28 NOV 2011

GLIKOGENESIS

GLUKONEOGENESIS

GLUKOGENOLISIS

1. Sebutkan dan jelaskan inhibitor-inhibitor dalam proses electron transport chain

2. Sebutkan dan jelaskan inhibitor-inhibitor dalam proses oxidative phosphoryllation

Complex I inhibitor:1. Amytal2. Rotenone Complex II1. Carboxin2. Malonate

Complex III1. Antimycin A Complex IV1. CN-

2. CO3. 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 -D-glukosa dan -D-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-D-glucose, 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 : Mg2+

Glukosa + ATP Glukosa 6-p + ADP Glukokinase / Heksokinase

Reaksi 2 : Glukosa 6-p Glukosa 1-p (reaksi isomerisasi) fosfoglukomutaseReaksi 3 : Glukosa 1-p + UTP UDPG + Pirofosfat UDPG PirofosforilaseReaksi 4

UDPG glikogen + UDPglikogen sintetase

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 -1,4 linkages. Another enzyme is required to form the -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 gluko- sa 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 breakdowncleaves 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 -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 transferaseand 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 -1,6-glycosidic linkage. -1,6-Glucosidase, also known as the debranching

enzyme, hydrolyzes the -1, 6-glycosidic bond, resulting in the release of a free glucose molecule.

Phosphoglucomutase Converts Glucose 1-phosphate into Glucose 6-phosphate

Glucose 1-phosphate formed in the phosphorolytic cleavage of glycogen must be converted into glucose 6-phosphate to enter the metabolic mainstream. This shift of a phosphoryl group is catalyzed by enzyme phosphoglucomutase.

2. Jelaskan regulasi-regulasi dari a.Glikogenesisb.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, duringstarvation, 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 either the gluconeogenic or the glycolytic pathway at dihydroxyacetone phosphate.

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 6-phosphate in a

reaction catalyzed by glucose 6-phosphatase.

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

GlukosaPi ATP

Piruvat

Piruvat

mitokondria

sitosol

Asetil-Koa

Asam lemak

Sitrat

PropionatSuksinil Ko-AFumarat

Oksalo-asetat

Malat

NADH + H+

NAD

Malat

Oksalo-asetat

NADNADH + H+

GDP

GTP

Fosfoenol PiruvatKarboksilase

Fosfoenol Piruvat

Fruktosa 6 P

Glkuosa 6 P

Fruktosa 1,6 di-P

Gliserol

Gliserol 3-P

Di-OH aseton-P

Fruktosa 1,6 di-P-ase

H2O

Pi

H2O

Glkuosa 6 P-ase

laktat

Glikogen

Piruvat Karboksilase

CO2 + ATP

ADP + Pi +

-Piruvat DH-ase

Sitrat

+Fosfofruktokinase

ATP

ADP

GlkokinaseHeksokinase

ADP

-

Piruvat kinase

+

PENTOSE PHOSPHATE PATHWAY (PPP); HEXOSE MONOPHOSPHATE (HMP) SHUNT

Definition:• The hexose monophosphate (HMP) shunt or The hexose monophosphate (HMP) shunt or

pentose phosphate pathway (PPP) is an pentose phosphate pathway (PPP) is an alternative pathway for the metabolism of alternative pathway for the metabolism of glucose. It does not generate ATP but glucose. It does not generate ATP but produces NADPH and pentose-5-phosphates produces NADPH and pentose-5-phosphates and other sugar-phosphates.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. Hati 2. Jar. Lemak 3. Kalenjar Korteks adrenal 4. Kalenjar Tiroid 5. Eritrosit 6. 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.

2. Produksi ribosa untuk biosintesis nukleotida serta asam nukleat.

3. JELASKAN PERSAMAN DAN PERBEDAAN PROSESHMP SHUNT DG GLIKOLISIS !!4. JELASKAN TAHAPAN-TAHAPAN REAKSI DLM HMP SHUNT !!

Importance of HMP shunt

1.1.Formation of NADPH + HFormation of NADPH + H++::which is required for:which is required for:a) Synthesis of fatty acids (lipogenesis).a) Synthesis of fatty acids (lipogenesis).b) Synthesis of cholesterol and other steroids.b) Synthesis of cholesterol and other steroids.c) Protecting RBCs wall against oxidation by c) Protecting RBCs wall against oxidation by keeping glutathione in the reduced form. keeping glutathione in the reduced form.d) Keeps Hb iron in the ferrous (Fe2+) d) Keeps Hb iron in the ferrous (Fe2+) state, not to be converted to met- state, not to be converted to met- hemoglobin. hemoglobin.e) Monoxygenases (hydroxylases), as it takes e) Monoxygenases (hydroxylases), as it takes part in the process of mixed function part in the process of mixed function oxidation (MFO). oxidation (MFO).

2. Formation of Pentoses:2. Formation of Pentoses: Xylulose, ribulose, and ribose. Xylulose, ribulose, and ribose. Pentoses Pentoses (e.g., ribose & deoxyribose) are (e.g., ribose & deoxyribose) are essential essential components of nucleic acids and components of nucleic acids and nucleotides nucleotides..

3. Energy production: HMP shunt is the source of energy HMP shunt is the source of energy in lens in lens and retina; one glucose molecule and retina; one glucose molecule gives 2 gives 2 NADPH + H+; (equivalent to 6 ATP). 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?

answers1. – 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 glikogenesis3. Masuk ke proses glukoneogenesis4. 2

SUMMARY OF CARBOHYDRATE METABOLISM

NO NAMA PROSES SENYAWA AWAL DAN PRODUK AKHIR

ATP DIHASILKAN/DIBUT

UHKAN

1 GLIKOLISIS AWAL=AKHIR=

2 GLIKOGENESIS AWAL=AKHIR=

3 GLIKOGENOLISIS AWAL=AKHIR=

4 GLUKONEOGENESIS AWAL=AKHIR=

NO NAMA PROSES SENYAWA AWAL DAN PRODUK AKHIR

ATP DIHASILKAN/DIBUTUH

KAN

1 GLIKOLISIS AWAL=glukosa 6-fosatAKHIR=piruvat

dihasilkan

2 GLIKOGENESIS AWAL=glukosa 6-fosfatAKHIR=glikogen

dibutuhkan

3 GLIKOGENOLISIS AWAL=glikogenAKHIR=glukosa 6-fosfat

Tidak ada ATP yg terlibat

4 GLUKONEOGENESIS AWAL=piruvatAKHIR=glkukosa 6-fosfat

dibutuhkan

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, glukagon

• 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 efek : memacu glikogenesis menghambat glikogenolisis

GANGGUAN METABOLISME KARBOHIDRAT

Diabetes melitus (Hiperglykemia)• Dasar penyakit adalah defisiensi insulin

• 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) NORMAL DIABETES IGT IFG

METODE PENGUKURAN

GULA DARAH PUASA

(FASTING GLUCOSE)

< 6.1 mmol/l< 110 mg/dL

> 7.0 mmol/L> 126 mg/dL

atau

< 7.0 mmol/L< 126 mg/dL

dan

6.1 < X< 7.0 mmol/L110 < X< 126 mg/dL

dan

GULA DARAH 2 JAM SETELAH

MAKAN(2-h GLUCOSE)

Tidak spesifik.

Nilai yang sering dipakai< 7.8

mmol/L< 140 mg/dL

> 11.1 mmol/L

> 200 mg/dL

7.8 < X < 11.1 mol/L140 < X < 200

mg/dL

< 7.8 mmol/L< 140 mg/dL(Jika diukur)

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 insulinAda 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 diabetes2. Pada pengobatan psykosis dengan shock hipoglikemik3. 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