Transcript Anaerobic & aerobic glycolysis

Section 6:
Carbohydrate Metabolism
3. Anaerobic & aerobic
glycolysis
10/21/2005
Complete oxidation of glucose
 stoichiometry:
glc + 6 O2  6 CO2 + 6 H2O
G'º = – 686 kcal/mol
 ATP yield
(686/7.3)
• theoretical: >90
• actual:
30-32
 first stage: glycolysis (10-11 steps)
• location: cytosol of all cells (including microorganisms)
• 2 parts
glc  2 glyceraldehyde 3-P (GAP) (steps 1-5)
2 GAP  2 pyruvate/lactate
(steps 6 -10/11)
1
Glycolysis
glc
1.
2-
2-
H 2 CO PO 3
O H
H H
C
OH H
OH
HO
H
OH
glucose 6-phosphate
(glc 6-P)
2
H 2 C O PO 3
ATP (see L2sl9 “Phosphorylation of glc”)
ADP
2-
O PO 3
H2C O
OH
CH 2
C
H H HO OH
O
HO C H
H C OH
H C OH
ATP ADP
HO H
fructose 6-phosphate
(frc 6-P)
2.isomerization
phosphoglucose
isomerase
C
2-
H 2 CO PO 3
fructose 1,6bis phosphate
(1,6FBP)
3. phosphoryl transfer
phosphofructokinase
irreversible
committed step
2-
2-
H2C O PO 3
C
O
H2C O PO 3
C
O
H2C OH
HO C H
H C O H
+
H C O
H COH
H C OH
2-
H2COPO 3
H2CO PO 3
fructose 1,6bis phosphate
(1,6FBP)
4. aldol cleavage
aldolase
3
2-
dihydroxyacetone
phosphate
(DHAP)
glyceraldehyde
3-phosphate
(GAP)
5. isomerization
triose phosphate
isomerase
6. oxidation-driven
phosphorylation
GAP DHase
H C O
H 2 C OH
H C OH
C O
2-
2-
H 2 C OPO 3
DHAP
H 2 COPO 3
GAP
NAD+ + Pi
NADH + H+
O
2-
C O PO 3
H C OH
1,3-bis phosphoglycerate
(1,3BPG)
2-
7. phosphoryl transfer
phosphoglycerate
kinase
H 2 COPO 3
ADP
ATP + H+
O
C O
–
H C OH
2-
4
H 2 COPO 3
3-phosphoglycerate
(3PG)
O
8. phosphoryl shift
phosphoglycerate
mutase
9. dehydration
enolase
O
C O–
2-
H C O PO 3
H 2 COPO 3
3PG
H 2 COH
2PG
H2O
O
C O–
C O PO 3
phosphoenolpyruvate
(PEP)
CH 2
ADP
ATP
O
C O–
C O
5
H C OH
2-
2-
10. phosphoryl transfer
irreversible
pyruvate kinase
C O–
CH 3
pyruvate
(pyr)
Regeneration of NAD+: 1. electron shuttles
 stoichiometry of steps 1-10:
glc + 2 NAD+ → 2 pyruvate + 2 NADH + 4 H+
 NAD present in cells in only catalytic amounts, so
regeneration of NAD+ is necessary
 cytosolic NADH cannot enter mitochondria
 solution: e– pair carried to mitochondrial e– transport chain
via a shuttle (short linking pathway)
 net reaction:
NADHcyt + oxid e– carriermito → NAD+cyt + red. e– carriermito
2 e–cyt → 2 e–mito
 malate-aspartate shuttle
• main shuttle in heart & liver cells
• e– pair eventually transferred to mitochondrial
matrix NAD+, so ATP yield is 2.5/ e– pair
6
GOP-DHAP shuttle
 main shuttle in brain & skeletal muscle
 net reaction

NADHcyt +
H+ + E-FAD
Fig. 18.37
↓
NAD+cyt +
E-FADH2
 yields
1.5 ATP
per e– pair
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
e–s from complex II, others
Regeneration of NAD+: 2. reduction of pyruvate
 conditions limiting electron shuttles:
• mitochondria scarce (“fast” muscle) or absent (RBC)
• limited O2 supply (ischemia)
• high demand for ATP causes glycolysis rate > shuttle rate
 e– pair is transferred to pyruvate:
O
_
lactate
DHase
_
O O
C
C
+
+
NAD +
NADH + H +
HO C H
O C
CH3
CH3 11. oxidationreduction
L-lactate
pyruvate
O
 as a result, glycolysis can occur without net
oxidation: anaerobically
fermentation: any anaerobic process
8
Glycolysis stoichiometries
Aerobic glycolysis:
ATP
yield
steps 1-10 glc + 2 NAD+ → 2 pyruvate + 2 NADH + 4H+ 2
Regen. of NAD+: GOP shuttle + ox phos
2 H+ + 2 NADH + O2 → 2 NAD+ + 2 H2O
3*
glc + O2 → 2 pyruvate + 2 H+ + 2 H2O
5
* 5 if malate-aspartate shuttle used
Anaerobic glycolysis:
steps 1-10 glc + 2 NAD+ → 2 pyruvate + 2 NADH + 4 H+ 2
step 11 2 pyruvate +2 NADH + 2H+ → 2 lactate +2 NAD+
(steps 1-11)
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glc → 2 lactate + 2 H+
2
Effect of glycolysis products (pyruvate/lactate):
acidification
 stoichiometry of both aerobic & anaerobic glycolysis
shows production of 2 H+/ glc
 unlike phosphate-containing metabolites,
lactate & pyruvate permeant to most cell membranes
(as protonated forms: lactic acid & pyruvic acid)
• microorganisms:
 their environment becomes acidic
e.g., plaque bacteria on enamel surface ferment carbs
 low pH increases solubility of Ca phosphate minerals
 repeated acid attacks produce carious lesion
• skeletal muscle during exercise:
+] rise
[lactate],
[pyruvate]
&
[H
10
Fate of pyruvate/lactate
pyruvate has a number of alternative fates
•e.g., oxidized further in mitochondria (next lecture)
•diffusion out of cell (efflux)
lactate has only 1 metabolic fate: oxidation back to pyruvate
•if oxidation limited, efflux occurs
blood distributes these
liver converts them
back to glc by
gluconeogenesis
(next lecture)
combination of muscle
glycolysis & liver
gluconeogenesis:
Cori cycle
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The Cori cycle
LIVER
MUSCLE
glucose   glucose
6 ATP 
2 ATP out
pyruvate blood pyruvate


lactate  lactate
gluconeogenesis
glycolysis
Net effect is transfer of energy
from liver to muscle
Control of glycolysis
step enzyme
1
3
inhibitor
hexokinase
glc 6-P
phosphofructokinase ATP,
citrate*
activator
AMP,
ADP
mechanism of control:
both kinases have allosteric sites to which
activators/inhibitors bind
* provides coordination with Krebs (citric acid) cycle
12
Next time:
4. Gluconeogenesis
Pyruvate oxidation