METABOLISM - Website Staff UIstaff.ui.ac.id/.../material/metabolismch-inter08.pdf · sriwidiaaj/ch metab/inter08 2 METABOLISM • Process of how cells acquire, transform, store and

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METABOLISM

Sri Widia A JusmanDepartment of Biochemistry & Molecular

Biology FMUI


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


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


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


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


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


Stage III

• acetyl CoA enter citric acid cycle, oxidized to CO2

• oxidative phosphorylation in respiratory chain - produced ATP & H2O


e-

Protein CH Lipid

AA glucose fatty acid

NH3

Acetyl CoA

Krebs cycle

CO2

H2O + ATP

RC

Catabolism Convergent


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


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


Anabolism and catabolism linked together

ATP - universal carrier of biochemical energy

The recycling of ATP is the central theme of metabolism


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


CARBOHYDRATE METABOLISM


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


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)


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


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 )


METABOLIC PATHWAYS of CH

• Glycolysis• HMP ( Hexose Mono Phosphate ) shunt• Glycogenesis• Glycogenolysis• Gluconeogenesis• Uronic acid pathway• Amino sugar pathway• Citric acid cycle ( Krebs cycle )


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


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


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


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


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


Aerobic GlycolysisAerobic Glycolysis


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+


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


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


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


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


TCA / Krebs cycle


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


Acetyl CoA

Citrate

α-ketoglutarate

Succinyl CoA

Malate

OxaloacetateFatty acids

amino acids

Heme

Gluconeogenesis

Amino acids

Anabolic role of TCA cycle


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.


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


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


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


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


Glycogen synthase

Branching enzyme

Biosynthesis of glycogen

Glycogen primer

1,4-glycosidic bonding

1,6-glycosidic bonding

39sriwidiaaj/ch metab/inter08glucose

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-

+


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


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


Glycogen phosphorylase

Glucan transferase

Steps of glycogenolysis

Debranching enzyme

Pi

Free glucose


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 )


substrate for gluconeogenesis

• lactate ( by lactate dehydrogenase)

• glycerol ( by glycerokinase )

• glycogenic amino acids ( via intermediates of TCA cycle - fumarat, oxaloacetate, α-ketoglutarate )


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


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



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


• 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


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


Glucagon

• Opposes the action of insulin• Secreted as a response to hypoglycemia• Activate gluconeogenesis and

glycogenolysis


METABOLISM - Website Staff UIstaff.ui.ac.id/.../material/metabolismch-inter08.pdf · sriwidiaaj/ch metab/inter08 2 METABOLISM • Process of how cells acquire, transform, store and

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