*

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

*Peranan TCC Dalam Biosintesa Asam Lemak

*Regulation of TCC

*PENCERNAAN, ABSORPSI DAN

METABOLISME KARBOHIDRAT

*FUNGSI KARBOHIDRATSUMBER ENERGI UTAMACADANGAN ENERGI ( GLIKOGEN )BAHAN PEMBENTUK ZAT LAIN : - AS. ASCORBAT ( VITAMIN C ) - AS. GLUCORONAT - PENTOSA * NUKLEOTIDA * AS. NUKLEAT - AS. AMINO - LIPID : TAG, GANGLIOSIDA, GLIKOLIPID4. STRUKTUR BIOLOGIS

*PENCERNAAN KARBOHIDRAT* MULUT : - MEKANIS - ENJIMATIK AMYLASE * OLIGOSAKARIDA AMILUM * MALTOTRIOSA SALIVA * MALTOSA ION Cl- pH : 7,1

** 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

* LACTASE LAKTOSA GLUKOSA + GALAKTOSA pH : 5,4 6

TRIHALASE TRIHALOSA GLUKOSA

GLUKOSIDASE OLIGOSAKARIDA GLUKOSA

INHIBITOR GLUKOSIDASE : OAD

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

*KETERANGANACTIVE TRANSPORTFACILITATED DIFFUSIONSIMPLE DIFFUSION

** Penghambatan transport aktif - Ouabain ( inhibitor K+ / Na+ pump ) - Phlorizin

*ASPEK KLINIKLACTOSE INTOLERANCE * DEF. : ENJIM LACTASE * GEJALA : - COLIC USUS - DIARE - FLATULENS a). DEF. LACTASE HEREDITER - JARANG TERJADI - PADA NEONATUS - PEMBERIAN SUSU DIARE - TH : * LLM (LOW LACT MILK) * YOGURT (PENGGANTI SUSU)

* 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

*2. SUCRASE DEFICIENCY - HEREDITER - NEONATUS - BERSAMA-SAMA DENGAN ISOMALTASE DEFICIENCY - GEJALA : * DIARE * COLIC USUS * FLATULENS3. DISSACHARIDURIA - DEF. : DISACHARIDASE - > 30 mg DISAKARIDA ( URINE )

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

*TRANSPORT GLUKOSA KE DALAM SEL(PERANAN GLUT)

*GLUCOSE TRANSPORTERS

Tissue Location FunctionsFacilitative bidirectional transportersGLUT 1 Brain, kidney, colon, placenta, erythrocyte Uptake of glucoseGLUT 2 Liver, pancreatic B cell, small intestine, Rapid uptake and kidney release of glucoseGLUT 3 Brain, kidney, placenta Uptake of glucoseGLUT 4 Heart and skeletal muscle, adipose tissue Insulin-stimulated uptake of glucose GLUT 5 Small intestine Absorption of glucoseSodium-dependent unidirectional transporter SGLT 1 Small intestine and kidney Active uptake of glucose from lumen of intestine and reabsorption of glucose in proximal tubule of kidney against a concentration gradient

*CARBOHYDRATE METABOLISM GLUCOSE METABOLISM

NONCARBOHYDRATE SUBSTRATE PENTOSE-PHOSPHATE

LACTATE Gluconeogenesis Hexose Monophosphate Shunt Anaerobic condition

PYRUVATE GLUCOSE GLUCORONATE Glycolysis EM Uronic acid Pathway Aerobic (Embden Meyerhof) condition Glycogenesis Glycogenolysis LACTATE PYRUVATEACETYL-CoA (liver)

Glycogenolysis GLYCOGEN GLUCOSE-6-P (Muscle) TCC

CO2 + H2O + E TCC = TRI CARBOXYLIC ACID CYCLE

*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 - NADH

*GLIKOLISIS EMBDEN MEYERHOF

*Three possible catabolic fates of the pyruvate formed in the pay off phase of glycolysisGLUCOSE Glycolysis (10 successive reactions)2 PYRUVATE Anaerobic conditions anaerobic conditions

2 ETHANOL + 2 CO2 LACTATE

2 ACETYL-CoA

4 CO2 + 4H2OO2 aerobic conditions

2C02Fermentation to lactate in vigorouslyContracting muscle, in erythrocytes, andis some microorganismeAlcohol fermentaion in yeastCitricAcidcycleAnimal, plant, and many microbialCells under aerobic conditions

*DEKARBOKSILASI OKSIDATIF PIRUVATASETIL-KoADEF. PIRUVAT DEHIDROGE- NASE LACTIC ACIDURIA

*The effect of insulin on glycolysis & gluconeogenesisSuppressor and inducer function of insulin on key liver enzymesPYRUVATECARBOXYL-ASEPEPCARBOCXY-KINASEFDP ASEG-6-P ASEPYRUVATE PEP - - PYRUVATEKINASEGLUCO-KINASEPHOSPHO-FRUCTOKINASE-GLUCOSE INSULINSUPPRESS0R OF KEYGLUCONEOGENICENZYMESOA OA= OxaloacetateF-6-p= Fructose 6-phosphatePEP= PhosphoenolpyruvateFDPase= Fructose diphosphataseF-1,6-P= Fructose-1,6-diphosphateG-6-P= Glucose- 6-phosphateG-6-PF-1,6-PF-6-P

*TOTAL ENERGY ARE GENERATED FROM OXIDATION OF ONE MOL OF GLUCOSE TO FORM CO2 + H2OGLUCOSE

8 ATP

Pyruvate Pyruvate

3 ATP 3 ATP

Acetyl- CoA Acetyl Co-A

TCC TCC 12 ATP 12 ATP

38 ATP

*EFICIENCY OF GLUCOSE OXIDATIONOne 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. 1961Eficiency : x 100% = 68% 2870 32% are liberated as heat.

*

*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)

** 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 Gluccogenesis - During fasting glycogenolysis

*GLIKOGENESIS DAN GLIKOGENOLISIS

*REGULASI GLIKOGENOLISIS DALAM OTOT

*Regulasi Glikogenesis Dalam Otot

*Regulasi Glikogenesis dan Glikogenolisis

*Hormonal Regulation of Glicogenolysis in Muscle and Liver

*REGULATION OF GLYCOGENESIS & GLYCOGENOLYSISPhosphodiesterase

cAMP

Glycogenesis

GlycogenolysisAdenyl Cyclase

cAMP

Glycogenesis

Glycogenolysis* Insulin* Epinephrin* Glucagon : (only on the liver)++Equilibrium

*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

*Glukoneogenesis dan Regulasinya

*Metabolism of propionateGlukoneogenesis dari Asam Propionat

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

Lactate

BLOOD

Pyruvate

Alanine

Urea

-NH2

AlaninePyruvate LactateTransaminationBLOOD

Glucose Lactate PyruvateGlucose 6-phosphateGlycogenLIVERMUSCLETransamination

-NH2

AlanineGlycogen Glucose 6-phosphateGluconeogenesis dari Asam Laktat (siklus cori)G-6-PASE

*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

* 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

*Hexosa Mono Phosphate Shunt (HMS)

*Fungsi Uronik acid Path.Menghasilkan :- Pentosa -P- Asam askorbat (Vit. C)- Asam Glukoronat (Konyugasi Bilirubin)- OksalatUronic Acid Pathway

*321METABOLISME FRUKTOSA

*Metabolisme Galactosa

*D-GlucoseLactoseTrehaloseSucrosePerubahan berbagai macam gula menjadi glukosaGlycogenGlucose-1-PhosphateGlucose-6-PhosphateFructose-6-PhosphateFructose-1,6-BiphosphateFructose-1-phospateLiceralhehide +Glyceraldehid-3-phospateMannose-6-phosphatePhosphomannose isomerasePhosphorylasePhosphoglucose-mutaseUDP-galactoseUDP-glucoseATPATPHexokinaseHexokinaseTriose phosphateisomeraseTriose kinasefruktokinaseSucraseLactasetrehalaseHexokinaseATPATPATPDihydroacetone phospatePiD-GalaktoseD-Mannose

*A Summary of the interrelationship in metabolism of amino sugarsGlycogenGlucose-6-PGlucoseATPADPFructose-6-PPyruvateCO2+H2OGlutamineGlucosamine-6-PAcetyl-CoAN-Acetyl-Glucosamine-6-PN-Acetyl-Mannosamine-6-PN-Acetyl-Glucosamine-1-PN-Acetyl-GlucosamineGlucosamineGlucosamine-1-PUDPGlucosamineMucopolysaccharida(eg, HeparinN-Acetyl-Neuraminic acid-9-PSialic Acid MucopolysaccharidesGlycoproteinsMucopolysaccharides(Chondroitins) GlycoproteinsUDPN-AcetylGlucos-amineUDPN-AcetylGalactos-amineMucopolysaccharides(Hyaluronic Acid), GlycoproteinsPhosphoenol-PyruvateATPADPATPADPPPiUTPEpimeraseEpimerasePhosphoglucomutaseseUTPPPiNAD+-Acetyl-CoAEmbden-MeyerhofPathwayCitricAcidCycle----------------->Inhibiting Alosteric Effect-

*Abnormal

AbnormalMetabolismIn the liverDuringUncontrolleDiabetes

GLYCOGEN

GLUCOSE-6-P

TRIOSE-P

P-ENOLPYRUVATE

PYRUVATE

OXALOACETATE

-KETOGLUTARATE

AMINO ACID

GLUCOSE (HYPERGLYCEMIA)

GLUCOSE (In Urine)

FAT(ADIPOSE TISSUE)

FFA (PLASMA)

ACYL COA

TRIGLYCERIDE

KETONE BODIES (HYPERKETONEMIA

KETONE BODIES IN URINE (KETONURIA)

AMINO ACIDSHexose Mono Phosphate Shunt

ACETIL CO A

AMINO ACIDScitrate

*BLOOD GLUCOSESources :Carbohydrate (Diet)Liver glycogens (Glycogenolysis)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%

** 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

*Glucose Tolerance Test (G.T.T)---------+++--+++++++ NormalMild DMSevere DMBenedict Reaction of the urineOral administration of 50 100 GR Glucose (0,75-1,50 GR/KG BW)

*REGULATION OF BLOOD GLUCOSE

*GLUCOSE TOLERANCEGlucose tolerance Diabetes mellitus Liver damage Several infection disease Obesity Hyperpituitarism Cortex adrenal hyperfunction Hyperglycemia Glucosuria

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

*