2.Glycolysis Kreb O.P

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Glycolysis and Krebs Cycle

Assoc. Prof. Dr. Suzana Makpol

Dept. of Biochemistry

Faculty of Medicine, UKM

[email protected]

Session 2011/2012


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Objectives (Glycolysis)

describe the glycolysis pathway

describe the regulation of glycolysis differentiate between aerobic and

anaerobic glycolysis

explain the role of 2,3-bisphosphoglycerate in red blood cells


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CARBOHYDRATE METABOLISM AFTER MEAL

Acetyl CoA

Glu

CO2 + H2O + ATP (Na+ / ATPase at neuron

cells membrane)

Rice

Small intestine

Insulin

Glucagon

Portal vein

Adipose cell

TG

TG

LactatePyruvate

Glucose

Glycogen

Acetyl CoA

CO2 + H2O

+ ATP

Glycogen

LIVER

CO2 + H2O + ATP

Lactate

Pyruvate

GluBRAIN RBC

Carbohydrate

Glucose VLDL

Glucose

Gly 3-P

-Amylase

-amylase pancreasedisaccharidases (lactase,maltase, sucrase)

MUSCLEGlu

Acetyl

CoA

Fatty acids

+ Glycerol

LDL


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Session 2007/2008 4

Release of Chemical Energy Cellular

respiration

occurs in three

sets of reactions:

glycolysis, the

citric acid cycle,

and the electron

transport chain

(oxidative

phosphorylation)


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Glucose pyruvate/lactate It occurs in the cytosol

Glycolysis aerobic & anaerobic (does not requireoxygen to proceed)

1st stage of glycolysis - glucose is phosphorylatedat two places, requiring ATP

2nd stage - the 6-carbon glucose is split into two 3-carbon pyruvate molecules

ATP is synthesized at the second stage of glycolysisat two places


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Role of Glycolysis

- provide ATP

- precursor for ribose sugar

- glycerol 3-phosphate triacylglycerol

- pyruvate FA synthesis

amino acid synthesis


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Glucose

Glucose 6-phosphate

ATP*

ADP

Hexokinase/Glucokinase (Hexokinase IV)

Fructose 6-phosphate

Fructose 1,6-bisphosphate/diphosphate

ATP*

ADP

Dihydroxyacetone P Glyceraldehyde 3-P

Glycerol

Glycerol 3-P

Phosphoglucose isomerase

Aldolase A

Triose phosphate isomerase

PHASE I

*irreversible reaction: endergonic

Glycerol-3P dehydrogenase


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1,3-Bisphosphoglycerate

3-Phosphoglycerate

Phosphoenolpyruvate (PEP)

Pyruvate

NAD+

NADH

ADP

ATP

ATP

Pyruvate kinase

Glyceraldehyde 3-P

Lactate

ADP

NADH NAD+

Glyceraldehyde-3P dehydrogenase

Phosphoglycerate kinase

2-Phosphoglycerate


1,3-Bisphosphoglycerate mutase


phosphatase

Phosphoglycerate mutase

Enolase

Lactate dehydrogenase

Pi

PHASE II


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Role of 2,3-BPG in RBC

Bisphosphoglycerate shunt

2,3-BPG as allosteric inhibitor of

oxygen binding to heme. 2,3-BPG reenters the glycolytic

pathway via dephosphorylation to

3-phosphoglycerate


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Session 2007/2008 10

Regulation of Glycolysis

Glu 6-P

ATP, Citrate

ATP,asetil KoA

AlanineGlucagon

_

_

_

F2,6-BP, AMP+

+ F1,6-BP

Phosphofructokinase 2


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Session 2007/2008 11

When oxygenis available,

pyruvatemoves from

cytosol intomitochondria.

Aerobic Respiration


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In the absence of O2

, lactate formed (eg. RBC,muscle of a sprinter muscle cramps)

Pyruvate ---> Lactate (NADH -->NAD+; LDH)

Source of NADH (G3-P --> 1,3-BPG)

Formation of NAD+ is important for glycolysis to goon

Formation of ATP 100x faster than aerobicrespiration (citric acid cycle and oxidativephosphorylation)

Lactate will return to the liver to be converted topyruvate and to undergo gluconeogenesis - CoriCycle


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Cori Cycle


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Overall reaction for Glycolysis

Glucose + 2ATP + 2 ADP + 2PO4

- + 2NAD+

2 Pyruvate + 2 NADH + 2H2O + 4 ATP

Net Energy : 2ATP

Anaerobic : no NADH


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Session 2011/2012 15

Objectives (Krebs Cycle)

explain how pyruvate enters the mitochondria

explain the conversion of pyruvate to acetyl CoA

describe the Krebs Cycle and its regulation explain how reduced coenzymes fuel the

production of ATP

describe the entry and exit of metabolites in

Krebs Cycle


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Krebs Cycle (overview)


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Function of Krebs cycle:

Release of chemical energy (NADH,FADH2, GTP/ATP)

Its intermediates are precursors ofmany important compounds(Succinyl CoA = heme synthesis,

OAA aspartate, an amino acid)


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Krebs cycle

Acetyl CoA combines with oxaloacetate to formcitrate.

A series of reactions regenerate oxaloacetate

and produce ATP, NADH + H+

, FADH2, andcarbon dioxide.

This cycle can be repeated as long as oxygenand pyruvate are available


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Session 2007/2008 19

Glucose


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PEP

ATP

Pyruvate

= Pyruvate kinase

Lactate

Pyruvate

Acetyl CoA

Citrate

Oxaloacetate

IsocitrateNADHAKGSuccinyl CoA

Fumarate

MalateNADH

FADH2

NADH

O2H2O

Malate/ Aspartate

Malate/ Aspartate

OAA

P

E

N

G

A

N

GK

U

T

EL

E

KT

R

O

N

GLUCONEOGENESIS

CITRIC ACIDCYCLE

Carboxykinase

ATP

P

E

N

G

A

N

GK

U

T

EL

E

KT

R

O

N

P

E

N

G

A

N

GK

U

T

T

R

A

NS

P

O

R

T

E

L

E

C

T

R

O

N

Glucose

ADP

Pyruvate dehydrogenase

Citrate synthase

Aconitase

Isocitrate dehydrogenaseAKG dehydrogenase

Succinate dehydrogenase

Fumarase

Malate dehydrogenase

NADH

GTP


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Pyruvate dehydrogenase

Pyruvate

Acetyl CoAMulti enzyme complex

Pyruvate dehydrogenase/pyruvatedecarboxylase (2 forms:nonphosphorylated is the active form whilethe phosphorylated is inactive form )

Dihydrolipoyl transacetylase

Dihydrolipoyl dehydrogenase


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E1complex

E3 complex

E2 complex

lipoamide


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Pyruvate dehydrogenase (PDH)

OOCCOCH3

+ CoA + NAD+ CoASCOCH3

+ CO2

+ NADH + H+

Pyruvate Acetyl CoA

Co-factors: TPP, coenzyme A, NAD+, lipoic acid (vitamins)

Acetyl CoA dan NADH, are negative effectors while ADP a positiveeffector

PDH deficiency (genetic disorder) lactic acid accumulates damageof neuron cells mental retardation (rare)

Treatment: supplement with thiamine if E1 is abnormal; lipoic acid ifE2 is abnormal and give diet low in carbohydrate


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Session 2007/2008 24

Regulation of

PDH complex


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Regulation of TCA Cycle


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Citrate synthase

Acetyl CoA + OAA citrate

An allosteric enzyme

Positive effector: ADPNegative effectors: ATP, NADH,

succinyl CoA, acyl CoA derivative ,

fatty acids

Isocitrate dehydrogenase:


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Isocitrate dehydrogenase:rate limiting TCA

CO2NADH (need Mg2+)

ADP , positive effectorATP and NADH negative effector

K t l t t d h d


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-Ketoglutarate dehydrogenase

Multi enzyme complex:

a-ketoglutarate dehydrogenase/decarboxylase,transsuccinylase,lipoamide dehydrogenase

a-Ketoglutarate Succinyl CoARelease of CO2Formation of NADHCoenzymes: NAD+, TPP, lipoic acid and CoA

Negative effectors: ATP , GTP, NADH andSuccinyl CoASimilar structure to PDH


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Succinate dehydrogenase

Succinate Fumarate

Formation of FADH2

Malonate is an analogue ofsuccinate, a competitive inhibitor ofthe enzyme

OVERALL REACTION OF CITRIC ACID


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O C O O C C CCYCLE

Acetyl CoA + 3NAD+ + FAD + GDP + Pi + 2H2O

2CO2 + 3NADH + FADH2 + GTP + 3H+ + CoA

Regulatory enzymes (mainly allosteric): citrate

synthase, isocitrate dehydrogenase, a-ketoglutarate dehydrogenase

Regulatory factors:

ADP/ATP and NAD+

/NADH = regulate respirationfor energy formation

Efflux of intermediates from TCA


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Session 2007/2008 31

Efflux of intermediates from TCA

cycle


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Thank You

2.Glycolysis Kreb O.P

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