SEMMELWEIS PETER PAZMANY UNIVERSITY CATHOLIC UNIVERSITY
Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework**
Consortium leader PETER PAZMANY CATHOLIC UNIVERSITY Consortium 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.
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BIOCHEMISTRY
(BIOKÉMIA )
CATABOLISM OF CARBOHYDRATES
(A SZÉNHIDRÁTOK LEBONTÁSA )
TRETTER LÁSZLÓ
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CatabolismDEF: Part of intermediary metabolism dealing with the energy-yielding degradation of nutrient molecules Examples for catabolic processes Decomposition of glucose to pyruvate or lactate called: glycolysis Decomposition of fatty acids to acetyl-CoA called: beta oxidation Decomposition of glycogen to glucose: called glycogenolysis Decomposition of acetyl-CoA to carbon dioxide + water called: citric acid cycle
Antonym of catabolism: anabolism
CarbohydratesDEF: Aldehyde or ketone derivatives of polyhydric alcohols
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 3 Biochemistry: Catabolism of carbohydrates http://semmelweis-egyetem.hu/www.se.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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Examples for monosaccharides
Aldoses Ketoses
Trioses (C3H6O3) Glycerose Dihydroxy- Synonym: acetone Glycer- aldehyde
Tetroses (C4H8O4) Erythrose Erythrulose
Pentoses (C5H10O5) Ribose Ribulose
Hexoses (C6H12O6) Glucose Fructose Galactose Mannose
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Table of contents:
Glycolysis, the anaerobic decomposition of glucose
Catabolism of non-glucose carbohydrates
Regulation of carbohydrate catabolism
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Learning objectives:
Carbohydrates are major energy giving substrates for a living organism Glycolysis 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 glycolysis 2. To understand the formation of ATP in the absence of oxygen 3. 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 pathway for 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 lactate thus glycolysis is the most universal metabolic pathway.
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 8 Biochemistry: Catabolism of carbohydrates Glycolysis http://semmelweis-egyetem.hu/www.se.hu Glycolysis -reactions Overview of glycolysis Glucose C6
Hexose phosphates (C6)
Triose phosphate Triose phosphate
CO2 ATP + + H2O formation NADH+H NAD ATP Pyruvate Lactate Lactate
+ O2 (C3) Without O2 (C3) or blood no mitochondria
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 9 Biochemistry: Catabolism of carbohydrates Glycolysis http://semmelweis-egyetem.hu/www.se.hu Glycolysis -reactions Overview of glycolysis
2 NAD+
2 NADH+H+
In the absence of oxygen or mitochondria In the presence of oxygen and mitochondria
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 10 Biochemistry: Catabolism of carbohydrates Glycolysis http://semmelweis-egyetem.hu/www.se.hu Glycolysis -reactions Preparatory phase of glycolysis
2 ATP invested and Hexose chain is converted into triose phosphates
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 11 Biochemistry: Catabolism of carbohydrates Glycolysis http://semmelweis-egyetem.hu/www.se.hu Important reactions of the preparatory phase
ATP requiring reactions of glycolysis
ΔG’o= -16.7 kJ/mol irreversible Hexokinase Glucokinase
ΔG’o= -14.2 kJ/mol Irreversible Phosphofructokinase-1 Rate limiting step of glycolysis
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 12 Biochemistry: Catabolism of carbohydrates Glycolysis http://semmelweis-egyetem.hu/www.se.hu Important reactions of the preparatory phase
Hexokinase and glucokinase are isoenzymes
IsoenzymesDEF: Enzymes catalyzing the same reaction But differ: In amino acid sequence
Vmax, and/or KM in regulation
Hexokinases are localized in the peripheral tissues Glucokinase is localized in the liver
Hexokinases show high affinity for glucose Glucokinase show low affinity for glucose Their regulation is different
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 13 Biochemistry: Catabolism of carbohydrates Glycolysis http://semmelweis-egyetem.hu/www.se.hu Important reactions of the payoff phase
Inorganic phosphate incorporation NADH formation High energy acyl-phosphate group formation on the 1st C atom ΔG’o= 6.3 kJ/mol reversible
The acyl-phosphate group is transferred to ADP Substrate level phosphorylation
ΔG’o= -18.5 kJ/mol reversible
From the high energy enol-phosphate bond the phosphoryl group is transferred to ADP Substrate level phosphorylation ΔG’o= -31.4 kJ/mol irreversible
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 14 Biochemistry: Catabolism of carbohydrates Glycolysis http://semmelweis-egyetem.hu/www.se.hu 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 from a compound having high energy bound
Examples for substrate level phosphorylation: in glycolysis: phosphoglycerate kinase reaction pyruvate kinase reaction in citric acid cycle: succinate thiokinase reaction
Antonym of substrate level phosphorylation: oxidative phosphorylation
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 15 Biochemistry: Catabolism of carbohydrates Glycolysis http://semmelweis-egyetem.hu/www.se.hu Glycolysis - Summary 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 glycolysis is continued in the citric acid cycle
- glycolysis has reversible and irreversible steps
- the irreversible reactions of glycolysis are catalyzed by hexokinase (glucokinase in liver), phosphofructokinase and pyruvate kinase
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 16 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu
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.
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Availability of fructose: Natural sources: fruit juices, honey, disaccharide sucrose Food industry: High Fructose Corn Syrup
Importance: Mainly changed to glucose in the liver and used in the body
Pathological significance: hereditary fructose intolerance (fructose accumulation plus hypoglycemia), obesity
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 19 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu Entry of fructose into glycolysis 1. In liver – major organ of fructose catabolism
Important: fructose catabolism in the liver bypasses phosphofructokinase-1!
Glycolysis, gluconeogenesis
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 20 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu Entry of fructose into glycolysis 2. In skeletal muscle – less important in fructose catabolism
Fructose Hexokinase - not entirely specific for glucose ATP - converts fructose to Fr 6-P Hexokinase at low [Glucose] ADP at high [Fructose] Fructose 6-phosphate
Glycolysis
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 21 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu Pathological aspects of fructose metabolism
1) Hereditary fructose intolerance Aldolase B deficiency [fr 1-P] increased
Symptom: hypoglycemia Why? See:regulation of carbohydrate breakdown
2) High fructose consumption - Susceptibility to obesity,hyperlipidemia X hyperlipidemiaDEF: increased concentration of lipids in the blood
Glycolysis, gluconeogenesis
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 22 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu Galactose metabolism
Availability of galactose: from milk sugar: lactose. Intestinal hydrolysis of lactose results 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
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 23 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu Galactose metabolism Galactose Glucose 1-P ATP galactokinase UTP UDP-Glc ADP
PPi pyrophosphorylase Galactose 1-phosphate
UDP-glucose UDP-Glc-Gal 1-P UDP-gal epimerease uridyltransferse
UDP-galactose Glucose 1-phosphate
phosphoglucomutase
Glucose 6-phosphate
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Pathological aspects of galactose metabolism [Galactose] Glucose 1-P ATP galactokinase UTP UDP-Glc ADP
PPi pyrophosphorylase [Galactose 1-phosphate]
UDP-glucose UDP-Glc-Gal 1-P UDP-gal epimerease uridyltransferseX UDP-galactose Glucose 1-phosphate Galactosemia: lack of UDP-Glc-Gal 1-P uridyltransferse phosphoglucomutase Consequence: increased [Galactose] symptom: cataractDEF:opacity in the lens of the eye Glucose 6-phosphate increased [Galactose 1-phosphate] symptoms: liver failure, mental retardation
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 25 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu Glycogen metabolism
Glycogen: the storage form of glucose in the body forms granules in the cytosol many cells contain glycogen the most important organs for storage: liver, skeletal muscle
function of liver glycogen: maintenance of blood sugar level function of muscle glycogen: energetic support of contraction
Structure: highly branched structure chains: alpha [1-4] glucosidic linkage branches: alpha [1-6] glucosidic linkage
protein glycogenin is localized in the core of glycogen glycogenin is required for the synthesis
molecular mass: in the order of millions
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 26 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu The structure of glycogen
6
1 4 1 1 6
4 1 4 1 4 1
Glycogenin
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GlycogenolysisDEF: Intracellular decomposition of glycogen Resulting glucose in the liver and kidney cortex Resulting glucose 6-P in the muscle
Synonym: glycogen breakdown Antonym: 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.
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 28 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu The fate of glycogen-derived glucose after breakdown Glycogen P In liver: release to the bloodstream i glycogen phosphorylase
In muscle: glycolysis then citric acid cycle Glucose 1-P In muscle in shortage of oxygen: glycolysis ending with lactate phosphoglucomutase production Glucose 6-P glucose 6-Pase Glycolysis Glucose Lactate Pyruvate Lactate PDH complex dehydrogenase Acetyl-CoA Citric acid cycle
CO2 + H2O
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 29 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu Steps of glycogen breakdown 1
Glycogen Debranching enzyme Debranching enzyme phosphorylase alpha (1→4) → alpha (1→4) Amylo (1→6)-glucosidase transferase activity activity gl 1-P H2O gl Pi P
Glycogen
Debranching enzyme has two catalytic activities Products of catabolism: shorter glycogen glucose 1-P glucose (captured by hexo- or glucokinase)
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 30 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu Steps of glycogen breakdown 2
phosphoglucomutase glucose 6-phosphatase H O 2 Pi
ER in liver
phosphohexose isomerase
fructose 6-phosphate
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 31 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu Pathological aspects of glycogen breakdown
Glycogen storage diseasesDEF:inherited disorders characterized by abnormal quantity or type of glycogen in tissues
Examples: Name Deficiency Consequences
Von Gierke’s disease Lack of glucose 6- Hypoglycemia, phosphatase in liver and hyperlipemia kidney
Cori’s disease Lack of debranching Accumulation of enzyme abnormally branched glycogen
Mc Ardle’s disesase Lack of glycogen Diminished tolerance to phosphorylase in the exercise skeletal muscle
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 32 Biochemistry: Catabolism of carbohydrates Catabolism of non-glucose carbohydrates http://semmelweis-egyetem.hu/www.se.hu 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.
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 33 Biochemistry: Catabolism of carbohydrates Regulation of carbohydrate catabolism http://semmelweis-egyetem.hu/www.se.hu
Learning objectives At 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
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 34 Biochemistry: Catabolism of carbohydrates Regulation of carbohydrate catabolism http://semmelweis-egyetem.hu/www.se.hu Multilevel regulation of glycolytic enzymes
Gene expression Covalent modification Allosteric
phosphorylat dephosphory Enzyme Inducer repressor activator inhibitor ion lation
Hexokinase Gluc 6-P
Glucagon Fructose 1-P Fructose 6-P (through through Glucokinase insulin (cAMP) glucokinase glucokinase regulatory Starvation regulatory protein) protein) Phosphofruct Fructose 2,6-P ATP, citrate, insulin starvation 2 okinase-1 AMP fatty acids Glucagon cAMP, Pyruvate insulin insulin (cAMP) Ca-CaM Fructose 1,6-P ATP, alanine kinase Activation 2 Starvation inactivation
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 35 Biochemistry: Catabolism of carbohydrates Regulation of carbohydrate catabolism http://semmelweis-egyetem.hu/www.se.hu Regulation of glucokinase (liver)
The regulation of glucokinase explains hypoglycemia detected in fructose intolerance. Accumulation of fructose 1-P suspends the Inative in regulatory protein-mediated inhibition of the nucleus glucokinase, thus glycolysis will be accelerated
Fructose 6-P mediated inhibition of glucokinase represents a negative fee back mechanism
Accumulation In fructose intolerance
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 36 Biochemistry: Catabolism of carbohydrates Regulation of carbohydrate catabolism http://semmelweis-egyetem.hu/www.se.hu Regulation of phosphofructokinase-1 in liver Insulin stimulates glycolysis Insulin
+
Dephosphorylated: Phosphorylated: inactive active
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 37 Biochemistry: Catabolism of carbohydrates Regulation of carbohydrate catabolism http://semmelweis-egyetem.hu/www.se.hu Regulation of phosphofructokinase-1 in liver Glucagon inhibits glycolysis
Phosphorylated: inactive X X
+ Glucagon
.2011.09.13.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 38 Biochemistry: Catabolism of carbohydrates Regulation of carbohydrate catabolism http://semmelweis-egyetem.hu/www.se.hu Structure of 6-phosphofructo 2-kinase/fructose 2,6-bisphosphatase enzyme
Tandem enzyme: one polypeptide chain – two catalytic activities
Liver specific enzyme: Phosphorylation (PKA) near the kinase domain inactivates kinase activity Phosphates activity will be dominant. Glycolysis is inactivated
Heart specific enzyme: Phosphorylation (PKA) of the phosphatase domain inactivates phosphatase activity Kinase activity will be dominant Glycolysis activated
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 39 Biochemistry: Catabolism of carbohydrates Regulation of carbohydrate catabolism http://semmelweis-egyetem.hu/www.se.hu 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 stimulated Glucagon decreases [Fr 2,6-P2], glycolysis is inhibited Adrenalin decreases [Fr 2,6-P2], glycolysis is inhibited BUT!
In the heart adrenaline elevates [Fr 2,6-P2], glycolysis is stimulated
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 40 Biochemistry: Catabolism of carbohydrates Regulation of carbohydrate catabolism http://semmelweis-egyetem.hu/www.se.hu Regulation of glycogen breakdown cAMP 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
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 41 Biochemistry: Catabolism of carbohydrates Regulation of carbohydrate catabolism http://semmelweis-egyetem.hu/www.se.hu 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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Recommended literature
Orvosi Biokémia (Ed. Ádám Veronika)
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 43 Biochemistry: Catabolism of carbohydrates http://semmelweis-egyetem.hu/www.se.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?
2011.09.13... TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 44 Biochemistry: Catabolism of carbohydrates http://semmelweis-egyetem.hu/www.se.hu Questions:
Which of the following statements are true for the PFK1?
1. The reaction catalized by the enzyme is irreversible in vivo 2. The activity of the enzyme can be inhibited by ATP 3. Its function is influenced by the ATP/ADP ratio 4. It is the fastest enzyme of the glycolysis 5. 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 liver 2. Fructose metabolism does require a specific aldolase for Fr 1-P 3. Fructose can be converted to either pyruvate or glucose 4. Fructose consumption can not elevate the blood sugar level 5. 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
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