Glycolysis. Biochemistry Hayder A Giha

Transcription

1 Glycolysis Biochemistry 2017 Hayder A Giha

2 Defiitio: It is a uiversal pathway for glucose (glycoge) metabolism, foud i the cytosol of all mammalia cells, ad give pyruvate ad/or lactate as a ed product.

3 Itroductio Most sugars coverted to glucose, so, it is the major carbohydrate utilized by huma tissues. Glycolysis is the major pathway for glucose metabolism. There is a basal requiremet for glucose i most of the tissues, e.g. the brai eeds is substatial, ad erythrocyte eeds is total ad absolute.

4 Characteristics of glycolysis Site: is the cytosol of all tissues Its uique i the sese that, it ca use oxyge (aerobic) whe its available, however, it ca operate i absece of oxyge (aaerobic). Aerobic utilizatio of glucose demads a set of mitochodrial ezymes (Kerbs cycle & respiratory chai).

5 The cell

6 Importace As glucose (Glc) eter the cell, it is phosphorylated at C6, becomes egatively charged, thus Glc remai iside the cell because the cell membrae iside is egatively charged. The fate of G6P: a. eergy productio (glycolysis) b. buildig of CHO or storage (glycogeesis) c. other pathways ( e.g. Petose Phosphate Pathway) Mai source of eergy for erythrocytes, ad exercisig muscles.

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10 Glycolysis Have 2 phases I. Eergy ivestmet phase (cosume eergy) (5 reactios) II. Eergy geeratio phase (eergy productio) (5 reactios) Three cotrol poit (irreversible reactios)

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12 Eergy ivestmet phase Two phosphorylatios; of Glc at C6 & Fructose at C1 I. Hexokiase (all cells) or Glucokiase (liver ad B- cells of pacreas) Hexokiase: have low Vmax & Km (high affiity), work at ormal or low blood glucose to provide eergy for tissues, ad ihibited by G6P Glucokiase: have high Vmax & Km (low affiity), work after meal (high BG) to store Glu Both ezymes catalyze irreversible reactios suitable for regulatio of the pathway

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14 compariso Hexokiase Glucokiase site All tissues -Liver parechymal cell -Pacreatic b-cells Affiity for substrate Fuctio High affiity Low Km & V-max To esure glucose supply for tissues Specificity Glucose ad other hexoses (low level) Cotrol Ihibited by glucose 6- phosphate Low affiity High Km & V-max To remove glucose from blood after meals Glucose oly Affected by utritioal state

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16 Glycolysis G6P isomerized (phosphoglucose isomerase) to F6P F6P phosphorylated by phosphofructokiase-1 (PFK-1) at C1 to Fructose 1,6 bisphosphate (F1,6P 2 ) This is the 2 d irreversible reactio, so is a cotrol (regulatio) poit High eergy state (ATP & citrate) ihibit PFK-1, ad the opposite is true (AMP & F2,6P 2 ) activate PFK-1 Small a mout of F6P is coverted to Fructose 2,6 bisphosphate (F2,6P 2 ) by phosphofructokiase-2 (PFK-2).

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18 Eergy ivestmet phase F1,6P 2 cleaved by aldolase A ito 2 triose-p; glyceraldehyde 3-P (GAP) & dihydroxyacetoe- P (DHAP). GAP ad DHAP are iter-covertible by triose phosphate isomerase

19 Eergy geeratio phase GAP is oxidized ad phosphorylated at C1 by GAP dehydrogease to a eergy-rich 1,3 bisphosphoglycerate (1,3-BPG)

20 Eergy geeratio phase 1,3-BPG phosphoglycerate (3-PG) ad productio of eergy at substrate level (ADP --- ATP); by phosphoglycerate kiase I RBCs, some 1,3 BPG is coverted to 2,3BPG by mutase ezyme (loss of ATP), 2,3 BPG decrease Hb affiity to O2.

21 3-PG (3 phosphoglycerate) PG by mutase 2PG phosphoeolpyruvate (PEP) by Eloase (with removal of H 2 O) This dehydratio raise the eergy level of P i PEP PEP pyruvate by pyruvate kiase (PK), associated with coversio of ADP to ATP (eergy at substrate level) (it is irreversible reactio, site for cotrol) PK is activated by F1,6P 2 ad camp-depedet protei kiase A

22 Glycolysis IA Glyceraldehyde 3-phosphate Dehydrogease Phosphoglycerate kiase Phosphoglycerate mutase H - C = O H - C - OH CH 2 - O - P P i Glyceraldehyde 3-phosphate O II C O ~ P H - C - OH CH 2 - O - P 1,3-Biphosphoglycerate Mg 2 NADH NAD NADH NAD ADP ATP COO - H - C - OH CH 2 - O - P 3-phosphoglycerate FL COO - H - C O - P CH 2 OH Eolase H 2 O Mg 2 COO - C O ~ P CH 2 Pyruvate kiase Mg 2 ADP ATP COO - C - OH II CH 2 2-phosphoglycerate Phosphoeolpyruvate (Eol) Pyruvate

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24 NAD is eeded for ATP productio at substrate level, but it is limited, so, the produced NADH+H + eed to be oxidized Uder aaerobic coditios or whe o mitochodria, H + is accepted by pyruvate which is coverted to lactate (by lactate dehydrogease) Whe produced i large quatities, lactate diffuse from cell to blood cause lactic acidosis

25 Glycolysis

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28 Eergy of glycolysis 2 ATP are cosumed durig glycolysis (ivestmet phase) i reactios catalyzed by: 1. Hexokiase (Glucokiase), 1 ATP 2. Phosphofructokiase-1, 1 ATP Note: if glycoge is the startig poit, 1 ATP will be saved, i.e. icreased et productio of eergy at substrate level.

29 Eergy productio i glycolysis 4 ATP are geerated i the eergy geeratio phase; 1. Phosphoglycerate kiase (2 ATP, substrate level) 2. Pyruvate kiase (2 ATP, substrate level). THE NET is 2 ATP I additio, two NADH + H + (Glyceraldehyde 3- phosphate dehydrogease), (uder aerobic coditios, i respiratory chai, each oe produce 3 ATP).

30 Regulatio of glycolysis Glycolysis is cotrolled at 3 steps (oequilibrium reactios) catalyzed by: 1. Hexokiase (glucokiase) 2. Phosphofructokiase-1 3. Pyruvate kiase

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33 Oxidatio of pyruvate Pyruvate oxidatio (uder aerobic coditios) occurs withi the mitochodria, its trasported ito the later via pyruvate trasporter Its oxidatively decarboxylated to Acetyl-CoA, before it eter the citric acid cycle. This reactio is catalysed by a complex of ezymes (3 ezymes), desigated as, pyruvate dehydrogease complex (PDH) The reactio eeds CoA, thiami diphosphate, lipoic acid, FAD ad NAD +

34 Oxidatio of pyruvate 2 NADH + H + are produced for each glucose molecule Also a high-eergy thio ester group i acetyl-coa is produced.

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36 The Ed