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Glucose Oxidation

major Pathway

I. Glycolysis

Definition:

Glycolysis means oxidation of glucose to give:

• Pyruvate (in the presence of oxygen) or,

• Lactate (in the absence of oxygen)

Site:Cytoplasm of all tissue cells, but it is of physiological importance

in: 1. Tissues with no mitochondria: mature RBCs, cornea and

lens. 2. Tissues with few mitochondria: Testis, leucocytes, medulla

of the kidney, retina, skin and gastrointestinal tract. 3. Tissues undergo frequent oxygen lack: skeletal muscles

especially during exercise.

Glycolysis

What are the possible fates of glucose?

Glycolysis

All the intermediates in glycolysis have either 3 or 6 carbon atoms

All of the reactions fall into one of 5 categories phosphoryl transfer phosphoryl shift isomerization dehydration aldol cleavage

Glycolysis

Entire reaction sequence may be divided into three stages glucose is trapped and destabilized six carbon molecule is split into two three carbon

molecules ATP is generated

Glycolysis – Stage 1

glucose converted to glucose-6-PO4ATP is neededcatalyzed by hexokinase or glucokinase


phosphoglucoisomerasealdose is converted to ketose


rate limiting enzyme – phosphofructokinase inhibited by high ATP, citric acid, long-chain fatty

acids stimulated by ADP or AMP

Glycolysis


six carbon molecule split into 2- 3 carbon molecules aldose and ketose



redox reactionenergy from redox used to form acyl

phosphate


Consists of two coupled processes


formation of ATP – substrate level phosphorylation


phosphoryl shift – uses 2,3 bisphosphoglycerate

Glycolysis

• In the energy investment phase, ATP provides activation energy by phosphorylating glucose.– This requires 2 ATP per glucose.

• In the energy payoff phase, ATP is produced by substrate-level phosphorylation and NAD+ is reduced to NADH.

• 2 ATP (net) and 2 NADH are produced per glucose.

Energy Investment Phase

Energy-Payoff Phase

Fate of Pyruvate

Alcoholic FermentationWhich organisms carry out this process?

yeast other microorganisms

PDC requires thiamine pyrophosphate as coenzyme

NAD+ is regenerated

Lactic Acid Fermentation

Occurs in muscle cells, microorganismsRegenerates NAD+

Substrate level phosphorylation:

• This means phosphorylation of ADP to ATP at the reaction itself .

• In glycolysis, there are 2 examples: - 1.3 Bisphosphoglycerate + ADP 3

Phosphoglycerate + ATP - Phospho-enol pyruvate + ADP Enolpyruvate +

ATP.

Special features of glycolysis in RBCs

1. Mature RBCs contain no mitochondria, thus:

a) They depend only upon glycolysis for energy production (=2 ATP).

b) Lactate is always the end product.

2. Glucose uptake by RBCs is independent on insulin hormone.

3. Reduction of met-hemoglobin: Glycolysis produces NADH+H+, which

used for reduction of met-hemoglobin in red cells

Biological importance (functions) of glycolysis:

• Energy production: a) anaerobic glycolysis gives 2 ATP. b) aerobic glycolysis gives 8 ATP.• Provides important intermediates: a) Dihydroxyacetone phosphate: can give glycerol-3phosphate,

which is used for synthesis of triacylglycerols and phospholipids (lipogenesis).

b) 3 Phosphoglycerate: which can be used for synthesis of amino acid serine.

c) Pyruvate: which can be used in synthesis of amino acid alanine.

• Aerobic glycolysis provides the mitochondria with pyruvate, which gives acetyl CoA Krebs' cycle.

Glycolysis

How can fructose be used for energy?

Glycolysis

To use galactose it must be converted to glucose-6-PO4

Glycolysis

Glycolysis

What causes lactose intolerance?

Reversibility of glycolysis (Gluconeoqenesis): 1. Reversible reaction means that the same enzyme can catalyzes the reaction in both directions. 2. all reactions of glycolysis -except 3- are reversible. 3. The 3 irreversible reactions (those catalyzed by kinase enzymes) can be reversed by using other enzymes.

Glucose-6-p Glucose F1, 6 Bisphosphate Fructose-6-pPyruvate Phosphoenol pyruvate

4. During fasting, glycolysis is reversed for synthesis of glucose from non- carbohydrate sources e.g. lactate. This mechanism is called: gluconeogenesis.

Importance of lactate production in anerobic glycolysis:

1. In absence of oxygen, lactate is the end product of glycolysis:

2. In absence of oxygen, NADH + H+ is not oxidized by the respiratory chain.3. The conversion of pyruvate to lactate is the mechanism for regeneration of NAD+. 4. This helps continuity of glycolysis, as the generated NAD+ will be

used once more for oxidation of another glucose molecule.

Glucose Pyruvate Lactate

What is galactosemia?

inability to metabolize galactose missing galactose 1-phosphate uridyl transferase

liver disease development of cataracts CNS malfunction

Control of Glycolysis

Of what value is glycolysis for cells? provides energy in form of ATP provides building blocks for synthetic reactions

Where are most control points found? enzymes that catalyze irreversible reactions

hexokinase phosphofructokinase pyruvate kinase

Phosphofructokinase

Most important control point in mammalian glycolytic pathway allosteric enzyme

activated by AMP and fructose 2,6 bisphosphate inhibited by high levels of ATP, citrate, fatty acids

Hexokinase

Hexokinase is inhibited by its product glucose-6-PO4 glucose remains in blood

Glucokinase, an isozyme of hexokinase is not inhibited by glucose-6-PO4 found in liver has lower affinity for glucose

Pyruvate Kinase

Pyruvate kinase exists as isozymes L form – predominates in liver M form – mostly in muscle and brain

PK is an allosteric enzyme activated by fructose 1,6 bisphosphate inhibited by ATP, alanine

L form of PK influenced by covalent modification inhibited by phosphorylation

Pyruvate Kinase

Gluconeogenesis

What is gluconeogenesis? synthesis of glucose from non-carbohydrate

precursorsWhy is this an important pathway?What are some of the major precursors?

lactate, amino acids, glycerolWhere does this process occur?

liver, kidney

Gluconeogenesis

If gluconeogenesis involves the conversion of pyruvate to glucose why is it not simply the reverse of glycolysis? glycolysis contains several irreversible reactions

Which reactions in glycolysis are irreversible? phosphoenolpyruvate to pyruvate fructose 6-phosphate to fructose 1,6-

bisphosphate glucose to glucose 6-phosphate

Gluconeogenesis

CH3 CCO2-

O

CH2 CCO2-

O

CO2-

+ CO2 + ATP

+ ADP + Pi

Pyruvate

Oxaloacetate

biotinpyruvate

carboxylas e

Gluconeogenesis

Pyruvate carboxylase is an allosteric enzyme activated by acetyl

CoA needed to form

carboxybiotin

Gluconeogenesis

Carboxylation of pyruvate occurs in the mitocondria but next step in reaction sequence occurs in cytosol

Gluconeogenesis

Decarboxylation of oxaloacetate is coupled with

phosphorylation by GTPenzyme is phosphoenolpyruvate

carboxykinase

CH2 = CCO2-

OPO32 -

CH2 CCO2-

O

CO2-

+ CO2

+ GTP

Phos phoenol pyruvate

Oxaloacetate + GDP

Gluconeogenesis

Which other steps in glycolysis are irreversible? conversion of fructose 1,6-bisphosphate to fructose 6-

phosphate conversion of glucose 6-phosphate to glucose

Gluconeogenesis

Fructose-6-phosphate

C

CH2 OP O32 -

OHHOOHHOHH

CH2 OH

Fructose-1 ,6-bisphosphate

C

CH2 OP O32 -

OHHOOHHOHH

CH2 OP O32 -

fructose-1 ,6 -bis-phosphatase

H2 O P i

G° = -16.7 kJ mol-1

fructose-1,6-bisphosphatase is an allosteric enzyme, inhibited by AMP and activated by ATP

Gluconeogenesis

Enzyme that catalyzes last reaction not found in all tissues liver and kidney cortex

Gluconeogenesis

Is gluconeogenesis an energetically favorable reaction in the cell?

What drives this reaction?

Are glycolysis and gluconeogenesis active at the same time?

Regulation of Glycolysis and Gluconeogenesis

What are some of the factors that ensure the reciprocal regulation of these processes? allosteric regulators of key enzymes energy charge fructose 2,6-bisphosphate hormones



fructose 2,6-bisphosphate stimulates PFK and inhibits fructose 1,6-bisphosphase controlled by insulin and glucagon and reflects the

nutritional status of the cell


How do hormones influence the enzymes associated with these processes? influence gene expression

change transcription rate influence degradation of m-RNA

insulin PFK, PK glucagon PEPCK, fructose 1,6-bisphosphatase


What are substrate cycles and why are they important? can amplify

metabolic signals can generate heat


What is the Cori cycle and why is it important?
