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Glucose Metabolism

Complete Oxidation of Glucose

C6H12O6

+ 6O2

6CO2 + 6H2O

Glucose Metabolism
Glucose

Central position in metabolism


A good cellular fuel (- 2,840 kJ/mol for complete oxidation)
Released from high molecular weight polymers
Production of ATP
Supplies metabolic intermediates for biosynthesis

Fates of glucose in animals and plants

Storage
Glycolysis: oxidation to 3-carbon compounds to provide ATP and metabolic
intermediates
Pentose phosphate pathway - oxidation to yield ribose-5-phosphate and
NADPH

Synthesis of glucose

Gluconeogenesis
Photosynthesis

Glycolysis
- A series of enzyme-catalyzed reactions in a pathway
- Overall conversion:

- Generation of 2 ATPs (net gain)

- These reactions are the way in which carbohydrate is broken down into
smaller units.
- Anaerobic metabolism: pyruvate is converted to lactate or ethanol
(fermentation)
- Aerobic metabolism: pyruvate is fed into the TCA cycle where
it is fully metabolized to carbon dioxide releasing more ATPs

Hexose stage:
(Preparatory phase)

Triose stage:
(Payoff phase)

The ten steps of glycolysis

Hexose stage: 1 to 4
Triose stage: 5 to 10

(1) Hexokinase: phosphorylation of glucose

Hexokinases
- Hexose kinases
- Four isoenzymes isolated from mammalian liver
- Hexokinase I, II, III: Km for glucose = 10-6 10-4 M
- Hexokinase IV = Glucokinase: Km for glucose = 10-2 M
(more active at high blood glucose conc.)

(2) Conversion of G-6-P to F-6-P:


(aldose-ketose isomerization)

(3) Transfer of a second phosphoryl group from ATP to F-6-P

PFK-1
(-D-fructofuranose form)
- The first committed step in glycolysis
Glucose

Glucose 6-P

other pathways
Fructose 6-P
PFK-1

other pathways

other pathways

Fructose 1,6-bisP

Glycolysis only

(4) Cleavage of C3-C4 bond


- Production of two triose phosphates

- Unfavorable under standard condition (G > 0)


- Actual free energy change ~ 0, thus a near-equilibrium reaction
- Rapid consumption of DHAP and G3P pulls the reaction forward

Aldolases
-

Class I: plants and animals


Class II: microorganisms
Classes I and II are not structurally related
An example of convergent evolution

Mechanism of F1,6-bisP cleavage by aldolases:

X an electron withdrawing group


- Lysine amino group in Class I
- Zn2+ cofactor in class II

(5) Conversion of DHAP to G3P

- Enzyme mechanism: general acid-base catalysis (see lecture notes on


enzyme mechanism)
- Only G3P continues in the glycolytic pathway
- Which direction of the reaction is favored?

Fate of carbon atoms from the hexose stage to the triose stage:

(6) Formation of a high-energy compound: 1,3-Bisphosphoglycerate


Acid anhydride linkage

- Beginning of the recovery of energy from triose phosphates


- Oxidation-reduction reaction catalyzed by a dehydrogenase (why is it called a
dehydrogenase?)
- Phosphorylation reaction (how is it different from the earlier kinase reactions?)

(7) Generation of ATP

- 1,3-BPG hydrolysis releases large amount of energy


- Substrate level phosphorylation

- Stabilization of product by resonance hybrid formation:

- G3P dehydrogenase and PG kinase associate to form a complex: efficient


channeling of 1,3-bisphosphoglycerate

Arsenate poisoning
- AsO43- replaces inorganic phosphate (PO43-) in phosphoryl transfer
reactions
Glyceraldehyde 3-P
+
AsO43+
NAD+
Glyceraldehyde 3-P
dehydrogenase

(No 1,3-pisphosphoglycerate
production)

(8) Intramolecular phosphoryl group transfer

2
3

Phosphoglycerate mutase

2
3

Mutase: an isomerase that catalyzes the intramolecular shifting of a chemical group

Phosphoglycerate kinase: mechanism

(9) Dehydration to an energy-rich compound, PEP

(PEP)

(10) Generation of ATP


- PEP: high-energy phosphate compound
- Tautomerization stabilizes products of hydrolysis
- Substrate level phosphorylation
- Glycolysis finally turns a profit!
tautomerization

(enol form)

(keto form)

Overall process of glycolysis


Glucose + 2ATP + 2NAD+ + 4ADP + 2Pi
2 pyruvate + 2ADP + 2NADH + 2H+ + 4ATP + 2H2O
Simplifying the equation will give you:
Glucose + 2NAD+ + 2ADP + 2Pi 2 pyruvate + 2NADH + 2H+ + 2ATP + 2H2O

The fate of pyruvate

Metabolism of pyruvate to ethanol


- Regeneration of NAD+ for glycolysis

Summary of glycolysis and ethanol formation

Reduction of pyruvate to lactate


- Regeneration of NAD+ for glycolysis
- Anaerobic bacteria
- Mammals (skeletal muscles during vigorous exercise)

Summary of glycolysis and lactate formation

Other sugars can enter glycolysis

Entry of fructose into glycolysis through fructokinase

Conversion of mannose to fructose 6-phosphate

Conversion of galactose to glucose 6-phosphate

Regulation of glycolysis
1. Regulation of hexose transporters
- Membrane-embedded transporters (e.g. GLUT family transporters)
- Stimulation of cellular glucose uptake by insulin

(Skeletal and heart muscle cells,


Adipocytes)

2. Regulation at 3 irreversible steps

(a) Hexokinase

Glucose + ATP Glucose 6-phosphate (G-6-P) + ADP


G-6-P
- Allosteric inhibitor of hexokinases I, II, III (found in muscles)

Glucokinase
- Not inhibited by G-6-P
- the major hexokinase in liver
- Converts glucose to G-6-P in liver after a meal
- G-6-P is used for glycogen synthesis when glucose is sufficient in other tissues
- High Km value for glucose
- Never saturated with glucose
- Activity increases with increasing concentration of available glucose

(b) Phosphofructokinase-1 (PFK-1)


Fructose 6-phosphate + ATP

Fructose 1,6-bisphosphate + ADP

ATP - a substrate and an allosteric inhibitor


AMP and ADP allosteric activators
AMP relieves the inhibition
by ATP

ATP reduces the affinity of


PFK-1 for F 6-P

Citrate feedback inhibitor; a TCA cycle intermediate


- high conc indicates that TCA cycle is blocked

Fructose 2, 6-bisphosphate an allosteric activator of PFK-1


In liver cells:

Low blood glucose

Glucagon

(Phosphofructokinase-2)

PFK-1 less active

(c) Pyruvate kinase


Phosphoenolpyruvate (PEP) + ADP

Pyruvate + ATP

ATP a strong allosteric inhibitor


Fructose 1,6-bisphosphate (F1,6BP) an allosteric activator

PFK-1 , F1,6BP , Pyruvate kinase


Thus, PFK-1 activation leads to subsequent pyruvate kinase activation
- Feed-forward activation

The Entner-Doudoroff Pathway in Bacteria


- No PFK-1 enzyme in bacteria
- No fructose 1,6-bisphosphate
formation from glucose
- Generates fewer ATP than glycolysis,
why?
- Earliest pathway for glucose
degradation

Two products in this pathway:


Pyruvate (end product of glycolysis)
Glyceraldehyde 3-phosphate
Glycolysis
(triose phase)
Pyruvate

fructose 6-phosphate
PFK-1
(not in
some
bacteria)
fructose 1,6bisphosphate