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1sriwidiaaj/ch metab/inter08
METABOLISM
Sri Widia A JusmanDepartment of Biochemistry & Molecular
Biology FMUI
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METABOLISM• Process of how cells acquire, transform, store and
use energy
• Study of the chemistry, regulation and energetics
of the reactions in biological cells
• All organisms use the same general pathway for extraction and utilization of energy
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In human • metabolism is a series of changes that a
substance undergoes after absorption from gastrointestinal tract, used for synthesis of tissue component (anabolism) or breakdown (catabolism) or altered and eliminated from the body
• metabolic process regulated by nerve and
hormonal control
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METABOLISM
• CATABOLISM - pathway for breakdown / oxidation of substances, produced energy
• ANABOLISM - pathway for synthesis of substances, need energy
ATP
Prot, CH, fat
CO2 + H2O
Food Small moldigest abs anabolism
catabolism
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CATABOLISM
• Degradative pathway of complex organic molecules ( fats, carbohydrate and proteins ) to a simpler molecule ( lactate, pyruvate, CO2, H2O and NH3)
• Characterized by oxidation reactions, released free energy from foodstuff, captured in the form of ATP
• Catabolic process release the potential energy from food and collect it in the reactive intermediate
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Stages of catabolism
Stage I• breakdown of macromolecules to building blocks - proteins → amino acids - triacylglycerols → fatty acids + glycerol - polysaccharides → glucose
Stage II• amino acids, fatty acids, monosaccharides are
oxidized to acetyl CoA • some energy released and captured in the form of
NADH and ATP• acetyl CoA – is a common catabolism product of
protein, CH and fat
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Stage III
• acetyl CoA enter citric acid cycle, oxidized to CO2
• oxidative phosphorylation in respiratory chain - produced ATP & H2O
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e-
Protein CH Lipid
AA glucose fatty acid
NH3
Acetyl CoA
Krebs cycle
CO2
H2O + ATP
RC
Catabolism Convergent
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ANABOLISM
• Construction of large, complex biomolecules from smaller precursor molecules
( amino acids → proteins, pyruvate → glucose, nucleotides → DNA, etc)
• Energy supplied by ATP, NADH / NADPH from catabolism
• Anabolic process use the energy stored in ATP
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STAGES OF ANABOLISM – 3 stages ∼ catabolism
• simple metabolites → macromolecules• need energy ( ATP, NADPH )• divergent
CHOxaloacetate / pyruvate / lactate → monosaccharide → polysaccharide
PROTEINacetyl CoA / pyruvate / α-ketoacids + NH3 → amino acids → proteins
FATAcetyl CoA → fatty acids → triacylglycerols
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Anabolism and catabolism linked together
ATP - universal carrier of biochemical energy
The recycling of ATP is the central theme of metabolism
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Protein CH Lipid
A A glucose Fatty acid + glycerol
Pyruvate
Acetyl CoA
H2ONH3
CO2
ATP ATP
ATP
ATP
ATP
Stage I
Stage II
Stage III
Macro mol
“building block”
Common catab product
Catab end-product
Krebs cycle
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CARBOHYDRATE METABOLISM
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Carbohydrate • 70%-80% of dietary intake • Function – energy source for metabolic processes• 3 monosaccharides absorbed amylum intestine glucose sucrose fructose lactose galactose
Glucose, fructose, galactose – after absorbed from intestine - were transported to the liver
Liver convert fructose, galactose glucose
CH used as a energy by cells - glucose
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Liver • some parts of glucose were oxidized ATP
(through glycolysis for liver cells )
• stored as glycogen (through glycogenesis)
• transport out to extrahepatic tissues to be oxidized ATP (glycolysis for brain, erythrocytes, muscle, adipose tissue)
• excess intake of carbohydrate stored as fat (through lipogenesis)
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Transport of glucose into the tissues - need insulin (except liver cells)
brain - absolutely need glucose as source of energy• glucose CO2 + H2O + ATP• blood glucose dizziness, headache
coma death
erythrocytes - absolutely need glucose• glucose pyruvate lactate + ATP
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Muscle can use different sources of energy - blood glucose - muscle glycogen - fattty acids glucose pyruvate lactic acid + ATP (anerobic) CO2 + H2O + ATP (aerobic)
Adipose tissue - use glucose as source of energy or stored as triacylglycerolsglucose CO2 + H2O + ATP (glycolysis)
triacylglycerols ( lipogenesis )
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METABOLIC PATHWAYS of CH
• Glycolysis• HMP ( Hexose Mono Phosphate ) shunt• Glycogenesis• Glycogenolysis• Gluconeogenesis• Uronic acid pathway• Amino sugar pathway• Citric acid cycle ( Krebs cycle )
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GLYCOLYSIS
• major metabolic pathway of glucose - produced energy for cell / tissues
• occurred in cytosol of all cells
• Step I - glucose undergoes phosphorylation - by hexokinase or glukokinase to produce G6-P
• G 6-P - important intermediate - related with - HMP shunt - glycogenesis - glycogenolysis - gluconeogenesis
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DIFFERENCES HEXOKINASE - GLUKOKINASE HK GK- present in all cells - only in liver and kidney- constitutive enzyme - inducible enzyme - inhibited by its product - not inhibited by its ( G 6-P ) product- affinity for glucose - affinity for glucose (Km for glucose ) ( Km for glucose )- can phosphorylate - only phosphorylate another hexoses glucose- function: for maintained - function: for lowering supply of energy to the blood glucose after tissues meal
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GLYCOLYSIS (Embden-Meyerhoff pathway)
• Major metabolic pathway of glucose – produced energy
• 1 mol glucose ( 6 C ) – split into 2 mol pyruvates (3 C ) through several steps
• Occurred in cytosol of all cells
• Can proceed in - aerobic condition - anaerobic condition
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GLYCOLYTIC PATHWAY (Embden-Meyerhoff pathway)
Glucose + ATP → glucose 6-P + ADP
Glucose 6-P ↔ fructose 6-PFructose 6-P + ATP → fructose 1,6-BP + ADPFructose 1,6-BP ↔ di-OHacetone-P + glyceraldehide 3-P
Glyceraldehide 3-P + Pi + NAD ↔ 1,3-bisphosphoglycerate + NADH + H+
1,3-bisphosphoglycerate + ADP ↔ 3-P glycerate + ATP
3-P glycerate ↔ 2-P glycerate
2-P glycerate ↔ P-enolpyruvate + H2O
P-enol pyruvate + ADP → pyruvate + ATP
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AEROBIC GLYCOLYSIS
• occur under aerobic condition• end product : pyruvate• under aerobic condition, pyruvate will be
oxidized further in mitochondria to acetyl CoA to produce CO2 + H2O + ATP via citric acid cycle
• energy yield / mol glucose : 38 ATP
gluc pyruvate pyruvate acetyl CoA CO2 + H2O + ATP
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Aerobic GlycolysisAerobic Glycolysis
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ANAEROBIC GLYCOLYSIS• occur under anerobic condition in all cells
and in erythrocytes• end product : lactate• pyruvate reduced to lactate by enzyme
lactate dehydrogenase ( LDH ), need NADH
• energy yield : 2 ATP/ mol oxidized glucose Gluc G 6P 2 pyruvate 2 Lactate
HK/GK LDH
NADH
+ H+
NAD+
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GLYCOLYSIS IN ERYTHROCYTE
• end product : always lactate ( although the surrounding medium is aerobic )
• produced 2,3-bisphosphoglycerate (2,3-BPG) - facilitate removal of oxygen from hemoglobin in the tissues where pO2 is low
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Acetyl CoAoxaloacetate
Glucose
Glucose 6-PGlycogen
Fructose 1,6-BP
Glyceraldehide 3-P
Di-OH acetone P
1,3-BP Glycerate
3-P Glycerate
pyruvate
pyruvate
ATP
Fructose 6-P
ATP
NAD+
NADH + H+
ATP
ATP
citrate
α−KGfumarate
malate
PDH Mitochondria
CytosolLactate LDH
GLYCOLYSIS
HK
PFK
GAPDH
PK
TCA cycle
CO2
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OXIDATIVE DECARBOXYLATION OF PYRUVATE TO ACETYL COA
• catalyzed by pyruvate dehydrogenase (PDH ) complex, need coenzymes :
- coenzyme A ( CoA ) - lipoic acid - thiamine pyrophosphate ( TPP ) - flavin adenine dinucleotide ( FAD ) - niacinamide adenine dinucleotida ( NAD ) PDHPyruvate acetyl CoA + CO2
CoA, lipoic acid, TPP
FAD, NAD+
FADH, NADH + H+
CO2 + ATPRC
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KREBS CYCLE (citric acid cycle, tricarboxylic acid cycle )
• series of reactions formed a cycle
• occur in matrix mitochondria
• common metabolic pathway for oxidation of carbohydrate, fat and protein convert to acetyl CoA or intermediates of citric acid cycle
catabolic role
• also play role in gluconeogenesis, transamination / deamination, lipogenesis
anabolic roleAMPHIBOLIC ROLE OF KREBS CYCLE
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TCA / Krebs cycle
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glucose Fatty acid Amino acid
Acetyl CoA
citrate
isocitrate
α-ketoglutarate
succynil CoAsuccinate
fumarate
malate
oxaloacetate
NAD
2H2H
2H
Fp
KoQ
Sit b
Sit c
Sit aa3
H2O
2H
∼P
∼P
∼P
Oxidative phosphorylation
Catabolic role of TCA Cycle
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Acetyl CoA
Citrate
α-ketoglutarate
Succinyl CoA
Malate
OxaloacetateFatty acids
amino acids
Heme
Gluconeogenesis
Amino acids
Anabolic role of TCA cycle
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HMP SHUNT(Pentose phosphate pathway)
• alternative oxidative pathway for glucose, besides glycolysis
• Function : not to produce energy, but to produce - NADPH for synthesis of fatty acid, steroid hormone, protect cells from oxidative damage - ribose for synthesis of nucleic acids (DNA/RNA)
• occur in cytosol of liver tissues, mammary tissues during lactation, gonades, adrenal cortex, liver, erythrocytes.
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HMP shunt - 2 steps:
I. Dehydrogenation and decarboxylation of G 6-P to ribulose 5-P catalyzed by enzyme G 6-P dehydrogenase (G6P DH)
Glucose G 6-P Ribulose 5-PNADP NADPH
G6P DH
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II. Resynthesis of G 6-P from ribulose 5-P under series of reaction, catalyzed by enzymes transketolase and transaldolase, need coenzyme TPP
( measurement of activity of transketolase - for diagnosis of thiamine deficiency )
Ribulose 5-P Glucose 6-P
Transketolse, transaldolase
TPP
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GLYCOGENESIS (synthesis glycogen from glucose)
• occur in liver and muscle tissues
• glycogen - stored form of carbohydrate in animal
(analog to amylum in plants) - polymer of glucose with 1,4-glycosidic bonding ( between C1 of one glucose with C4 of next glucose ) - at branch point, 1,6-glycosidic bonding
• Enzymes - glycogen synthetase - branching enzymes
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Glycogen synthesisGlucose
G 6-P
G 1-P
UDPGlucose Glycogen
UTP
PPi
Glycogen synthase
(active)
Glycogen synthase
(inactive)
ATP
ADPProtein kinase A Protein phosphatase
Pi+ insulin- glucagon
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Glycogen synthase
Branching enzyme
Biosynthesis of glycogen
Glycogen primer
1,4-glycosidic bonding
1,6-glycosidic bonding
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G 6-P
G 1-P
Glycogen
α1→ 4 & α1→ 6 glucosyl units
ATPADP
Pi
Free glucose (from debranching enzyme)
phosphorylase
Debranching enzymeUDPG
Glycogen primer
Branching enzyme
α1→ 4 glucosyl units
Glycogen synthase
GK G 6-Pase
Glycogenolysis
Glycogen synthesis UTP
cAMP + -
Glukagon
Insulin-
+
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GLYCOGENOLYSIS
Liver glycogen • convert to glucose (Glycogen → G 1P → G 6 P →
glucose)• if there is need for glucose of the tissues ( in fasting)
Muscle glycogenolysis • to supply energy for muscle iself• end product: glucose 6-P – because muscle does not
contain enzyme G 6Pase• glycogenolysis continues with glycolysis in muscle
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Liver glycogenolysis
• to maintained blood glucose between normal range for energy
• Important for supply of glucose to particular tissues - especially brain, erythrocytes
• end product: free glucose, diffuse into blood circulation which then uptake by tissues
• Enzymes : - Glycogen phosphorylase - Glycogen transferase - debranching enzyme
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Glycogen phosphorylase
Glucan transferase
Steps of glycogenolysis
Debranching enzyme
Pi
Free glucose
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GLUCONEOGENESIS(synthesis of glucose from non-CH precursors)
• occur when there is no sufficient carbohydrate in diet intake
• glucose absolutely need as a source energy for certain tissues
• most active tissue - liver, kidney
• gluconeogenesis process - reversal of glycolysis process, except on certain points, need certain enzymes ( key enzymes )
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substrate for gluconeogenesis
• lactate ( by lactate dehydrogenase)
• glycerol ( by glycerokinase )
• glycogenic amino acids ( via intermediates of TCA cycle - fumarat, oxaloacetate, α-ketoglutarate )
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Glucose
F 6P
Pyruvate
Acetyl CoA
CitrateOxaloacetate
Glycolysis
Gluconeogenesis
TCA
G6Pase
Malate
PEP
F1,6BP
G 6P
F1,6BPase
Pyr carboxylase
Pyr carboxykinase
Lactate, Amino acid
Glycerol
Amino acid
Amino acid
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Cori cycle • Lactic acid formed by glycolysis in muscle (anaerobic)
and erythrocyte – transported to the liver & kidney – reformed to glucose - enter circulation – uptake by muscle tissues
Glucose – alanine cycle• Alanine (from degradation of protein in muscle tissue
during starvation) – transported to the liver – reformed to glucose – enter circulation – uptake by muscle tissues – transamination to alanine
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REGULATION OF BLOOD GLUCOSECarbohydrate currency of the body - glucose
postprandial ( after meal ) • glucose concentration increased up to 110 - 140 mg/
dL - rapidly taken-up by all tissues - in a few hour restored to fasting level
• blood glucose level - stimulate insulin secretion from pancreas - glucose enter cells - pathways for glucose consumption of tissues - glycolysis, glycogenesis, HMP shunt - blood glucose level back to normal
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• even in fasting – there is always a minimum concentration of glucose ( 60 - 90 mg/dL )
exercise/fasting • blood glucose level - stimulate glucagon secretion from
pancreas, epinephrine from adrenal medulla - glycogenolysis, gluconeogenesis - blood glucose level back to normal
Insulin & glucagon - regulate blood glucose level
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Insulin
• play a central role in regulating blood glucose• Secreted as a direct response to hyperglycemia• facilitate uptake of glucose into extrahepatic
tissues• Stimulate the liver to store glucose as glycogen• Stimulate the glycolysis, HMP shunt• Stimulate the lipogenesis in adipose tissues
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Glucagon
• Opposes the action of insulin• Secreted as a response to hypoglycemia• Activate gluconeogenesis and
glycogenolysis
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