CITRIC ACID CYCLE

(TRICARBOYLIC ACID CYCLE = TCC)

(KREBS CYCLE)

CITRIC ACID CYCLE

(TRICARBOXYLIC ACID CYCLE = TCC)
(KREBS CYCLE)
* The final common pathway for the oxidation of :
- Carbohydrate
- Lipids
- Protein
* Amphibolic (anaphlerotic) reaction
(Plays roles in both oxidative & synthetic
processes)
* Plays a major role in gluconeogenesis,
transamination
* Occur in the mitochondrial matrix of the cells

* Not occur in :
- Erythrocyte (there is not mitochondria)
- Muscle (anaerobic condition)
* Influenced by several factors
Inducer

: ADP

Supressor : - ATP
- NADH
- Fluoro acetate
- Arsenite
- Malonate
- Citrate

TRICARBOXYLIC ACID CYCLE (TCA = TCC)

TRICARBOXYLIC ACID CYCLE (TCA = TCC)

TRANSFER REDUCING
EQUIVALENT DARI TCC
KEDALAM RANTAI
PERNAFASAN

* Energi yang dihasilkan pada TCC :

3 NADH

: 9 ATP

1 FADH2

: 2 ATP

1 ATP tingkat substrat

: 1 ATP

Total

:12 ATP

Three stages of protein,

carbohydrate and lipids
catabolism

Peranan TCC Dalam Proses Transaminasi dan Glukoneogenesis

10

Peranan TCC Dalam Biosintesa Asam Lemak

11

Regulation of TCC

12

PENCERNAAN, ABSORPSI DAN

METABOLISME KARBOHIDRAT

13

FUNGSI KARBOHIDRAT
1. SUMBER ENERGI UTAMA
2. CADANGAN ENERGI ( GLIKOGEN )
3. BAHAN PEMBENTUK ZAT LAIN :
- AS. ASCORBAT ( VITAMIN C )
- AS. GLUCORONAT
- PENTOSA

* NUKLEOTIDA
* AS. NUKLEAT

- AS. AMINO
- LIPID : TAG, GANGLIOSIDA, GLIKOLIPID
4. STRUKTUR BIOLOGIS

14

PENCERNAAN KARBOHIDRAT
* MULUT :
- MEKANIS
- ENJIMATIK
AMYLASE
AMILUM

* OLIGOSAKARIDA
* MALTOTRIOSA

SALIVA

* MALTOSA

ION ClpH : 7,1

15

* USUS HALUS
AMILUM

AMYLASE

- OLIGOSAKARIDA

GLIKOGEN

PANCREAS

- MALTOTRIOSA

pH : 7,1

- MALTOSA

SUKRASE

SUKROSA

GLUKOSA + FRUKTOSA
pH : 5 7

MALTASE

MALTOSA

GLUKOSA
pH : 5,8 6,2

16

LACTASE
LAKTOSA

GLUKOSA + GALAKTOSA
pH : 5,4 6

TRIHALASE
TRIHALOSA

GLUKOSA
GLUKOSIDASE

OLIGOSAKARIDA

GLUKOSA

INHIBITOR GLUKOSIDASE : OAD

17

ABSORPSI KARBOHIDRAT
* ABSORPSI : - HEKSOSA : * GLUKOSA
* GALAKTOSA
* FRUKTOSA
* MANNOSA
- PENTOSA : RIBOSA
* ABSORPSI : - PASIF : * SIMPLE DIFFUSION
* FACILITATED DIFFUSION
(GLUT-5)
- ACTIF :
SGLT-1 (K+)Na+ PUMP)

18

KETERANGAN

2
Gluc.

1.

ACTIVE TRANSPORT

2.

FACILITATED DIFFUSION

3.

SIMPLE DIFFUSION

Gluc.

19

* Penghambatan transport aktif

- Ouabain ( inhibitor K+ / Na+ pump )
- Phlorizin

20

ASPEK KLINIK
1. LACTOSE INTOLERANCE
* DEF. : ENJIM LACTASE
* GEJALA : - COLIC USUS
- DIARE
- FLATULENS
a). DEF. LACTASE HEREDITER
- JARANG TERJADI
- PADA NEONATUS
- PEMBERIAN SUSU
- TH

DIARE

: * LLM (LOW LACT MILK)

* YOGURT (PENGGANTI SUSU)

21

b). PRIMARY LOW LACTASE ACTIVITY

- SERING TERJADI
- PADA ORANG DEWASA
- PENURUNAN AKTIVITAS LAKTASE SECARA
BERANGSUR-ANGSUR
c). SECONDARY LOW LACTASE ACTIVITY
- SEKUNDER DARI PENYAKIT :
* TROPICAL SPRUE
* CELIAC DISEASE
* KWASHIORKOR
* COLITIS
* GASTRO ENTERITIS

22

2. SUCRASE DEFICIENCY
- HEREDITER
- NEONATUS
- BERSAMA-SAMA DENGAN ISOMALTASE
DEFICIENCY
- GEJALA : * DIARE
* COLIC USUS
* FLATULENS
3. DISSACHARIDURIA
- DEF. : DISACHARIDASE
- > 30 mg DISAKARIDA ( URINE )
23

4. MONOSACHARID MALABSORPSION
- CONGENITAL
- ABSORPSI GLUK / GAL : LAMBAT
- GANGGUAN : GLUT : SGLT-1
- GEJALA : * DIARE
* COLIC USUS
* FLATULENS

24

TRANSPORT GLUKOSA
KE DALAM SEL
(PERANAN GLUT)

25

GLUCOSE TRANSPORTERS
Tissue Location
Facilitative bidirectional transporters
GLUT 1 Brain, kidney, colon, placenta, erythrocyte
GLUT 2 Liver, pancreatic B cell, small intestine,
kidney
GLUT 3 Brain, kidney, placenta
GLUT 4 Heart and skeletal muscle, adipose tissue
GLUT 5 Small intestine
Sodium-dependent unidirectional transporter
SGLT 1 Small intestine and kidney

Functions
Uptake of glucose
Rapid uptake and
release of glucose
Uptake of glucose
Insulin-stimulated uptake
of glucose
Absorption of glucose
Active uptake of glucose
from lumen of intestine
and reabsorption of
glucose in proximal
tubule of kidney against
26
a concentration gradient

CARBOHYDRATE METABOLISM
GLUCOSE METABOLISM
NONCARBOHYDRATE SUBSTRATE
LACTATE

PENTOSE-PHOSPHATE

Gluconeogenesis

Hexose Monophosphate Shunt

Anaerobic
condition
PYRUVATE
Aerobic
condition
ACETYL-CoA

Glycolysis EM
(Embden Meyerhof)

GLUCOSE

Glycogenesis

Glycogenolysis
(liver)

GLYCOGEN
TCC
CO2 + H2O + E

GLUCORONATE
Uronic acid Pathway
LACTATE

Glycogenolysis
(Muscle)

TCC = TRI CARBOXYLIC ACID CYCLE

PYRUVATE

GLUCOSE-6-P

27

GLYCOLYSIS EMBDEN MEYERHOF

* Oxidation of glucose to form pyruvate or lactate
* Occur in all of the tissues, in cytosol of the cells
* ATP are generated from 1 mol of glucose
- In aerobic condition : 8 ATP
- In anaerobic condition : 2 ATP
* Influenced by several factors
Inducer
: - AMP
- ADP
- C.H. Meal
Supresor
: - ATP
- Yodo acetate
- Citrate
- Fluoride
- Glucose-6P
- Fast condtion
28
- NADH

GLIKOLISIS EMBDEN MEYERHOF

29

Three possible catabolic fates of the pyruvate formed in

the pay off phase of glycolysis
GLUCOSE
Glycolysis (10 successive reactions)
2 PYRUVATE
Anaerobic conditions

O2

2 ETHANOL + 2 CO2
Alcohol fermentaion in yeast

aerobic
conditions
2C02

anaerobic conditions
LACTATE

Fermentation to lactate in vigorously

Contracting
muscle, in erythrocytes,
and
is some microorganisme

2 ACETYL-CoA
Citric
Acid
cycle

4 CO2 + 4H2O
Animal, plant, and many microbial
Cells under aerobic conditions

30

DEKARBOKSILASI
OKSIDATIF PIRUVAT
ASETIL-KoA

DEF. PIRUVAT DEHIDROGENASE

LACTIC ACIDURIA
31

The effect of insulin on glycolysis & gluconeogenesis

INSULIN

SUPPRESS0R OF KEY
GLUCONEOGENIC
ENZYMES

Suppressor
and inducer
function of
insulin on
key liver
enzymes

PEP
CARBOCXY
KINASE

PYRUVATE
CARBOXYL
- ASE

FDP ASE

G-6-P ASE

OA

PEP

PYRUVATE

PYRUVATE
KINASE

F-1,6-P-

F-6-P
-

PHOSPHO FRUCTOKINASE

G-6-P
-

GLUCOSE

GLUCO
KINASE

INSULIN

INDUCER OF KEY
GLYCOLYTIC ENZYMES

OA
PEP
F-1,6-P

= Oxaloacetate
= Phosphoenolpyruvate
= Fructose- 1,6-diphosphate

F-6-p
FDPase
G-6-P

= Fructose 6- phosphate
= Fructose diphosphatase
= Glucose- 6- phosphate

32

TOTAL ENERGY ARE GENERATED FROM

OXIDATION OF ONE MOL OF GLUCOSE TO
FORM CO2 + H2O
GLUCOSE
8 ATP
Pyruvate

Pyruvate

3 ATP

3 ATP

Acetyl- CoA

Acetyl Co-A

TCC
12 ATP

TCC
12 ATP

33

38 ATP

EFICIENCY OF GLUCOSE OXIDATION

One mol of glucose oxidation to form.
CO2 + H2O, are generated 38 ATP
38 ATP = 38 x 51,6 KJ (Kilo Joule)
= 1961 KJ

One mol of glucose is combusted in a calorimeter (in vitro),

approximatelly 2870 KJ are liberated as heat.
1961
2870
32% are liberated as heat.

34

Pengaturan glikolisis, TCC dan oksidasi fosforilasi oleh ATP dan ADP
ADP

Oxaloacetate

Glucose
Pi

Succinyl CoA

Respiratory
Chains
NAD+

Glycolysis

Glucose 6 phosphate
ATP, NADH

AMP
ATP, citrate

Fruktose1,6-biphosphate

-Ketoglutarate
dehydrogenase

-Ketoglutarate

ADP
ATP

Citric acid cycle

Citrate
Syntase

Acetyl-CoA

ADP
ATP,
NADH

Oxidative
phosphorylation

Isocitrate
dehydrogenase

Citrate

Pyruvate
Dehydrogenase compl.

Pyruvate
AMP, ADP, NAD +

H2O

ATP

ADP
ATP

Phosphoenolpyruvate

ADP + Pi

O2

ATP, NADH
35

GLYCOGENESIS & GLYCOGENOLYSIS

* Almost occur in all of the tissues
Especially in the liver and muscles
* Biomedical importance :
- Liver glycogen is source of blood glucose, because
there is glucose-6-phosphatase activity in the liver
- Muscle glycogen is not source of blood glucose, because
there is not glucose-6-phosphatase activity in muscle.
So muscle glycogen is only source of glucose for glycolysis
within the muscle itself (anaerobic glycolysis)
36

* Glycogen storage diseases

- Inherited
- Deficient mobilization of glycogen
- Or deposition of abnormal forms of glycogen
muscular weakness or even death

* Influenced by several factors

- Hormonal : insulin, glucagon etc.
- Nutrition : - Carbohydrate meal
- During fasting

Gluccogenesis
glycogenolysis
37

GLIKOGENESIS DAN GLIKOGENOLISIS

38

REGULASI GLIKOGENOLISIS
DALAM OTOT

39

Regulasi Glikogenesis Dalam Otot

40

Regulasi Glikogenesis dan Glikogenolisis

41

Hormonal Regulation
of Glicogenolysis in
Muscle and Liver

42

REGULATION OF GLYCOGENESIS &

GLYCOGENOLYSIS
* Epinephrin
* Glucagon :
(only on the liver)

* Insulin
+

Equilibrium

Phosphodiesterase

Adenyl Cyclase

cAMP

cAMP

Glycogenesis

Glycogenesis

Glycogenolysis

Glycogenolysis

43

GLUCONEOGENESIS
* Biomedical importance :
- To maintain blood glucose concentration
- To clear the products of the metabolism of other tissues
from the blood
eg, Lactate & Glycerol
* Occur especially in the liver and kidney
* Influenced by several factors :
- hormonal
- Nutrition
* Sources of noncarbohydrate substrates :
- Lactate
- Propionat (Plants)
- Glycerol (fat)
- Glucogenic Amino Acids

44

Glukoneogenesis dan
Regulasinya

45

Glukoneogenesis dari Asam Propionat

CH3

CoA SH

|
CH2
|
COO- ATP

ACYL-CoA
SYNTHETASE

Mg2+
AMP+PPi

Propionate

CH3

CO2+H2O

|
CH2

Biotin

|
ATP
CO S CoA

PROPIONYL-CoA
CARBOXYLASE

ADP+Pi

Propionyl-CoA

CH3
|
H C COO|
CO S CoA
D-Methyl-

malonyl-CoA
METHYLMALONYL-CoA
RACEMASE

Intermediates
of Citric Acid Cycle

COO|
CH2
|
CH2

METHYLMALONYLCoA ISOMERASE

B12 coenzyme

|
CO S CoA

Succinyl-CoA

Metabolism of propionate

CH3
|
OOC C H
|
CO S CoA

L-Methylmalonyl-CoA
46

Gluconeogenesis dari Asam Laktat (siklus cori)

BLOOD
Glucose

G-6-PASE

LIVER
Glucose 6-phosphate
Pyruvate

Urea

Pyruvate

-NH2
n
io

Lactate

at
in

Alanine

in

Lactate

Glucose 6-phosphate

m
sa

an
Tr

m
sa

Lactate

Glycogen

an
Tr

-NH2

io
at

Glycogen

MUSCLE

BLOOD
Pyruvate
Alanine

The lactic acid (Cori) cycle and glucose-alanine cycle

Alanine

47

HEXOSE MONOPHOSPAHTE SHUNT

(HMP) SHUNT)
= Pentosa Phosphate Pathway
Oxidation of glucose to form Pentose Phosphate
& NADPH
Extra mitochondrial
H Acceptor : NADP
Active in several Tissues :
- Liver
- Mamma lactans
- Adipose Tissues
- Erythrocytes
- Testis
- Ovarium
- Adrenal cortex
- etc

48

 Biomedical importance :
- Pentose Phosphates are required for synthesis of
nucleotide & nucleic acid
- NADPH are required for reductive synthesis such as
fatty acid and steroid biosynthesis, and integrity of
erythrocytes membrane
- Deficiency of glucose-6-phosphate dehydrogenase
enzym (G6PD)

hemolytic anemia
49

Hexosa
Mono
Phosphate
Shunt
(HMS)

50

Uronic Acid Pathway

Fungsi Uronik acid Path.

Menghasilkan :
- Pentosa -P
- Asam askorbat (Vit. C)
- Asam Glukoronat
(Konyugasi Bilirubin)
- Oksalat

51

METABOLISME FRUKTOSA

2
3
1

52

Metabolisme Galactosa

53

Perubahan berbagai macam gula menjadi glukosa

Lactose

Trehalose

CH2OH

Lactase

trehalase

CH2OH

H
D-Glucose

OH

OH

Glucose-1Phosphate

ATP

Phosphoglucose
-mutase

Hexokinase

HOCH2 O CH2OH
H

HO

ATP

Glucose-6Phosphate

Hexokinase

Fructose-6Phosphate

CH2OH
H
OH

ATP

fruktokinase

OH
HO

OH

Fructose-1,6Biphosphate

Hexokinase

Mannose-6-phosphate
Phosphomannose
isomerase

+ Dihydroacetone phospate

Triose kinase

ATP

OH

H
H
D-Mannose

ATP

Fructose-1-phospate
Liceralhehide

UDP-glucose

OH

OH H
D-Fructose

UDP-galactose

OH

OH

H
OH
D-Galaktose

Phosphorylase

OH
Sucrase

H
OH

OH

Sucrose

Glycogen
Pi

OH

H
OH

Triose phosphate
isomerase

Glyceraldehid-3-phospate

54

ATP

ADP

Glucose

Glycogen

----------------->Inhibiting
Alosteric Effect

Glucose-6-P
EmbdenMeyerhof
Pathway

ATP

ADP

Glucosamine
ATP

ADP

CO2+H2O
UTP

Glucosamine-1-P
PPi

Acetyl-CoA

N-AcetylGlucosamine-6-P
Epimerase

N-AcetylMannosamine-6-P
PhosphoenolPyruvate
N-Acetyl-Neuraminic acid-9-P
Sialic Acid Mucopolysaccharides
Glycoproteins

Pyruvate

Phosphogluco
mutasese

Glucosamine-6-P

Acetyl-CoA

N-AcetylGlucosamine

Fructose-6-P
Glutamine

Citric
Acid
Cycle

N-AcetylGlucosamine-1-P
UTP
PPi
UDP
N-AcetylGlucosamine
NAD+

Epimerase

UDP
Glucosamine

Mucopolysaccharida
(eg, Heparin
Mucopolysaccharides
(Hyaluronic Acid),
Glycoproteins

UDP
N-AcetylGalactosamine
Mucopolysaccharides
(Chondroitins) Glycoproteins
55

A Summary of the interrelationship in metabolism of amino sugars

GLYCOGEN

FAT
(ADIPOSE TISSUE)

Abnormal
Abnormal
Metabolism
In the liver
During
Uncontrolle
Diabetes

GLUCOSE
(HYPERGLYCEMIA)

GLUCOSE-6-P
Hexose
Mono
Phosphate

GLUCOSE
(In Urine)

TRIOSE-P

FFA (PLASMA)
Shunt

ACYL COA
AMINO

P-ENOLPYRUVATE

ACIDS

TRIGLYCERIDE

PYRUVATE
ACETIL CO A
OXALOACETATE
KETONE BODIES
citrate
AMINO
-KETOGLUTARATE

ACIDS
AMINO ACID

(HYPERKETONEMI
A

56 BODIES
KETONE
IN URINE

BLOOD GLUCOSE
Sources :
1. Carbohydrate (Diet)
2. Liver glycogens (Glycogenolysis)
3. Noncarbohydrate substrates (Gluconeogenesis)
* Concentration :
During fasting : 3,3 - 3,9 mmol/l = 60 - 70 mg%
After the ingestion of a carbohydrate meal :
6,5 7,2 mmol/l = 120 130 mg%
Post absorptive state : 4,5 5,5 mmol/l = 80 100 mg%
Normal fasting blood glucose : 3,9 6 mmol/l
= 70 110 mg%
57

* Renal threshold : 9,5 10 mmol/l = 170 180 mg%

More than 9,5 mmol/l = 170 mg%
Glucosuria
* Influenced by several factors :
- Hormonal : insulin & secretin
Epinephrin / nor epinephrin
Glucagon
Growth Hormon
ACTH
Glucocorticoids
Tyroxin
- Nutrition & Drug :
Tolbutamid (OAD)
Amino acids
FFA

58

Glucose Tolerance Test (G.T.T)

300
280
260
240
220
200
180
160
140
120
100
80
60
40
20

Normal
Mild DM
Severe DM

0,5

Severe DM

Renal Threshold

+
+

1,5

+
+

Mild. DM

Normal

+
+

2,5

Benedict Reaction of the urine

Oral administration of 50 100 GR Glucose
(0,75-1,50 GR/KG BW)

59

REGULATION OF BLOOD GLUCOSE

Insulin

+
Phosphodiesterase enzyme
Glycolytic enzymes
Glucose transporters

Glucagon
Epinephrin
Nor epinephrin

+
Adenyl Cyclase
Gluconeogenetic
Enzzymes

Glycogenesis
Glycolysis
Glucose transport into
the cells

Glucogenolysis
Gluconeogenesis

Blood Glucose

Blood Glucose

60

GLUCOSE TOLERANCE
Glucose tolerance
Diabetes mellitus
Liver damage
Several infection disease
Obesity
Hyperpituitarism
Cortex adrenal hyperfunction
Hyperglycemia
Glucosuria
61

Glucose tolerance
Hypopitutarissm
Cortex adrenal hypofunction
(Addisons disease)
Hyper insulinism

Hypoglycemia

62