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METABOLISME KARBOHIDRAT21 NOVEMBER 2011

TUGAS1. TULISKAN JUMLAH TOTAL ATP YANG DIHASILKAN PADA PROSES GLIKOLISIS DAN PERSAMAAN TOTAL REAKSI GLIKOLISIS (DG MENGABAIKAN ION H+)

Glycolysis - total pathway, omitting H+: glucose + 2 NAD+ + 2 ADP + 2 Pi 2 pyruvate + 2 NADH + 2 ATP Jumlah total ATP yang dihasilkan : 2 Kalau ATP dari NADH dihitung (2x3) + 2 = 8 ATP

2. Jalur glikolisis diregulasi oleh 3 enzim yang mengkatalisis reaksi-reaksi yang yg berjalan spontan, yaitu : heksokinase, fosfofruktokinase, dan piruvat kinase. Jelaskan masing-masing regulasinya !

6 CH 2OH

H4

5

O H2

ATP ADP H H1 4

6 CH OPO 2 2 3 5

O H2

H1

H OH3

OH

OH

Mg

2+

H OH3

OH

OH

H

OH

Hexokinase

H

OH

glucose

glucose-6-phosphate

Hexokinase is inhibited by product glucose-6phosphate: by competition at the active site by allosteric interaction at a separate enzyme site. Cells trap glucose by phosphorylating it, preventing exit on glucose carriers. Product inhibition of Hexokinase ensures that cells will not continue to accumulate glucose from the blood, if [glucose-6-phosphate] within the cell is sufficient

6 CH 2OH

Glucokinase is a variant of Hexokinase found in liver.

H4

5

O H2

ATP ADP H H1 4

6 CH OPO 2 2 3 5

O H2

H1

H OH3

OH

OH

Mg2+ OH

H OH3

OH

H

OH

Hexokinase

H

OH

glucose

glucose-6-phosphate

Glucokinase has a high KM for glucose. It is active only at high [glucose]. Glucokinase is not subject to product inhibition by glucose-6-phosphate. Liver will take up & phosphorylate glucose even when liver [glucose-6phosphate] is high.

Phosphofructokinase6 CH OPO 2 2 3

O

1CH2OH

6 CH OPO 2 2 3

ATP ADP HO H2 5

O

1CH2OPO32

5

H4

H4

HO H

2

H

3 OH

Mg2+

H

3 OH

OH

OH

fructose-6-phosphate

fructose-1,6-bisphosphate

Phosphofructokinase is usually the ratelimiting step of the Glycolysis pathway.

Phosphofructokinase is allosterically inhibited by ATP. At low concentration, the substrate ATP binds only at the active site. At high concentration, ATP binds also at a low-affinity regulatory site, promoting the tense conformation.

Inhibition of Phosphofructokinase when [ATP] is high prevents breakdown of glucose in a pathway whose main role is to make ATP. It is more useful to the cell to store glucose as glycogen when ATP is plentiful.

Pyruvate KinaseO C 1 C 2 OPO323 CH 2

O

ADP ATP

O1 2

O C C O

3 CH 3

phosphoenolpyruvate

pyruvate

Pyruvate Kinase, the last step Glycolysis, is controlled in liver partly by modulation of the amount of enzyme.

High [glucose] within liver cells causes a transcription factor carbohydrate responsive element binding protein (ChREBP) to be transferred into the nucleus, where it activates transcription of the gene for Pyruvate Kinase. This facilitates converting excess glucose to pyruvate, which is metabolized to acetyl-CoA, the main precursor for synthesis of fatty acids, for long term energy storage.

KREBS CYCLE TRIVIA QUIZ

Complete the following statements: A. When 1 acetyl CoA enters the citric acid cycle, the C atoms produce ____CO2. B. In 1 cycle, a total of ____NADH are produced. C. In 1 cycle, a total of ____FADH2 are produced.13

KREBS CYCLE TRIVIA QUIZ

Complete the following statements: A. When 1 acetyl CoA enters the citric acid cycle, the C atoms produce 2 CO2. B. In 1 cycle, a total of 3 NADH are produced. C. In 1 cycle, a total of 1 FADH2 are produced.14

3. Jelaskan fungsi-fungsi utama (peranan) dari siklus krebs! (minimal 2)

The function of TCA cycle : 1. Oxidized of Acetyl CoA ATP ( 1 mol Acetyl CoA 12 mol ATP ) 2. The citric acid cycle is AMPHIBOLIC : - it can oxidized to yield ATP 3. It also has a central role in gluconeogenesis, lipogenesis, and interconversion of amino acids.

4. The final common pathway for the aerobic oxidation of carbohydrate, lipid and protein

The citric acid cycle is the final common pathway for the oxidation of carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids are metabolized to acetyl-CoA

ANGGOTA TCA CYCLE BERSIFAT AMFIBOLIK Dapat dioksidasi lebih lanjut menjadi energi * katabolisme asam amino anggota tca cycle energi * oksidasi beta asam lemak asetil KoA anggota siklus krebs energi * oksidasi glukosa piruvat asetil KoA anggota siklus krebs energi Dapat disintesis menjadi senyawa lain, misalnya menjadi : * glukosa (melalui glukoneogenesis) * asam amino tertentu * asam lemak (lipogenesis)

Tugas no 4 Jelaskan inhibitor-inhibitor pada siklus krebs ? (minimal 2)

INHIBITOR SIKLUS ASAM SITRAT Fluoroasetat : * Dgn KoA-SH membentuk fluoroasetil-KoA * Fluoroasetil-KoA berkondensasi dgn oksaloasetat membentuk fluorositrat ( dikatalisis oleh sitrat sintase) * Fluorositrat menghambat enzim akonitase terjadi akumulasi sitrat * Fluoroasetat didapatkan misalnya dari pestisida Malonat : menghambat enzim suksinat dehidrogenase Arsenit : menghambat enzim -ketoglutarat dehidrogenase kompleks

VITAMINS PLAY KEY ROLES IN KREBS CYCLE Four of the B vitamins are essential in the citric acid cycle (1) riboflavin, (VIT B2) in the form of flavin adenine dinucleotide (FAD), a cofactor for succinate dehydrogenase (2)niacin, in the form of nicotinamide adenine dinucleotide (NAD), the electron acceptor for isocitrate dehydrogenase,-ketoglutarate dehydrogenase, and malate dehydrogenase

3. thiamin (vitamin B1), as thiamin diphosphate, the coenzyme for decarboxylation in the ketoglutarate dehydrogenase reaction 4 pantothenic acid, as part of coenzyme A, the cofactor attached to "active" carboxylic acid residues such as acetyl-CoA and succinyl-CoA.

VITAMIN B1 (Thiamine) B2 (Riboflavin) B3(Pantothenate) B6(Pyridoxine) B12 (Cobalamine) Niacin=Nicotinat Folic Acid

KOENSIM TPP = Thiamine Pyrophosphate FAD = Flavin Adenine Dinucleotide CoA = Coenzyme-A PLP = Pyridoxal Phosphate 5- deoxy adenocyl cobalamine NAD = Niacin Adenine Dinucleotide Tetrahydrofolate

Biotin

Biotin

Citric Acid Cycle

Regulation of Citric Acid Cycle Operates when ATP is needed High levels of ATP and/or NADH inhibit citrate synthetase (first step in cycle) High levels of ADP and NAD+ activate isocitrate dehydrogenase Low levels of ATP or high levels of acetyl CoA speed up the cycle to give energy

26

Summary Krebs cycle reactions

FAD

FADH2

Cellular respiration

The final stage of aerobic respiration occurs in the electron systems embedded in the inner membrane of the mitochondrion. Oxidation phosphorylation (which takes place on the cristae of the mitochondria) processes the H+ ions and electrons to generate high yields of ATP. NADH and FADH2 give up their electrons to transport (enzyme) systems embedded in the mitochondrial inner membrane.

32

Diagram of the ProcessOccurs across Cristae

Occurs in CytoplasmOccurs in Matrix

Review of Mitochondria Structure Smooth outer Membrane Folded inner membrane called Cristae Space inside cristae called the Matrix

definitions Electron Transport: Electrons carried by reduced coenzymes (NADH or FADH2) are passed sequentially through a chain of proteins and coenzymes (so called electron transport chain) to O2 . Oxidative Phosphorylation: Coupling e- Transport (Oxidation) and ATP synthesis (Phosphorylation) .

Organization of Chain NADH dehydrogenase or NADH-Q oxidoreductase (complex I) Succinate-Q reductase (complex II) Coenzyme Q (CoQ) (also called ubiquinone) Cytochrome c oxidase (complex III) Cytochrome c (Cyt c) Cytochrome c oxidase (complex IV)

Succinate-Q reductase (Complex II), in contrast with the other complexes, does not pump protons.

Each complex accepts and donates electrons to a relatively mobile electron carriers. The electrons ultimately combine with oxygen and protons to form water. It requires oxygen that is why it is also called respiratory chain. It accounts for the greatest portion of the body's use of oxygen.

Electron Transport Chain

1. 2. 3. 4. 5. 6.

Coenzymes which take part are: NAD NADP FAD FMN Coenzyme Q (CoQ) Fe-S proteins

Coenzyme Q It is also called ubiquinone. They contain isoprene units in their side chains. Can accept H atoms from both FMNH2 and FADH2. the only electron carrier not bound to a protein. it can accept/donate 1 or 2 e-. Q can mediate e- transfer between 2 e- that transfer and 1 e- carriers

When bound to special sites in respiratory complexes, CoQ can accept 1 e- to form a semiquinone radical (Q-).O CH3O CH3 CH3 CH3O O (CH2 CH C CH3O O CH3 CH3 CH3O O (CH2 CH C CH2)nH

e

CH2)nH

coenzyme Q

coenzyme Q

e + 2 H+OH CH3O CH3 CH3 CH3O OH (CH2 CH C CH2)nH

coenzyme QH2

Iron-sulfur Centers (clusters)Iron-sulfur centers (Fe-S) are prosthetic groups containing 1-4 iron atomsIron-sulfur centers transfer only one electron, even if they contain two or more iron atoms. E.g., a 4-Fe center might cycle between redox states: Fe+++3, Fe++1 (oxidized) + 1 e Fe+++2, Fe++2(reduced)

Cys S S Cys Cys S S Fe

S S Fe Fe S Fe

Fe S

S Cys Cys S S Cys

Fe S S Cys

Cys

S

Iron-Sulfur Centers

Complex I. Steps1. The initial step is the binding of the NADH and transfer of 2 electrons t