit war es daher, eine große Anzahl von Testergebnissen von Somalis und Abessiniern zu erfassen, um die Verbreitung in Deutschland und anderen europäischen Ländern zu evaluieren. Die Krankengeschichten homozygot betroffener Katzen wurden mittels Fragebogen erfasst und alle vorhandenen Laboruntersuchungen ausgewertet. PK- Testergebnisse von insgesamt 503 Somali- und Abessinierkatzen aus Deutschland und anderen europäischen Ländern waren vorhanden. 7,5 % der Katzen waren homozygot von PK-Defizienz betroffen, 23,3 % waren Anlageträger und 69,2 % waren frei von diesem Defekt. PK-defiziente Katzen konnten in Deutschland, in der Schweiz, Österreich, Finnland und den Niederlanden identifiziert werden. Das Verhältnis von PK-defizienten Katzen, Anlageträgern und normalen Katzen unterschied sich zwischen den beiden Rassen und zwischen den Geschlechtern nur unwesentlich. Der Krankheitsverlauf konnte von 26 der 38 PK-defizienten Katzen über einen Zeitraum von 0,8 bis 11,3 Jahren (M = 4,2 Jahre) erfasst werden. 11 Tiere waren laut Besitzerangaben bis zu einem Alter von 0,8 bis 7,8 Jahren (Median [M] = 4,4 Jahre) symptomlos. 15 Katzen zeigten ab einem Alter von 0,1 bis 5 Jahren (M = 1,7 Jahre) intermittierend verschiedene Symptome, wie Apathie, Durchfall, blasse Schleimhäute und Ikterus. Vier Besitzer stellten einen Zusammenhang zwischen Stresssituationen und der Ausbildung von Symptomen fest. Eine hämatologische Untersuchung konnte bei 22 Katzen durchgeführt werden, wovon 16 Katzen eine Anämie mit Hkt-Werten von 0,13 – 0,31 l/l (M = 0,28) aufwiesen. 12 der anämischen Katzen wiesen verschiedene Symptome auf und 4 Katzen waren mit Hkt-Werten von 0,25 − 0,29 l/l klinisch unauffällig. Fünf von 14 Katzen mit Folgeuntersuchungen des Blutbildes wiesen initial und bei jeder Kontrolle eine Anämie auf; 6 Katzen wiesen Perioden mit Hkt-Werten im Normbereich und mit Hkt-Werten unter dem Referenzbereich auf und 3 Katzen wiesen zu keinem Zeitpunkt eine Anämie auf und der Hkt blieb über einen Zeitraum von 1, 2,9 und 3,8 Jahren stabil. 95 % der Katzen wiesen erhöhte absolute aggregierte Retikulozytenwerte auf. Die OF der Ec lag bei den PK- defizienten Katzen meist im Referenzbereich, was zur Abgrenzung des bei den gleichen Rassen vorkommenden Krankheitsbildes der „Erhöhten OF der Ec“ dienen kann. Bei der klinisch-chemischen Blutuntersuchung hatten 44 % der Katzen eine gering- bis hochgradige Hyperbilirubinämie und bei ebenfalls 44 % war mindestens ein Leberenzym erhöht. 88 % der Katzen wiesen eine Hyperglobulinämie auf. 13 von 30 PK-defizienten Katzen verstarben in einem Alter von 1,3 – 11,3 Jahren (M = 4,8 Jahre) spontan bzw. wurden euthanasiert. Die restlichen Katzen waren mindestens bis zu einem Alter von 0,8 – 7,8 Jahren (M = 4,3) am Leben. Von 15 Katzen mit Symptomen wurden 9 behandelt, davon 6 mit Prednisolon. Fünf von 6 Katzen sprachen eventuell darauf an, jedoch war die Anzahl der behandelten Tiere zu gering, um eine Aussage treffen zu können. Eine Katze mit schwerer hämolytischer Krise erhielt eine Bluttransfusion. Eine histopathologische Untersuchung wurde bei 3 Katzen durchgeführt. Neben Hämosiderose und extramedullärer Hämatopoese in Leber und Milz konnte bei einer Katze eine Leberzirrhose mit hochgradigen Eisenablagerungen identifiziert werden. Diese Arbeit verdeutlicht die hohe Verbreitung der PK- Defizienz in Deutschland und angrenzenden Ländern. Da die Krankheit lange Zeit klinisch und auch labordiagnostisch symptomlos verlaufen kann, sollten alle Somalis und Abessinier vor einem Zuchteinsatz mittels DNA-Untersuchung getestet werden. Grundsätzlich sollten sowohl homozygot betroffene Katzen als auch Anlageträger von der Zucht ausgeschlossen werden, um die Erkrankung zu eliminieren. Sollten aufgrund züchterischer Belange Anlageträger eingesetzt werden, so dürfen diese nur mit gesunden Partnern verpaart werden., In humans, PK deficiency is one of the most common hereditary forms of haemolytic anaemia caused by an enzymopathy. PK deficiency has also been described in several canine breeds. In 1992, the first case of feline PK deficiency has been described in the United States in an Abyssinian male cat and in 2002 the first case was described in Germany. Since then, the disease was identified in other Abyssinians, Somalis, and a few domestic shorthair cats. Since only limited clinical data has been published until now, the objective of this study was to evaluate clinical signs, laboratory parameters, and the progression of the disease in PK deficient cats. Moreover the prevalence of PK deficiency in Germany and other European countries should be evaluated. The progression of the disease in affected cats was evaluated with a questionnaire and all available laboratory parameters were analysed. PK DNA test results of 503 Somali and Abyssinian cats from Germany and other European countries were available. 7.5 % were homozygous affected, 23.3 % were heterozygous carriers, and 69.2 % had no mutation of the PK allele. Affected cats were identified in Germany, Switzerland, Austria, Finland, and the Netherlands. The distribution of affected cats, carriers and healthy cats was similar in both breeds and showed no remarkable difference between males and females. The progression of the disease of 26 PK deficient cats could be followed over a time of 0.8 to 11.3 years (median 4.2). In 11 cats, the owners did not notice any signs of disease up to an age of 0.8 to 7.8 years (median 4.4). 15 cats started displaying various clinical signs at ages ranging from 0.1 to 5 years (median 1.7). The clinical signs included lethargy, diarrhoea, pale mucous membranes, and icterus. Four owners observed a relationship between stressful situations and the appearance of clinical signs. A haematological examination was performed for 22 PK deficient cats and the CBC revealed anaemia with PCV values of 0.13 - 0.31 l/l (median 0.28) in 16 cats. In 12 cats, the owners noticed no signs of disease and 4 cats were clinically healthy despite PCV values of 0.25 – 0.29 l/l. In 5 of 14 cats with follow-up examinations the PCV was below the reference range in every sample, 6 other cats had periods with normal PCV values as well as periods with PCV values below the reference range and 3 cats did not display anaemia at any time and had a stable PCV over a time period of 1, 2.9, and 3.8 years. The absolute number of aggregated reticulocytes was increased in 95 % of the cats. In contrast to cats suffering from the disease “Increased osmotic fragility of erythrocytes”, the mean erythrocytic osmotic fragility of most cats suffering from PK deficiency was within the reference range. Therefore, the osmotic fragility test can be useful to differentiate between these two diseases. 44 % of the cats displayed mild to severe hyperbilirubinaemia and in another 44 % at least one liver enzyme was increased. Hyperglobulinaemia was present in 88 % of the cats. 13 of 30 affected cats died or were euthanised at ages ranging from 1.3 – 11.3 years (median 4.8), the others were alive until to an age of 0.8 – 7.8 years (median 4.3). Nine of 15 cats with clinical signs were treated by different veterinarians, 6 of them with prednisolon. In 5 of these 6 cats a transient or partial effect was observed, but the number of treated cats did not warrant any conclusions. One cat did develop a severe haemolytic crisis and required a transfusion. For 3 cats a histopathologic examination was performed. Next to haemosiderosis and extramedullary haematopoesis, a cirrhosis caused by severe iron deposits could be shown in one cat. Based upon this survey, the mutant PK allele appears to occur frequently in Somalis and Abyssinians from Germany and other European countries. Since PK deficiency can be asymptomatic in regard to clinical and laboratory parameters for a long time, DNA analysis in Abyssinian and Somali cats before use for breeding is strongly recommended. Carriers and affected cats should be excluded from breeding to eliminate this disease. Should carriers be used because of breeding aspects they should paired only with healthy cats.
- Published
- 2009
13. Topological analysis of metabolic and regulatory networks by decomposition methods
- Author
-
Oancea, Ionela, Holzhütter, Hermann-Georg, Heinrich, Reinhart, and Schuster, Stefan
- Subjects
Enzymdefizienzen ,Immunodefizienz ,32 Biologie ,multifunktionelle Enzyme ,Petri-Netze ,nucleotide metabolism ,Signaltransduktion ,WD 9200 ,ddc:570 ,hemireactions ,Nukleotidstoffwechsel ,570 Biowissenschaften, Biologie ,enzyme deficiencies ,Petri Nets ,multifunctional ,signalling network ,elementary flux modes ,low specificity ,proliferative Krankheiten ,Enzyme niedriger Spezifität ,Signalnetzwerk ,WD 5050 ,Computer modelling ,Halbreaktionen ,proliferative diseases ,Computermodellierung ,immunodeficiency ,Elementarmoden ,signal transduction ,WD 2200 - Abstract
Die lebenden Organismen sind für eine wissenschaftliche Analyse zu kompliziert, wenn man sie als Ganzes und in ihrer vollen Komplexität betrachtet. Die vorliegende Arbeit behandelt die topologischen Eigenschaften von zwei wichtigen Teilen der lebenden Organismen: die metabolischen und die regulatorischen Systeme. Topolgische Eigenschaften sind solche, die durch die Netwerkstruktur bedingt werden. Ein Signalsystem ist eine spezielle Art von regulatorischem System. Zwischen den metabolischen und Signalnetzen gibt es wichtige Unterschiede, die ihre Behandlung in unterschiedlicher Weise erfordert. In der metabolischen Pfadanalyse ist das Konzept der elementaren Flussmoden bereits als ein passendes Instrument für die Charakterisierung der einfachsten essentiellen Wege in biochemischen Systemen etabliert. Wir untersuchen die Eigenschaften und Vorteile dieses Konzepts in einigen besonderen Fällen. Zuerst untersuchen wir die vielfach vorkommenden Enzyme mit niedriger Spezifität (z.B. Nukleosiddiphosphokinase, Uridinkinase, Transketolase, Transaldolase). Sie können parallel verschiedene Substrate und Produkte umwandeln. Auch die Enzym-Mechanismen sind vielfältig, wie wir mit dem Reaktionsschema für bifunktionelle Enzyme veranschaulichen. Wir betrachten dabei nur den Fall, dass ein bestimmtes aktives Zentrum mehrere Reaktionen katalysiert. Der Fall, dass das studierte Enzym mehrere solche aktiven Zentren hat, kann in den Fall mehrerer Enzyme transformiert werden, die nur ein aktives Zentrum haben. Wenn eine Krankheit das Ausgangsenzym ändert, werden dann in der Analyse auch alle ersetzenden Enzyme geändert. Es gibt zwei unterschiedliche Betrachtungsweisen, um multifunktionelle Enzyme zu beschreiben. Zum einen kann man die Gesamtreaktionen betrachten und zum anderen die elementaren Reaktionsschritte (Hemireaktionen, Halbreaktionen). Für Enzyme mit zwei oder mehr Funktionen ist es wichtig, nur linear unabhängige Funktionen zu betrachten, weil sonst zyklische elementare Moden auftreten würden, die keine Nettoumwandlung durchführen. Jedoch ist die Wahl der linear unabhängigen Funktionen nicht a priori eindeutig. Wir stellen eine Methode für das Treffen dieser Wahl vor, indem wir die konvexe Basis des Hemireaktions-Systems betrachten. Eine formale Anwendung des Algorithmus für das Berechnen der elementaren Flussmoden (Routen) erbringt das Resultat, dass die Zahl solcher Moden manchmal vom Niveau der Beschreibung abhängt, wenn einige Reaktionen reversibel sind und die Produkte der multifunktionellen Enzyme externe Metabolite sind, oder einige multifunktionelle Enzyme zum Teil die gleichen Stoffwechselprodukte umwandeln. Jedoch kann dieses Problem durch eine geeignete Deutung der Definition der elementaren Moden und die korrekte Wahl der unabhängigen Funktionen der Multifunktionsenzyme gelöst werden. Die Analyse wird durch einige kleinere Beispiele und ein größeres biochemisches Beispiel veranschaulicht, das aus dem Nukleotidmetabolismus stammt und die zwei Arten der Beschreibung für Nukleosiddiphosphokinase und Adenylatekinase vergleicht. Der Nukleotidmetabolismus spielt eine wichtige Rolle in lebenden Organismen und ist gegenüber allen möglichen Störungen in seiner internen Balance sehr empfindlich. Gefährliche Krankheiten können auftreten, wenn einige Enzyme nicht richtig funktionieren. Mit Hilfe des Konzeptes des elementaren Flussmodus erklären wir das Auftreten und den Schweregrad von Krankheiten, die auf Enzymdefizienzen basieren. Wenn ein Enzym vollständig gehemmt wird, werden einige metabolische Wege blockiert. Wenn jedoch einige alternative Wege noch bestehen, ist die Krankheit weniger gefährlich. Unsere Analyse ist darauf gerichtet, alternative Wege, wesentliche Enzyme und solche Enzyme, die immer zusammenarbeiten zu finden. Der letzte Begriff ist auch als "Enzyme subset" bekannt und stellt einen intermediären Schritt im Algorithmus zur Berechnung der elementaren Flussmoden dar. Wir diskutieren bereits bekannte und bisher nur hypothetische Mechanismen einiger Krankheiten (proliferative Krankheiten, Immundefizienzen), die auf Störungen des Nukleotidmetabolismus oder seiner Ausbeutung durch Viren und Parasiten beruhen. Die meisten Strategien, die für das Bekämpfen solcher Krankheiten eingesetzt werden, basieren auf der Unterbrechung des Nukleotidmetabolismus an bestimmten Stellen. Diese Strategien können aber auch zur Akkumulation toxischer Stoffe führen und dadurch Nebenwirkungen hervorrufen. Deswegen hilft ein besseres Verständnis dieses Systems, wirkungsvollere Medikamente zu entwickeln, und eine gute strukturelle Analyse kann viele experimentelle Bemühungen ersparen. Konzepte aus der Theorie der Petri-Netze liefern zusätzliche Werkzeuge für das Modellieren metabolischer Netzwerke. In Kapitel 4 werden die ähnlichkeiten zwischen einigen Konzepten in der traditionellen biochemischen Modellierung und analogen Konzepten aus der Petri-Netztheorie besprochen. Zum Beispiel entspricht die stochiometrische Matrix eines metabolischen Netzwerkes der Inzidenzmatrix des Petri-Netzes. Die Flussmoden und die Erhaltungs-Relationen haben die T-Invarianten beziehungsweise P-Invarianten als Gegenstücke. Wir decken die biologische Bedeutung einiger weiterer Begriffe aus der Theorie der Petri-Netze auf, nämlich "traps", "{siphons", "deadlocks" und "Lebendigkeit". Wir konzentrieren uns auf der topologischen Analyse anstatt auf die Analyse des dynamischen Verhaltens. Die geeignete Behandlung der externen Stoffwechselprodukte wird ebenfalls besprochen. Zur Illustration werden einige einfache theoretische Beispiele vorgestellt. Außerdem werden einige Petri-Netze präsentiert, die konkreten biochemischen Netzen entsprechen, um unsere Resultate zu belegen. Zum Beispiel wird die Rolle der Triosephosphatisomerase (TPI) im Metabolismus von Trypanosoma brucei ausgewertet, indem "traps" und "siphons" ermittelt werden. Alle behandelten Eigenschaften von Petri-Netzen werden anhand eines Systems illustriert, das aus dem Nukleotidmetabolismus stammt. Während viele Bemühungen für das Zerlegen metabolischer Systeme, (elementare Flußmoden, extreme Wege) erfolgt sind, sind bisher unseres Wissens keine Versuche in dieser Richtung für Signalübertragungssysteme unternommen worden. Eine spezielle Eigenschaft von Signalnetzwerken in lebenden Zellen ist, dass Aktivierungen, Hemmungen und biochemische Reaktionen normalerweise gleichzeitig anwesend sind. Selbst wenn sie nicht Reaktionen enthalten, machen Mehrfach-Aktivierungen oder Mehrfach-Hemmungen die Netzwerke in hohem Grade verzweigt. Es ist eine schwierige und sehr zeitraubende Aufgabe, alle Faktoren, die einen Einfluss auf ein gegebenes Ziel haben, ohne eine automatische Methode zu ermitteln. Bereits in Kapitel 1 heben wir die ähnlichkeiten und Unterschiede zwischen den metabolischen und Signal-Netzwerken hervor. In Kapitel 5 errichten wir einen Rahmen und präsentieren einen Algorithmus für die Zerlegung von Signalnetzwerken in kleinere Einheiten, die einfacher zu studieren und zu verstehen sind. Zwei Fälle werden untersucht: ein einfacheres, wenn nur monomolekulare Aktivierungen oder Reaktionen anwesend sind, und ein komplizierterer Fall, wenn die Aktivierungen und die Reaktionen multimolekular sein können. Ihre Beschreibung erfordert unterschiedliche Methoden: klassische Graphen bzw. Petrinetze. Wir besprechen die Probleme, die in unserem Modell wegen des Vorhandenseins von Hemmungen oder von unbekannten Effekten im Netz auftreten. Der vorgeschlagene Algorithmus ermittelt die Faktoren, die zusammenwirken und die Zielsubstanzen, die auf dem gleichen Weg beeinflusst werden. Die Zyklen, die im System auftreten, und mögliche fehlende Reaktionen werden ebenfalls ermittelt . Theoretische Beispiele veranschaulichen unsere Resultate. Anhand der T-Zell-Antigen-Rezeptor-Signalkaskade zeigen wir, wie die Methoden in realen Systemen angewendet werden können. The living organisms are too complex when considering them as a whole. The present thesis deals with the topological properties of two important parts of living organisms: the metabolic and the regulatory systems. The topological properties are those features that are determined by the network structure. A classification in metabolic and regulatory systems is often used. A signalling system is a special kind of regulatory system. Between metabolic and signalling networks, there are important differences that impose their treatment in different ways. In metabolic pathway analysis, the elementary flux mode concept is already established as a proper tool for identifying the smallest essential routes in biochemical systems. We examine its features and advantages in some particular cases. Firstly, many enzymes operate with low specificity (e.g. nucleoside diphosphokinase, uridine kinase, transketolase, transaldolase), so that various substrates and products can be converted. Also the enzymatic mechanisms are diverse, as we have illustrated with reaction schemes for bifunctional enzymes. Therefore, there are two different approaches to describe multifunctional enzymes (We considered only the case when a certain active site hosts several reactions. The case when the studied enzyme has several such active sites can be transformed into that of several enzymes having only one active site. If a disease alters the initial enzyme, also all substituting enzymes are altered.): in terms of overall reactions and in terms of reactions steps (hemi-reactions, half-reactions). For enzymes with two or more functions, it is important to consider only linearly independent functions, because otherwise cyclic elementary modes would occur which do not perform any net transformation. However, the choice of linearly independent functions is not a priori unique. In Chapter 2, we give a method for making this choice unique by considering the convex basis of the hemi-reactions system. The set of linearly independent functions provided by our algorithm coincides, in the case of transketolase in pentose phosphate pathway, with the set of linearly independent functions mentioned in literature. A formal application of the algorithm for computing elementary flux modes (pathways) yields the result that the number of such modes sometimes depends on the level of description if some reactions are reversible and the products of the multifunctional enzymes are external metabolites or some multifunctional enzymes partly share the same metabolites. However, this problem can be solved by appropriate interpretation of the definition of elementary modes and the correct choice of independent functions of multifunctional enzymes. The analysis is illustrated by a biochemical example taken from nucleotide metabolism, comparing the two ways of description for nucleoside diphosphokinase and adenylate kinase, and by several smaller examples. The nucleotide metabolism plays an important role in living organisms and is very sensitive to any perturbations in its internal balance. Dangerous diseases may occur if some enzymes do not work properly. With the help of elementary flux mode concept, we explain the occurrence and severity of diseases based on enzyme deficiencies. If an enzyme is completely inhibited, some metabolic routes are blocked. If, however, some alternative routes still exist, the disease is less dangerous. In Chapter 3, we focus on finding alternative routes, essential enzymes and enzymes operating together. The latter notion is also known as ,,enzyme subset`` and represents an intermediary step in calculating the elementary flux modes. The known or hypothesised mechanisms of several disorders, occurred due to the malfunctioning of nucleotide metabolism (proliferative diseases, immunodeficiency diseases) or due to its hijacking by viruses and parasites, are given. Most strategies adopted for curing such diseases are based on nucleotide metabolism interruption. Therefore, a better understanding of this system helps developing more effective drugs and a good structural analysis can spare many experimental efforts. Petri net concepts provide additional tools for the modelling of metabolic networks. In Chapter 4, the similarities between the counterparts in traditional biochemical modelling and Petri net theory are discussed. For example, the stoichiometry matrix of a metabolic network corresponds to the incidence matrix of the Petri net. The flux modes and conservation relations have the T-invariants, respectively, P-invariants as counterparts. We reveal the biological meaning of some notions specific to the Petri net framework (traps, siphons, deadlocks, liveness). We focus on the topological analysis rather than on the analysis of the dynamic behaviour. The treatment of external metabolites is discussed. Some simple theoretical examples are presented for illustration. Also the Petri nets corresponding to some biochemical networks are built to support our results. For example, the role of triose phosphate isomerase (TPI) in Trypanosoma brucei metabolism is evaluated by detecting siphons and traps. All Petri net properties treated in above-mentioned chapter (4) are exemplified on a system extracted from nucleotide metabolism. While for decomposing metabolic systems, many efforts have been done (elementary flux modes, convex basis, extreme pathways), for signalling maps, as far as we know, no attempt in this direction has been made. A special characteristic of signalling networks is that activations, inhibitions, and biochemical reactions are normally present in parallel. Even if they do not contain reactions, multi-part activations or inhibitions make them highly branched. To detect all factors that have an influence on a given target, without using an automatic method, is a difficult and very time-consuming effort. Already in Chapter 1 (Backgrounds), we highlight the similarities and differences between metabolic and signalling networks. In Chapter 5, we build a framework and algorithm for decomposing signalling networks in smaller units, which are easier to study and understand. Two cases are investigated: a simpler one, when only monomolecular activations or reactions are present, and a more complex case, when the activations and reactions can be multimolecular. Their description requires different instruments: classical graphs and Petri nets, respectively. We discuss the problems that occur in our model due to the presence of some inhibitions or unknown effects in the network. The algorithm that we propose detects the factors that are acting together and the targets that are affected on the same route. The cycles that occur in the system are also highlighted. We point out possible missing reactions. Theoretical examples illustrate out findings. Using the T cell antigen-receptor signalling cascade, we show how it can be applied to real systems.
- Published
- 2004
14. Topological analysis of metabolic and regulatory networks by decomposition methods
- Author
-
Holzhütter, Hermann-Georg, Heinrich, Reinhart, Schuster, Stefan, Oancea, Ionela, Holzhütter, Hermann-Georg, Heinrich, Reinhart, Schuster, Stefan, and Oancea, Ionela
- Abstract
Die lebenden Organismen sind für eine wissenschaftliche Analyse zu kompliziert, wenn man sie als Ganzes und in ihrer vollen Komplexität betrachtet. Die vorliegende Arbeit behandelt die topologischen Eigenschaften von zwei wichtigen Teilen der lebenden Organismen: die metabolischen und die regulatorischen Systeme. Topolgische Eigenschaften sind solche, die durch die Netwerkstruktur bedingt werden. Ein Signalsystem ist eine spezielle Art von regulatorischem System. Zwischen den metabolischen und Signalnetzen gibt es wichtige Unterschiede, die ihre Behandlung in unterschiedlicher Weise erfordert. In der metabolischen Pfadanalyse ist das Konzept der elementaren Flussmoden bereits als ein passendes Instrument für die Charakterisierung der einfachsten essentiellen Wege in biochemischen Systemen etabliert. Wir untersuchen die Eigenschaften und Vorteile dieses Konzepts in einigen besonderen Fällen. Zuerst untersuchen wir die vielfach vorkommenden Enzyme mit niedriger Spezifität (z.B. Nukleosiddiphosphokinase, Uridinkinase, Transketolase, Transaldolase). Sie können parallel verschiedene Substrate und Produkte umwandeln. Auch die Enzym-Mechanismen sind vielfältig, wie wir mit dem Reaktionsschema für bifunktionelle Enzyme veranschaulichen. Wir betrachten dabei nur den Fall, dass ein bestimmtes aktives Zentrum mehrere Reaktionen katalysiert. Der Fall, dass das studierte Enzym mehrere solche aktiven Zentren hat, kann in den Fall mehrerer Enzyme transformiert werden, die nur ein aktives Zentrum haben. Wenn eine Krankheit das Ausgangsenzym ändert, werden dann in der Analyse auch alle ersetzenden Enzyme geändert. Es gibt zwei unterschiedliche Betrachtungsweisen, um multifunktionelle Enzyme zu beschreiben. Zum einen kann man die Gesamtreaktionen betrachten und zum anderen die elementaren Reaktionsschritte (Hemireaktionen, Halbreaktionen). Für Enzyme mit zwei oder mehr Funktionen ist es wichtig, nur linear unabhängige Funktionen zu betrachten, weil sonst zyklische elementare Moden au, The living organisms are too complex when considering them as a whole. The present thesis deals with the topological properties of two important parts of living organisms: the metabolic and the regulatory systems. The topological properties are those features that are determined by the network structure. A classification in metabolic and regulatory systems is often used. A signalling system is a special kind of regulatory system. Between metabolic and signalling networks, there are important differences that impose their treatment in different ways. In metabolic pathway analysis, the elementary flux mode concept is already established as a proper tool for identifying the smallest essential routes in biochemical systems. We examine its features and advantages in some particular cases. Firstly, many enzymes operate with low specificity (e.g. nucleoside diphosphokinase, uridine kinase, transketolase, transaldolase), so that various substrates and products can be converted. Also the enzymatic mechanisms are diverse, as we have illustrated with reaction schemes for bifunctional enzymes. Therefore, there are two different approaches to describe multifunctional enzymes (We considered only the case when a certain active site hosts several reactions. The case when the studied enzyme has several such active sites can be transformed into that of several enzymes having only one active site. If a disease alters the initial enzyme, also all substituting enzymes are altered.): in terms of overall reactions and in terms of reactions steps (hemi-reactions, half-reactions). For enzymes with two or more functions, it is important to consider only linearly independent functions, because otherwise cyclic elementary modes would occur which do not perform any net transformation. However, the choice of linearly independent functions is not a priori unique. In Chapter 2, we give a method for making this choice unique by considering the convex basis of the hemi-reactions system. The set of l
- Published
- 2004
15. Topological analysis of metabolic and regulatory networks by decomposition methods
- Author
-
Heinrich, Reinhart, Holzhütter, Hermann-Georg, Schuster, Stefan, Oancea, Ionela, Heinrich, Reinhart, Holzhütter, Hermann-Georg, Schuster, Stefan, and Oancea, Ionela
- Abstract
Die lebenden Organismen sind für eine wissenschaftliche Analyse zu kompliziert, wenn man sie als Ganzes und in ihrer vollen Komplexität betrachtet. Die vorliegende Arbeit behandelt die topologischen Eigenschaften von zwei wichtigen Teilen der lebenden Organismen: die metabolischen und die regulatorischen Systeme. Topologische Eigenschaften sind solche, die durch die Netwerkstruktur bedingt werden. Ein Signalsystem ist eine spezielle Art von regulatorischem System. Zwischen den metabolischen und Signalnetzen gibt es wichtige Unterschiede, die ihre Behandlung in unterschiedlicher Weise erfordert. In der metabolischen Pfadanalyse ist das Konzept der elementaren Flussmoden bereits als ein passendes Instrument für die Charakterisierung der einfachsten essentiellen Wege in biochemischen Systemen etabliert. Wir untersuchen die Eigenschaften und Vorteile dieses Konzepts in einigen besonderen Fällen. Zuerst untersuchen wir die vielfach vorkommenden Enzyme mit niedriger Spezifität (z.B. Nukleosiddiphosphokinase, Uridinkinase, Transketolase, Transaldolase). Sie können parallel verschiedene Substrate und Produkte umwandeln. Auch die Enzym-Mechanismen sind vielfältig, wie wir mit dem Reaktionsschema für bifunktionelle Enzyme veranschaulichen. Wir betrachten dabei nur den Fall, dass ein bestimmtes aktives Zentrum mehrere Reaktionen katalysiert. Der Fall, dass das studierte Enzym mehrere solche aktiven Zentren hat, kann in den Fall mehrerer Enzyme transformiert werden, die nur ein aktives Zentrum haben. Wenn eine Krankheit das Ausgangsenzym ändert, werden dann in der Analyse auch alle ersetzenden Enzyme geändert. Es gibt zwei unterschiedliche Betrachtungsweisen, um multifunktionelle Enzyme zu beschreiben. Zum einen kann man die Gesamtreaktionen betrachten und zum anderen die elementaren Reaktionsschritte (Hemireaktionen, Halbreaktionen). Für Enzyme mit zwei oder mehr Funktionen ist es wichtig, nur linear unabhängige Funktionen zu betrachten, weil sonst zyklische elementare Moden au, The living organisms are too complex when considering them as a whole. The present thesis deals with the topological properties of two important parts of living organisms: the metabolic and the regulatory systems. The topological properties are those features that are determined by the network structure. A classification in metabolic and regulatory systems is often used. A signalling system is a special kind of regulatory system. Between metabolic and signalling networks, there are important differences that impose their treatment in different ways. In metabolic pathway analysis, the elementary flux mode concept is already established as a proper tool for identifying the smallest essential routes in biochemical systems. We examine its features and advantages in some particular cases. Firstly, many enzymes operate with low specificity (e.g. nucleoside diphosphokinase, uridine kinase, transketolase, transaldolase), so that various substrates and products can be converted. Also the enzymatic mechanisms are diverse, as we have illustrated with reaction schemes for bifunctional enzymes. Therefore, there are two different approaches to describe multifunctional enzymes (We considered only the case when a certain active site hosts several reactions. The case when the studied enzyme has several such active sites can be transformed into that of several enzymes having only one active site. If a disease alters the initial enzyme, also all substituting enzymes are altered.): in terms of overall reactions and in terms of reactions steps (hemi-reactions, half-reactions). For enzymes with two or more functions, it is important to consider only linearly independent functions, because otherwise cyclic elementary modes would occur which do not perform any net transformation. However, the choice of linearly independent functions is not a priori unique. In Chapter 2, we give a method for making this choice unique by considering the convex basis of the hemi-reactions system. The set of l
- Published
- 2004
16. Lysosphingolipids and sphingolipidoses: Psychosine in Krabbe's disease.
- Author
-
Spassieva S and Bieberich E
- Subjects
- Animals, Brain metabolism, Brain pathology, Glycoside Hydrolases deficiency, Humans, Leukodystrophy, Globoid Cell pathology, Membrane Microdomains genetics, Membrane Microdomains metabolism, Psychosine genetics, Glycoside Hydrolases genetics, Leukodystrophy, Globoid Cell genetics, Leukodystrophy, Globoid Cell metabolism, Mutation genetics, Psychosine metabolism
- Abstract
Until recently, lipids were considered inert building blocks of cellular membranes. This changed three decades ago when lipids were found to regulate cell polarity and vesicle transport, and the "lipid raft" concept took shape. The lipid-driven membrane anisotropy in form of "rafts" that associate with proteins led to the view that organized complexes of lipids and proteins regulate various cell functions. Disturbance of this organization can lead to cellular, tissue, and organ malfunction. Sphingolipidoses, lysosomal storage diseases that are caused by enzyme deficiencies in the sphingolipid degradation pathway, were found to be particularly detrimental to the brain. These enzyme deficiencies result in accumulation of sphingolipid metabolites in lysosomes, although it is not yet clear how this accumulation affects the organization of lipids in cellular membranes. Krabbe's disease (KD), or globoid cell leukodystrophy, was one of the first sphingolipidosis for which the raft concept offered a potential mechanism. KD is caused by mutations in the enzyme β-galactocerebrosidase; however, elevation of its substrate, galactosylceramide, is not observed or considered detrimental. Instead, it was found that a byproduct of galactosylceramide metabolism, the lysosphingolipid psychosine, is accumulated. The "psychosine hypothesis" has been refined by showing that psychosine disrupts lipid rafts and vesicular transport critical for the function of glia and neurons. The role of psychosine in KD is an example of how the disruption of sphingolipid metabolism can lead to elevation of a toxic lysosphingolipid, resulting in disruption of cellular membrane organization and neurotoxicity. © 2016 Wiley Periodicals, Inc., Competing Interests: The authors declare no conflict of interest., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
17. Frequency of Glutathione Reductase, Pyruvate Kinase and Glucose-6-Phosphate Dehydrogenase Deficiency in a Spanish Population
- Author
-
Ángela Casado Moragón, M.E. López-Fernández, and S. C. García
- Subjects
Male ,inorganic chemicals ,Pyruvate decarboxylation ,Pyruvate dehydrogenase lipoamide kinase isozyme 1 ,Pyruvate dehydrogenase kinase ,Enzyme deficiencies ,Pyruvate Kinase ,Glutathione reductase ,Pyruvate dehydrogenase phosphatase ,fluids and secretions ,Gene Frequency ,hemic and lymphatic diseases ,Genetics ,Humans ,Pyruvate kinase ,Glucose-6-phosphate dehydrogenase ,Genetics (clinical) ,Chemistry ,Pyruvate dehydrogenase complex ,Glucosephosphate Dehydrogenase Deficiency ,Glutathione Reductase ,Biochemistry ,Spain ,Female ,Branched-chain alpha-keto acid dehydrogenase complex ,Metabolism, Inborn Errors ,Spanish population - Abstract
The frequencies of deficiencies of glutathione reductase (GSSG-R), pyruvate kinase (PK) and gIucose-6-phosphate dehydrogenase (G6PD) in a Spanish sample are presented. A total of 2,129 individuals was analyzed for GSSG-R, 1,636 for PK, and 1,066 (629 males and 437 females) for G6PD. Beutler’s method was used. The frequencies obtained for these deficiencies were: GSSG-R, 0.09%; PK, 0.24%; and G6PD, 0.79%. The results are discussed.
- Published
- 1979
18. Frequency of glutathione reductase, pyruvate kinase and glucose-6-phosphate dehydrogenase deficiency in a spanish population
- Author
-
García, S. C., Casado Moragón, Ángela, López-Fernández, M.E., García, S. C., Casado Moragón, Ángela, and López-Fernández, M.E.
- Abstract
The frequencies of deficiencies of glutathione reductase (GSSG-R), pyruvate kinase (PK) and gIucose-6-phosphate dehydrogenase (G6PD) in a Spanish sample are presented. A total of 2,129 individuals was analyzed for GSSG-R, 1,636 for PK, and 1,066 (629 males and 437 females) for G6PD. Beutler’s method was used. The frequencies obtained for these deficiencies were: GSSG-R, 0.09%; PK, 0.24%; and G6PD, 0.79%. The results are discussed.
- Published
- 1979
19. Genetic burden of red cell enzyme glucose-6-phosphate dehydrogenase deficiency in two major Scheduled Tribes of Sundargarh district, Northwestern Orissa, India
- Author
-
Balgir, R. S.
- Published
- 2007
20. Casey's Problem: Interpreting and Evaluating a New Test
- Author
-
Smith, James E. and Winkler, Robert L.
- Published
- 1999
21. Enzyme Null Alleles in Natural Populations of Drosophila melanogaster: Frequencies in a North Carolina Population
- Author
-
Voelker, Robert A., Langley, Charles H., Ohnishi, Seido, Dickson, Barbara, Montgomery, Elizabeth, and Smith, Sandra C.
- Published
- 1980
22. Recessive Lethal Deletion on Mouse Chromosome 7 Affects Glucocorticoid Receptor Binding Activities
- Author
-
Goldfeld, Anne E., Firestone, Gary L., Shaw, Phyllis A., and Gluecksohn-Waelsch, Salome
- Published
- 1983
23. Frequency of Enzyme Deficiency Variants in Erythrocytes of Newborn Infants
- Author
-
Mohrenweiser, Harvey W.
- Published
- 1981
24. Genetic Variants of Glucose 6-Phosphate Dehydrogenase from Human Erythrocytes: Unique Properties of the A - Variant Isolated from ``Deficient'' Cells
- Author
-
Babalola, Olaniyi, Cancedda, Ranieri, and Luzzatto, Lucio
- Published
- 1972
25. Hemolytic Anemia and G6PD Deficiency
- Author
-
Yoshida, Akira
- Published
- 1973
26. 6-phosphogluconolactonase Deficiency, a Hereditary Erythrocyte Enzyme Deficiency: Possible Interaction with Glucose-6-phosphate Dehydrogenase Deficiency
- Author
-
Beutler, Ernest, Kuhl, Wanda, and Gelbart, Terri
- Published
- 1985
27. Lymphocyte Ecto-5′-Nucleotidase Deficiency in Agammaglobulinemia
- Author
-
Edwards, N. Lawrence, Magilavy, Daniel B., Cassidy, James T., and Fox, Irving H.
- Published
- 1978
28. Hepatocellular Transplantation for Metabolic Deficiencies: Decrease of Plasma Bilirubin in Gunn Rats
- Author
-
Matas, Arthur J., Steffes, Michael W., Mauer, S. Michael, Lowe, Ann, Simmons, Richard L., and Najarian, John S.
- Published
- 1976
29. Negro Variant of Glucose-6-Phosphate Dehydrogenase Deficiency (A$^{-}$) in Man
- Author
-
Yoshida, Akira, Stamatoyannopoulos, George, and Motulsky, Aṛno G.
- Published
- 1967
30. Serogenetic Studies in Gypsy Sikligars of Northwestern India
- Author
-
Balgir, R. S.
- Published
- 1986
31. Red cell enzyme deficiencies in the tribal population groups of the Bastar District, Madhya Pradesh, India
- Author
-
Basu, S. and Jindal, A.
- Published
- 1995
32. BIOGENETICAL STUDIES OF NAGAS: GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY IN ANGAMI NAGAS
- Author
-
SETH, PRAVEEN KUMAR and SETH, SWADESH
- Published
- 1971
33. Malaria In African Children With Deficient Erythrocyte Glucose-6-Phosphate Dehydrogenase
- Author
-
Allison, A. C. and Clyde, D. F.
- Published
- 1961
34. Glucose-6-Phosphate Dehydrogenase Activity Levels In Enzyme-Deficient Greek Individuals
- Author
-
Choremis, C., Kattamis, Chr., Zannos-Mariolea, L., and Paraschopoulou-Prevedouraki, P.
- Published
- 1963
35. DEFICIENCY OF GLUCOSE-6-PHOSPHATE DEHYDROGENASE—OBSERVATIONS ON A SAMPLE FROM BOMBAY
- Author
-
Baxi, A. J., Balakrishnan, V., and Sanghvi, L. D.
- Published
- 1961
36. Gene Defect Located for Gaucher's Disease
- Published
- 1987
37. Medical Sciences
- Published
- 1972
38. Life Sciences Notes
- Published
- 1967
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.