28 NOV 2011 GLIKOGENESIS GLUKONEOGENESIS GLUKOGENOLISIS 1.Sebutkan dan jelaskan inhibitor-inhibitor dalam proses electron transport chain 1.Sebutkan dan jelaskan inhibitor-inhibitor dalam proses oxidative phosphoryllation Complex I inhibitor: 1.Amytal 2.Rotenone Complex II 1.Carboxin 2.Malonate Complex III 1. Antimycin A Complex IV 1. CN2. CO 3. Sodium azide Inhibitor utk complex V • Oligomycin and dicyclohexylcarbodiimide (DCCD) prevent the influx of protons through ATP synthase. • If actively respiring mitochondria are exposed to an inhibitor of ATP synthase, the electron transport chain ceases to operate. • Indeed, this observation clearly illustrates that electron transport and ATP synthesis are normally tightly coupled. • This tight coupling of electron transport and phosphorylation in mitochondria can be disrupted (uncoupled) by 2,4-dinitrophenol and certain other acidic aromatic compounds. These substances carry protons across the inner mitochondrial membrane. • In the presence of these uncouplers, electron transport from NADH to O2 proceeds in a normal fashion, but ATP is not formed by mitochondrial ATP synthase because the proton-motive force across the inner mitochondrial membrane is dissipated. • This loss of respiratory control leads to increased oxygen consumption and oxidation of NADH. • Indeed, in the accidental ingestion of uncouplers, large amounts of metabolic fuels are consumed, but no energy is stored as ATP. Rather, energy is released as heat. GLIKOGENESIS • Sintesis glikogen dari glukosa • Terjadi di dalam jaringan hati dan otot • Terjadi bila jumlah glukosa berlebih harus disimpan • Glikogen hati dapat dibentuk dari asam laktat (hasil glikolisis) melalui siklus cori TUGAS 1. JELASKAN YANG DIMAKSUD DENGAN SIKLUS CORI (CORRI CYCLE) ? GLIKOGEN Merupakan polimer glukosa sangat bercabang di sitoplasma sel (dari residu α-D-glukosa dan βD-glukosa), dihubungkan oleh ikatan 1,4 glikosida dengan 1,6 glikosida titik cabangnya. The picture on the next slide shows a very small portion of a glycogen chain. All of the monomer units are alpha-Dglucose, and all the alpha acetal links connect C # 1 of one glucose to C # 4 of the next glucose. The branches are formed by linking C # 1 to a C # 6 through an acetal linkages. In glycogen, the branches occur at intervals of 8-10 glucose units. Glycogen synthesis (GLYCOGENESIS) requires an activated form of glucose, uridine diphosphate glucose (UDP-glucose, UDPG), which is formed by the reaction of UTP and glucose 1-phosphate. UDPG is added to the nonreducing end of glycogen molecules. UDPG dibentuk dari reaksi uridin trifosfat (UTP) dengan glukosa-1-fosfat, dengan katalis enzim UDP glukosa pirofosforilase. Reaksinya : Struktur molekul UDPG TAHAPAN GLIKOGENESIS Reaksi 1 : Glukosa + ATP p + ADP Mg2+ Glukosa 6Glukokinase / Heksokinase Reaksi 2 : Glukosa 6-p (reaksi isomerisasi) fosfoglukomutase Reaksi 3 : Glukosa 1-p + UTP Reaksi 4 Pirofosfat UDPG glikogen sintetase Glukosa 1-p UDPG + UDPG Pirofosforilase glikogen + UDP GB. REAKSI GLIKOGENESIS (dari reaksi ke-3) Glycogen Synthase Catalyzes the Transfer of Glucose from UDP-Glucose to a Growing Chain Glycogen synthase is the key enzyme is glycogen synthesis. Glycogen synthase catalyzes only the synthesis of α-1,4 linkages. Another enzyme is required to form the α-1,6 linkages that make glycogen a branched polymer. • Enzim Glikogen sintetase ( sintase ) • membentuk ikatan α-1,4 Glikosidik ( rantai lurus ) dr glikogen • Enzim Pencabang ( Branching Enzyme ) membentuk ikatan α-1,6 Glikosidik ( rantai cabang ) dr glikogen Molekul glikogen seperti pohon + cabang + rantingnya Action of branching enzyme: GLIKOGENOLISIS • Proses pemecahan glikogen • Dalam otot : * tujuannya untuk mendapat energi bagi otot * hasil akhirnya : piruvat / laktat sebab glukosa 6-p yg dihasilkan dr glikogenolisis masuk ke jalur glikolisis di otot • Dalam hati : * tujuannya : untuk mempertahankan kadar glukosa darah di antara dua waktu makan Glycogen is broken down principally by glycogen phosphorylase. Glycogen phosphorylase, the key enzyme in glycogen breakdown cleaves its substrate by the addition of orthophosphate (Pi) to yield glucose 1-phosphate. The cleavage of a bond by the addition of orthophosphate is referred to as phosphorolysis. Notice that the reaction is not hydrolytic; no water is used in the cleavage reaction. Instead, inorganic phosphate combines with the nonreducing terminal glucose residue to give glucose 1-phosphate. Reaksinya: Glucose 1-phosphate released from glycogen can be readily converted into glucose 6-phosphate by the enzyme phosphoglucomutase The phosphorolytic cleavage of glycogen is energetically advantageous because the released sugar is already phosphorylated. In contrast, a hydrolytic cleavage would yield glucose, which would then have to be phosphorylated at the expense of the hydrolysis of a molecule of ATP to enter the glycolytic pathway. An additional advantage of phosphorolytic cleavage for muscle cells is that glucose 1-phosphate, negatively charged under physiological conditions, cannot diffuse out of the cell. A Debranching Enzyme Also Is Needed for the Breakdown of Glycogen Phosphorylase stops cleaving α-1,4 linkages when it reaches a terminal residue four residues away from a branch point. Because about 1 in 10 residues is branched, glycogen degradation by the phosphorylase alone would come to a halt after the release of six glucose molecules per branch. Two additional enzymes, a transferase and a-1,6-glucosidase, remodel the glycogen for continued degradation by the phosphorylase. The transferase shifts a block of three glycosyl residues from one outer branch to the other. This transfer exposes a single glucose residue joined by an α-1,6-glycosidic linkage. α-1,6-Glucosidase, also known as the debranching enzyme, hydrolyzes the α-1, 6-glycosidic bond, resulting in the release of a free glucose molecule. Phosphoglucomutase Converts Glucose 1-phosphate into Glucose 6phosphate Glucose 1-phosphate formed in the phosphorolytic cleavage of glycogen must be converted into glucose 6phosphate to enter the metabolic mainstream. This shift of a phosphoryl group is catalyzed by enzyme phosphoglucomutase. 2. Jelaskan regulasi-regulasi dari a.Glikogenesis b.Glikogenolisis GLUKONEOGENESIS • Pembentukan glukosa dari bahan bukan karbohidrat (non carbohydrate precursor) • Pada mamalia sebagian besar terjadi di hati, dan sebagian kecil terjadi di ginjal • Glukoneogenesis penting sekali untuk penyediaan glu kosa bila karbohidrat tidak cukup dlm diet The gluconeogenesis pathway converts pyruvate into glucose • The major noncarbohydrate precursors are lactate, amino acids, and glycerol. • Lactate is formed by active skeletal muscle when the rate of glycolysis exceeds the rate of oxidative metabolism. • Lactate is readily converted into pyruvate by the action of lactate dehydrogenase. • Amino acids are derived from proteins in the diet and, during starvation, from the breakdown of proteins in skeletal muscle . • The hydrolysis of triacylglycerols in fat cells yields glycerol and fatty acids. • Glycerol is a precursor of glucose, but animals cannot convert fatty acids into glucose, for reasons that will be discussed later Glycerol may enter Gluconeogenesis Is Not a Reversal of Glycolysis • In glycolysis, glucose is converted into pyruvate; in gluconeogenesis, pyruvate is converted into glucose. • However, gluconeogenesis is not a reversal of glycolysis. • In gluconeogenesis, the following new steps bypass these virtually irreversible reactions of glycolysis: • 1. Phosphoenolpyruvate is formed from pyruvate by way of oxaloacetate through the action of pyruvate carboxylase and phosphoenolpyruvate carboxykinase. • 2. Fructose 6-phosphate is formed from fructose 1,6-bisphosphate by hydrolysis of the phosphate ester at carbon 1. Fructose 1,6-bisphosphatase catalyzes this exergonic hydrolysis. • 3. Glucose is formed by hydrolysis of glucose 6phosphate in a reaction catalyzed by glucose 6phosphatase. Ada 3 tahapan reaksi dalam glikolisis yang tidak reversibel. Yaitu : Tahap 1, tahap 3, dan tahap 9 (dilihat lagi proses glikolisis) Sehingga proses glukoneogenesis melalui tahapan reaksi lain, yaitu: 1. Asam piruvat + ATP + GTP + H2O PEP + ADP + GDP + Pi + 2H+ 2. fruktosa-1,6-difosfat + H2O fruktosa-6-fosfat + Pi 3. Glukosa-6-fosfat + H2O glukosa + Pi Glkuosa Pi 6 P-ase H2O Glikogen Fruktosa 1,6 Pi di-P-ase H2O Glukosa Glkuosa 6 P Fruktosa 6 P ATP Glkokinase Heksokinase ADP - ATP Fosfofruk ADP tokinase Di-OH aseton-P + Fruktosa 1,6 di-P Fosfoenol Piruvat Gliserol 3-P Piruvat kinase laktat Gliserol Asam lemak Piruvat + GDP Fosfoenol Piruvat Karboksilase sitosol mitokondria Piruvat CO2 + ATP Sitrat GTP Piruvat Karboksilase Asetil-Koa Piruvat DH-ase Oksalo-asetat NADH + H+ NADH + H+ ADP + Pi Oksalo-asetat Sitrat + Malat NAD NAD Malat Fumarat Suksinil Ko-A Propionat PENTOSE PHOSPHATE PATHWAY (PPP); HEXOSE MONOPHOSPHATE (HMP) SHUNT Definition: • The hexose monophosphate (HMP) shunt or pentose phosphate pathway (PPP) is an alternative pathway for the metabolism of glucose. It does not generate ATP but produces NADPH and pentose-5phosphates and other sugar-phosphates. HMP SHUNT (HEKSOSA MONO PHOSPHAT SHUNT) • • • • Disebut juga : Pentose Phosphate Pathway Merupakan jalan lain untuk oksidasi glukosa Tidak bertujuan menghasilkan energi ( ATP ) Aktif dalam : 1. 2. 3. 4. 5. 6. Hati Jar. Lemak Kalenjar Korteks adrenal Kalenjar Tiroid Eritrosit Kalenjar Mammae ( laktasi ) HMP (HEKSOSA MONOPHOSPHAT) SHUNT • • Jalur metabolisme utama penggunaan glukosa selain glikolisis. Secara Kuantitatif kecil, berperan penting. 1. Menghasilkan NADPH sintesis reduktif : biosintesis asam lemak, steroid.asam-asam amino amino lewat lewat glutamat dehidrogenase, sintesis glutation tereduksi di dalam eritrosit. Produksi ribosa untuk biosintesis nukleotida serta asam nukleat. 2. 3. JELASKAN PERSAMAN DAN PERBEDAAN PROSES HMP SHUNT DG GLIKOLISIS !! 4. JELASKAN TAHAPAN-TAHAPAN REAKSI DLM HMP SHUNT !! Importance of HMP shunt 1.Formation of NADPH + H+: which is required for: a) Synthesis of fatty acids (lipogenesis). b) Synthesis of cholesterol and other steroids. c) Protecting RBCs wall against oxidation by keeping glutathione in the reduced form. d) Keeps Hb iron in the ferrous (Fe2+) state, not to be converted to methemoglobin. e) Monoxygenases (hydroxylases), as it takes part in the process of mixed function oxidation (MFO). 2. Formation of Pentoses: Xylulose, ribulose, and ribose. Pentoses (e.g., ribose & deoxyribose) are essential components of nucleic acids and nucleotides. 3. Energy production: HMP shunt is the source of energy in lens and retina; one glucose molecule gives 2 NADPH + H+; (equivalent to 6 ATP). • Summary Questions: 1. If you have glucose-6-phosphate, name three things you can do with it. 2. If you have just eaten, have plenty of glucose in the blood, and ATP is plentiful, what happens? 3.If ATP is sufficient and there are excess amino acids, what happens? 4. How many pyruvic acid molecules are required to make glucose? answers 1. – dpt diubah menjadi glukosa dan masuk ke aliran darah -Digunakan utk glikolisis, jika ATP dibutuhkan -diubah menjadi glikogen, utk disimpan, jika ATP tdk diibutuhkan 2. Glukosa akan diubah mnjd glikogen pd proses glikogenesis 3. Masuk ke proses glukoneogenesis 4. 2 SUMMARY OF CARBOHYDRATE METABOLISM NO NAMA PROSES SENYAWA AWAL DAN PRODUK AKHIR 1 2 3 4 GLIKOLISIS GLIKOGENESIS GLIKOGENOLISIS AWAL= AKHIR= AWAL= AKHIR= AWAL= AKHIR= ATP DIHASILKAN/DI BUTUHKAN GLUKONEOGENESIS AWAL= AKHIR= NO NAMA PROSES SENYAWA AWAL DAN ATP PRODUK AKHIR DIHASILKAN/DIBU TUHKAN AWAL=glukosa 6-fosat AKHIR=piruvat dihasilkan 1 2 3 GLIKOLISIS GLIKOGENESIS GLIKOGENOLISIS AWAL=glukosa 6-fosfat dibutuhkan AKHIR=glikogen AWAL=glikogen Tidak ada ATP yg AKHIR=glukosa 6-fosfat terlibat AWAL=piruvat dibutuhkan AKHIR=glkukosa 6-fosfat 4 GLUKONEOGENESIS GLUKOSA DARAH • Glukosa dapat dipakai oleh semua jaringan tubuh, disimpan : * hati dan otot Glikogen * jaringan lemak Triasilgliserol ( TG ) • Sumber glukosa darah : 1. Karbohidrat Makanan 2. Glikogenolisis hepar 3. Glukoneogenesis • Hormon yg mengatur glukosa darah : * Insulin * Hormon dr. klj. Hipofisa anterior : Growth Hormone * Hormon klj. Medula adrenal : epinefrin, • PENGARUH HORMON : * Keadaan kadar glukosa darah merangsang sekresi hormon glukagon * Keadaan kadar glukosa darah merangsang sekresi hormon insulin * Keadaan darurat merangsang sekresi hormon adrenalin • Glukagon (hati) Pembentukan cAMP • Epinefrin (otot) 1. cAMP menghambat Glikogen sintase menghambat glikogenesis 2. cAMP memacu fosforilase memacu glikogenolisis • INSULIN : 1. Memacu glikogen sintase 2. Memacu fosfodiesterase yg akan memecah cAMP menjadi 5’AMP GANGGUAN METABOLISME KARBOHIDRAT • Dasar penyakit adalah defisiensi insulin Diabetes melitus (Hiperglykemia) • Gejala klinis penyakit : • Hiperglikemia • Glikosuria • Dapat diikuti gangguan sekunder metabolisme protein dan lemak • Dapat berakhir dengan kematian • Insidensi terbanyak usia 50 – 60 thn • Dapat juga dekade pertama atau pada yang sudah lanjut • Penyakit ini diturunkan secara autosomal resesif KADAR GULA DALAM DARAH (KONDISI) METODE PENGUKURAN GULA DARAH PUASA (FASTING GLUCOSE) NORMAL DIABETES IGT IFG < 6.1 mmol/l > 7.0 mmol/L < 110 mg/dL > 126 mg/dL atau < 7.0 mmol/L < 126 mg/dL dan 6.1 < X< 7.0 mmol/L 110 < X< 126 mg/dL dan < 7.8 mmol/L < 140 mg/dL (Jika diukur) GULA DARAH 2 Tidak > 11.1 mmol/L 7.8 < X < 11.1 mol/L JAM SETELAH spesifik. Nilai > 200 mg/dL 140 < X < 200 mg/dL MAKAN yang sering (2-h GLUCOSE) dipakai < 7.8 mmol/L < 140 mg/dL IGT (Impaired Glocose Tolerance=Toleransi Glukosa Terganggu). IFT (Impaired Fasting Glucose=Glukosa Puasa Terganggu). Etiologi: • Sebab tepat belum diketahui • berhubungan dgn kelainan hormonal • Insulin • Growth hormon • Hormon steroid • Keadaan diabetes timbul akibat ketidak seimbangan dalam interaksi pankreas, hipofisis dan adreanal Pankreas • Pankreas mempunyai pulau Langerhans : sel beta dan sel alpha • Sel beta : hormon insulin • Sel alpha : menghasilkan hormon glukgon • Efek anti insulin → berfungsi sebagai faktor hiperglikemik dan glikogenolitik → meningkatkan kadar gula darah Cara kerja insulin Ada 2 teori cara kerja insulin • Teori 1 = Teori Levine : • Insulin mentransfer glukosa melalui membran sel otot serat lintang, tetapi tidak mengganggu perpindahan glukosa melalui sel membran hati • Teori 2 • Insulin diperlukan untuk fosforilasi glukosa dalam sel → glukosa 6 posfatase • Untuk pengikatan ini dibutuhkan enzim hexokinase yang dihasilkan oleh sel hati • Kelenjar hipofisis menghasilkan zat inhibitor hexokinase • Insulin merupakan zat antagonis terhadap hexokinase Hipoglykemia Patologis : Sering ditemukan pada 3 keadaan: 1. Akibat pemakaian insulin berlebihan pada diabetes 2. Pada pengobatan psykosis dengan shock hipoglikemik 3. Akibat pembentukan insulin berlebihan pada tumor pankreas yg dibentuk oleh sel beta 5. SEBUTKAN DAN JELASKAN GANGGUAN LAIN AKIBAT KELAINAN METABOLISME KARBOHIDRAT TUGAS DIKUMPULKAN SENIN DEPAN TGL 5 DESEMBER 2011 MAKSIMUM DISKUSI : 3 ORANG