PETER PAZMANY CATHOLIC UNIVERSITY · PDF filesubdivision: trioses, tetroses, pentoses,...
Transcript of PETER PAZMANY CATHOLIC UNIVERSITY · PDF filesubdivision: trioses, tetroses, pentoses,...
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Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework**
Consortium leader
PETER PAZMANY CATHOLIC UNIVERSITYConsortium members
SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER
The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund ***
**Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben
***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg.
PETER PAZMANY
CATHOLIC UNIVERSITYSEMMELWEIS
UNIVERSITY
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BIOCHEMISTRY
CATABOLISM OF CARBOHYDRATES
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(BIOKÉMIA )
(A SZÉNHIDRÁTOK LEBONTÁSA )
TRETTER LÁSZLÓ
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Biochemistry: Catabolism of carbohydrateswww.se.huhttp://semmelweis-egyetem.hu/
CatabolismDEF: Part of intermediary metabolism dealing with the energy-yielding degradation of nutrient molecules
CarbohydratesDEF: Aldehyde or ketone derivatives of polyhydric alcohols
Antonym of catabolism: anabolism
Examples for catabolic processesDecomposition of glucose to pyruvate or lactate called: glycolysisDecomposition of fatty acids to acetyl-CoA called: beta oxidationDecomposition of glycogen to glucose: called glycogenolysisDecomposition of acetyl-CoA to carbon dioxide + water called: citric acid cycle
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Biochemistry: Catabolism of carbohydrateswww.se.huhttp://semmelweis-egyetem.hu/
CLASSIFICATION of CARBOHYDRATES
MonosacharidesDEF: those carbohydrates that cannot be hydrolyzed into a simpler form
subdivision: trioses, tetroses, pentoses, hexoses, heptoses depending upon the number of carbon atom
subdivision: aldoses or ketoses depending upon the presence of of aldehyde or ketone group
DisaccharidesDEF: hydrolysis of disaccharides yields 2 molecules of monosaccharides
OligosaccharidesDEF: Hydrolysis yields 3-6 monosaccharide units
PolysaccharidesDEF: Hydrolysis yields more than 6 monosaccharide units
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Biochemistry: Catabolism of carbohydrateswww.se.huhttp://semmelweis-egyetem.hu/
Examples for monosaccharides
Aldoses Ketoses
Trioses (C3H6O3) GlyceroseSynonym:Glycer-aldehyde
Dihydroxy-acetone
Tetroses (C4H8O4) Erythrose Erythrulose
Pentoses (C5H10O5) Ribose Ribulose
Hexoses (C6H12O6) GlucoseGalactoseMannose
Fructose
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Biochemistry: Catabolism of carbohydrateswww.se.huhttp://semmelweis-egyetem.hu/
Table of contents:
Glycolysis, the anaerobic decomposition of glucose
Catabolism of non-glucose carbohydrates
Regulation of carbohydrate catabolism
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Biochemistry: Catabolism of carbohydratesGlycolysis
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Glycolysis -reactions
Learning objectives:
Carbohydrates are major energy giving substrates for a living organismGlycolysis an universal pathway to decompose glucose even in the absence of oxygen
At the end of the presentation students will be able:
1. To reproduce the most important steps of glycolysis2. To understand the formation of ATP in the absence of oxygen3. To demonstrate important principles of thermodinamics
using examples taken from glycolysis
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GlycolysisDEF
-Anaerobic degradation of glucose to lactate or
-Anaerobic degradation of glucose to pyruvate – a preparatory pathwayfor the aerobic metabolism of glucose
-Can occur in every cell
-Energy yielding pathway (2 ATP/glucose)
In the absence of oxygen every cell would perform glycolysis and the end-product will be lactatethusglycolysis is the most universal metabolic pathway.
Biochemistry: Catabolism of carbohydratesGlycolysis
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Glycolysis -reactions
Overview of glycolysis GlucoseC6
Hexose phosphates(C6)
Triose phosphate Triose phosphate
Pyruvate(C3)
Lactate(C3)
Lactate
blood
NADH+H+ NAD+ CO2H2OATP
+ O2 Without O2orno mitochondria
ATPformation
Biochemistry: Catabolism of carbohydratesGlycolysis
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Overview of glycolysis
In the absence of oxygen or mitochondria
2 NAD+
2 NADH+H+
In the presence of oxygen and mitochondria
Glycolysis -reactions
Biochemistry: Catabolism of carbohydratesGlycolysis
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Glycolysis -reactions
Preparatory phase of glycolysis
2 ATP investedandHexose chain is converted into triose phosphates
Biochemistry: Catabolism of carbohydratesGlycolysis
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ATP requiring reactions of glycolysis
HexokinaseGlucokinase
Phosphofructokinase-1
ΔG’o= -16.7 kJ/molirreversible
ΔG’o= -14.2 kJ/molIrreversibleRate limiting step of glycolysis
Important reactions of the preparatory phase
Biochemistry: Catabolism of carbohydratesGlycolysis
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Important reactions of the preparatory phase
Hexokinase and glucokinase are isoenzymes
IsoenzymesDEF: Enzymes catalyzing the same reactionBut differ:In amino acid sequenceVmax, and/or KMin regulation
Hexokinases are localized in the peripheral tissuesGlucokinase is localized in the liver
Hexokinases show high affinity for glucoseGlucokinase show low affinity for glucoseTheir regulation is different
Biochemistry: Catabolism of carbohydratesGlycolysis
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Important reactions of the payoff phase
ΔG’o= 6.3 kJ/molreversible
ΔG’o= -18.5 kJ/molreversible
ΔG’o= -31.4 kJ/molirreversible
Inorganic phosphate incorporationNADH formationHigh energy acyl-phosphate group formation on the 1st C atom
The acyl-phosphate group is transferred to ADPSubstrate level phosphorylation
From the high energy enol-phosphate bond the phosphoryl group is transferred to ADP
Substrate level phosphorylation
Biochemistry: Catabolism of carbohydratesGlycolysis
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Energetic balance of glycolysis
Preparatory phase 2 ATP invested - 2
Payoff phase 2x2 ATP produced(1 hexose 2 triose) +4
Summary Net ATP production +2
Substrate level phosphorylationDEF: Formation of ATP by phosphoryl group transfer froma compound having high energy bound
Examples for substrate level phosphorylation: in glycolysis: phosphoglycerate kinase reaction
pyruvate kinase reactionin citric acid cycle: succinate thiokinase reaction
Antonym of substrate level phosphorylation: oxidative phosphorylation
Biochemistry: Catabolism of carbohydratesGlycolysis
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Glycolysis – the most important decomposition pathway of the most important carbohydrate
- glycolysis produces energy even in the absence of oxygen
- every higher eukaryotic cells are able to perform glycolysis
- 2 mol of ATP produced from 1 mol of glucose
- in the presence of oxygen and mitochondria glycolysisis continued in the citric acid cycle
- glycolysis has reversible and irreversible steps
- the irreversible reactions of glycolysis are catalyzed byhexokinase (glucokinase in liver), phosphofructokinaseand pyruvate kinase
Biochemistry: Catabolism of carbohydratesGlycolysis
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Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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Catabolism of non-glucose carbohydrates
Introduction
Carbohydrates are major energy giving substrates for living organism
Besides glucose other carbohydrates (e.g. fructose and galactose) are also taken up by the organism, which sugars can be catabolized or can participate in the synthesis of other molecules
Glycogen is a special storage form of glucose with a function in the maintenance of blood sugar level and in the energy supply of the muscle cells.
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Learning objectives
At the end of the presentation students will be able:
To understand the pathways used by individual carbohydrates to join to the mainstream of the metabolism
To understand that consumption of different carbohydrates could change physiological pathways and could have pathological consequences as well.
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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Fructose metabolism
Availability of fructose: Natural sources: fruit juices, honey, disaccharide sucroseFood industry: High Fructose Corn Syrup
Importance: Mainly changed to glucose in the liver and used in the body
Pathological significance: hereditary fructose intolerance (fructose accumulationplus hypoglycemia), obesity
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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Entry of fructose into glycolysis1. In liver – major organ of fructose catabolism
Glycolysis, gluconeogenesis
Important: fructose catabolism in theliver bypasses phosphofructokinase-1!
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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Entry of fructose into glycolysis2. In skeletal muscle – less important in fructose catabolism
Fructose
Fructose 6-phosphate
ATP
ADPHexokinase
Glycolysis
Hexokinase - not entirely specific for glucose
- converts fructose to Fr 6-Pat low [Glucose]at high [Fructose]
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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Glycolysis, gluconeogenesis
Pathological aspects of fructose metabolism
X
1) Hereditary fructose intoleranceAldolase B deficiency[fr 1-P] increased
Symptom: hypoglycemiaWhy? See:regulation of carbohydrate breakdown
2) High fructose consumption- Susceptibility to obesity,hyperlipidemia
hyperlipidemiaDEF: increased concentrationof lipids in the blood
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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Galactose metabolism
Availability of galactose: from milk sugar: lactose. Intestinal hydrolysis of lactoseresults in formation of galactose+glucose
Galactose is metabolized mainly in the liver, can be converted to glucose
Importance: needed for synthesis of glycoproteins, glycolipids, lactose (in lactating women)
Pathological significance: galactosemia
Lactose galactose + glucose
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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Galactose metabolismGalactose
galactokinase
Galactose 1-phosphate
UDP-Glc-Gal 1-Puridyltransferse
Glucose 1-phosphate
phosphoglucomutase
Glucose 6-phosphate
ATP
ADP
Glucose 1-P
UDP-Glcpyrophosphorylase
UDP-glucose
UDP-galactose
UTP
PPi
UDP-gal epimerease
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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[Galactose]
galactokinase
[Galactose 1-phosphate]
UDP-Glc-Gal 1-Puridyltransferse
Glucose 1-phosphate
phosphoglucomutase
Glucose 6-phosphate
ATP
ADP
Glucose 1-P
UDP-Glcpyrophosphorylase
UDP-glucose
UDP-galactose
UTP
PPi
UDP-gal epimerease
Pathological aspects of galactose metabolism
XGalactosemia:lack of UDP-Glc-Gal 1-P uridyltransferse
Consequence: increased [Galactose] symptom: cataractDEF:opacity in the lens of the eye
increased [Galactose 1-phosphate] symptoms: liver failure, mental retardation
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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Glycogen: the storage form of glucose in the bodyforms granules in the cytosolmany cells contain glycogenthe most important organs for storage: liver, skeletal muscle
function of liver glycogen: maintenance of blood sugar levelfunction of muscle glycogen: energetic support of contraction
Structure: highly branched structurechains: alpha [1-4] glucosidic linkagebranches: alpha [1-6] glucosidic linkage
protein glycogenin is localized in the core of glycogenglycogenin is required for the synthesis
molecular mass: in the order of millions
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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1
6
6
144 1 4 1
141
Glycogenin
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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GlycogenolysisDEF: Intracellular decomposition of glycogenResulting glucose in the liver and kidney cortexResulting glucose 6-P in the muscle
Synonym: glycogen breakdownAntonym: glycogenesis or glycogen synthesis
The purpose of glycogenolysis in liver (and to a smaller extent in kidney cortex): maintenance of blood sugar level. Blood sugar level should be kept constant, because there are cells and tissues which gain energy exclusively from glucose
The purpose of glycogenolysis in muscle cells: to support the energy requirement of contraction.
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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The fate of glycogen-derived glucoseafter breakdown
In liver: release to the bloodstream
In muscle: glycolysis then citric acid cycleIn muscle in shortage of oxygen:
glycolysis ending with lactateproduction
phosphoglucomutase
Lactatedehydrogenase
Pi
Glycogen
glycogen phosphorylase
Glucose 1-P
Glucose 6-P
PyruvatePDH complex
Acetyl-CoACitric acid cycle
CO2 + H2O
Glycolysisglucose 6-Pase
Glucose
Lactate
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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Glycogen
Glycogenphosphorylase
Debranching enzymealpha (1→4) → alpha (1→4)
transferase activity
Debranching enzymeAmylo (1→6)-glucosidase
activity
PPi
gl 1-PglH2O
Debranching enzyme has two catalytic activitiesProducts of catabolism: shorter glycogen
glucose 1-Pglucose (captured by hexo- or glucokinase)
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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phosphoglucomutase glucose 6-phosphatase
H2O Pi
fructose 6-phosphate
phosphohexoseisomerase
ER inliver
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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Pathological aspects of glycogen breakdown
Glycogen storage diseasesDEF:inherited disorders characterized byabnormal quantity or type of glycogen in tissues
Examples: Name Deficiency Consequences
Von Gierke’s disease Lack of glucose 6-phosphatase in liver and kidney
Hypoglycemia, hyperlipemia
Cori’s disease Lack of debranching enzyme
Accumulation of abnormally branched glycogen
Mc Ardle’s disesase Lack of glycogen phosphorylase in the skeletal muscle
Diminished tolerance to exercise
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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Summary:
Catabolism of non-glucose carbohydrates were discussed
Glycogen, fructose and galactose catabolism follows individual pathways
All of the individual decomposition pathways will join to glycolysis, so the complete breakdown of these saccharides will be similar to that of glucose.
Biochemistry: Catabolism of carbohydratesCatabolism of non-glucose carbohydrates
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Biochemistry: Catabolism of carbohydratesRegulation of carbohydrate catabolism
Learning objectivesAt the end of the presentation students will be able:
To understand the adaptation of carbohydrate catabolic pathways to the current requirement of the organism and the cell.
To understand the concept that metabolic pathway can be regulated by different ways: the most important ones are:
- Regulation by changing the gene expression- Regulation by reversible covalent modification (e.g.
phosphorylation/dephosphorylation of the key enzymes- Regulation by allosteric effectors
To understand that only a few of the enzymes are regulated in the metabolic pathways, usually the rate-limiting ones and those which catalyze irreversible reactions
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Biochemistry: Catabolism of carbohydratesRegulation of carbohydrate catabolism
Multilevel regulation of glycolytic enzymes
Gene expression Covalent modification Allosteric
Enzyme Inducer repressor phosphorylation
dephosphorylation activator inhibitor
Hexokinase Gluc 6-P
Glucokinase insulinGlucagon (cAMP)
Starvation
Fructose 1-P(through
glucokinase regulatory protein)
Fructose 6-Pthrough
glucokinase regulatory protein)
Phosphofructokinase-1 insulin starvation
Fructose 2,6-P2
AMPATP, citrate, fatty acids
Pyruvate kinase insulin
Glucagon (cAMP)
Starvation
cAMP,Ca-CaM
inactivation
insulinActivation
Fructose 1,6-P2 ATP, alanine
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Biochemistry: Catabolism of carbohydratesRegulation of carbohydrate catabolism
Regulation of glucokinase (liver)
Inative inthe nucleus
The regulation of glucokinase explains hypoglycemia detected in fructose intolerance. Accumulation of fructose 1-P suspends the regulatory protein-mediated inhibition of glucokinase, thus glycolysis will be accelerated
Fructose 6-P mediated inhibition of glucokinase represents a negative fee back mechanism
AccumulationIn fructose intolerance
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Biochemistry: Catabolism of carbohydratesRegulation of carbohydrate catabolism
Regulation of phosphofructokinase-1 in liverInsulin stimulates glycolysis
Insulin
+
Phosphorylated: inactiveDephosphorylated: active
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Biochemistry: Catabolism of carbohydratesRegulation of carbohydrate catabolism
Phosphorylated: inactive
Glucagon
+
XX
Regulation of phosphofructokinase-1 in liverGlucagon inhibits glycolysis
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Biochemistry: Catabolism of carbohydratesRegulation of carbohydrate catabolism
Structure of 6-phosphofructo 2-kinase/fructose 2,6-bisphosphatase enzyme
Tandem enzyme: one polypeptide chain – two catalytic activities
Heart specific enzyme: Phosphorylation (PKA) of the phosphatase domain inactivates phosphatase activityKinase activity will be dominantGlycolysis activated
Liver specific enzyme: Phosphorylation (PKA) near the kinase domain inactivates kinase activityPhosphates activity will be dominant. Glycolysis is inactivated
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Biochemistry: Catabolism of carbohydratesRegulation of carbohydrate catabolism
Allosteric regulation of glycolysis
Meaning of regulators
High [gluc 6-P] indicates that hexokinase activity is too high
High [AMP] – indicates low energy charge of the cell (local regulator)High [ATP] – indicates high energy charge of the cell
High [citrate] indicates the overflow of fatty acid synthesis precursors from the mitochondria to the cytosol
Fructose 2,6-P2 the most important regulator of the rate limiting step of glycolysis. The level of Fr 2,6-P2 reflects hormonal changes.
In liver insulin elevates [Fr 2,6-P2], glycolysis is stimulatedGlucagon decreases [Fr 2,6-P2], glycolysis is inhibitedAdrenalin decreases [Fr 2,6-P2], glycolysis is inhibitedBUT!In the heart adrenaline elevates [Fr 2,6-P2], glycolysis is stimulated
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Biochemistry: Catabolism of carbohydratesRegulation of carbohydrate catabolism
Regulation of glycogen breakdowncAMP level is elevated by some hormones
cAMP activated protein kinase A phosphorylates and activates phosphorylase kinase
Activated phosphorylase kinase phosphorylates and activates glycogen phosphorylase
Activated glycogen phosphorylase catalyzes glycogen breakdown
Those hormones which decrease cAMP level has opposite effect on glycogen breakdown
Calcium activates phosphorylase kinase.
Activated phosphorylase kinase phosphorylates and activates glycogen phosphorylase, which catalyzes glycogen breakdown
Glucose (in liver) inhibits glycogen phosphorylase, i.e. inhibits glycogenolysis
AMP in muscle stimulates glycogen phosphorylase, i.e. activates glycogenolysis
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Biochemistry: Catabolism of carbohydratesRegulation of carbohydrate catabolism
Summary:
Carbohydrates are important sources of energy for the organisms.
Glycolysis is a fundamental energy yielding metabolic pathway in every cell.
The rate of glycolysis is strictly regulated by various mechanisms
Changes of the gene expression of the most important enzymes are regulated by hormones and by the nutrition.
Reversible chemical modification of the enzymes (phosphorylation/dephosphorylation) usually reflects hormonal influence.
The level of allosteric modificators might reflect the actual changes in the local intracellular environment, but could be changed by hormonal effects as well (e.g. [fruc 2,6-P2] is dependent upon hormonal status).
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Biochemistry: Catabolism of carbohydratesRegulation of carbohydrate catabolism
Recommended literature
Orvosi Biokémia (Ed. Ádám Veronika)
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Biochemistry: Catabolism of carbohydrateswww.se.huhttp://semmelweis-egyetem.hu/
Questions:
Describe the regulation of fructose catabolism, compare it with the regulation of glucose catabolism
Which are the irreversible steps of glycolysis?
Which enzyme reaction is the rate-limiting enzyme in the glycolysis?
How many ATP can be produced, if glycolysis starts from previously synthesized glycogen and ends up with lactate formation?
What is the consequence of having different PFK2 isoenzymes in the heart and liver considering the effect of adrenaline on glycolysis?
. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 2011.09.13.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 45
Biochemistry: Catabolism of carbohydrateswww.se.huhttp://semmelweis-egyetem.hu/
Questions:
Which of the following statements are true for the PFK1?
1. The reaction catalized by the enzyme is irreversible in vivo2. The activity of the enzyme can be inhibited by ATP3. Its function is influenced by the ATP/ADP ratio4. It is the fastest enzyme of the glycolysis5. It works even in the absence of ATP
A:2,3,5 B:1,2,3 C:1,2,3,4 D:2,3,4,5 E:1,3,4,5
Which of the following statements are true for the fructose metabolism?
1. Fructose is phosphorylated by hexokinase in the liver2. Fructose metabolism does require a specific aldolase for Fr 1-P3. Fructose can be converted to either pyruvate or glucose4. Fructose consumption can not elevate the blood sugar level5. Fructose catabolism in the liver bypasses phosphofructokinase
A:2,3,5 B:1,2,3 C:1,2,3,4 D:2,3,4,5 E:1,3,4,5