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Section 6: Section 6:
Carbohydrate MetabolismCarbohydrate Metabolism
3. Anaerobic & aerobic 3. Anaerobic & aerobic glycolysisglycolysis
10/21/200510/21/2005
Complete oxidation of glucoseComplete oxidation of glucose
stoichiometry:stoichiometry:glc + 6 Oglc + 6 O22 6 CO 6 CO22 + 6 H + 6 H22OO G'G' º = – 686 kcal/molº = – 686 kcal/mol
ATP yieldATP yield• theoretical: >90theoretical: >90• actual: actual: 30-3230-32
first stage: glycolysis (10-11 steps)first stage: glycolysis (10-11 steps)• location: cytosol of all cells (including microorganisms)location: cytosol of all cells (including microorganisms)• 2 parts2 parts
glc glc 2 glyceraldehyde 3-P (GAP) 2 glyceraldehyde 3-P (GAP) ((steps 1-5steps 1-5))
2 GAP 2 GAP 2 pyruvate/lactate 2 pyruvate/lactate ((steps 6steps 6 -10/11-10/11))
(686/7.3)(686/7.3)
1
GlycolysisGlycolysis
glucose 6-phosphate(glc 6-P)
H
C
OH
OH
CH2
OHOH
HO
H
O
H
H
PO2-
3
C
H
CH2
OH
OH
CH2
OH
OH
HH
O
O
PO2-
3
fructose 6-phosphate(frc 6-P)
C
C H
CH2
O
O
C
C
CH2
OH
OHH
OHH
OPO2-
3
PO2-
3
ADP
fructose 1,6-bis phosphate(1,6FBP)
ATP
3.3. phosphoryl transferphosphoryl transfer phosphofructokinasephosphofructokinase
irreversibleirreversiblecommitted stepcommitted step
2.2. isomerizationisomerizationphosphoglucosephosphoglucoseisomeraseisomerase
glc
1.1. ATP ((see L2sl9 “Phosphorylation of glc”see L2sl9 “Phosphorylation of glc”)) ADP
2
4. aldol cleavage4. aldol cleavagealdolasealdolase
C
C H
CH2
O
O
C
C
CH2
OH
OH
OH
OPO2-
3
PO2-
3 C
CH2
CH2
O
O
OH
PO2-
3
C
C
CH2
OH
OHH
OPO2-
3
+
fructose 1,6-bis phosphate(1,6FBP)
dihydroxyacetonephosphate(DHAP)
glyceraldehyde3-phosphate(GAP)
H
H
3
5. isomerization5. isomerizationtriose phosphatetriose phosphate isomerase isomerase
6. oxidation-driven6. oxidation-driven phosphorylation phosphorylation
GAP DHaseGAP DHase
7. phosphoryl transfer7. phosphoryl transferphosphoglycerate phosphoglycerate
kinase kinase3-phospho-glycerate(3PG)
PO2-
3
C
CH2
CH2
O
OH
OPO2-
3
C
C
CH2
OH
OHH
OPO2-
3
C
C
CH2
OO
OHH
OPO2-
3
C
C
CH2
OO
OHH
OPO2-
3
ADP
ATP + H+
NAD+ + Pi
NADH + H+
1,3-bis phospho-glycerate(1,3BPG)
GAP DHAP
–
4
8. 8. phosphoryl shiftphosphoryl shift phosphoglyceratephosphoglycerate mutase mutase
9. dehydration9. dehydration enolaseenolase
10. phosphoryl transfer10. phosphoryl transfer irreversibleirreversible pyruvate kinasepyruvate kinase
C
C
CH2
OO
OHH
OPO2-
3
C
C
CH2
OO
OH
OH
PO2-
3
C
C
CH2
OO
OPO2-
3
C
C
CH3
OO
O
ADP
ATP
H2O
2PG 3PG
phosphoenolpyruvate(PEP)
pyruvate(pyr)
–
–
–
–
5
Regeneration of NADRegeneration of NAD++: 1. electron shuttles: 1. electron shuttles stoichiometry of steps 1-10:stoichiometry of steps 1-10:
glc + 2 NADglc + 2 NAD++ →→ 2 pyruvate + 2 NADH + 4 H 2 pyruvate + 2 NADH + 4 H++
NAD present in cells in only catalytic amounts, so NAD present in cells in only catalytic amounts, so regeneration of NADregeneration of NAD++ is necessary is necessary
cytosolic NADH cannot enter mitochondriacytosolic NADH cannot enter mitochondria solutionsolution: : ee–– pair carried to mitochondrial pair carried to mitochondrial ee–– transport chain transport chain
via a shuttle (short linking pathway)via a shuttle (short linking pathway) net reaction:net reaction:
NADHNADHcytcyt + oxid + oxid ee– – carriercarriermitomito → NAD → NAD++cytcyt + red. + red. ee– – carriercarriermitomito
22 e e––cytcyt →→ 22 e e––mitomito malate-aspartate shuttlemalate-aspartate shuttle
• main shuttle in heart & liver cellsmain shuttle in heart & liver cells• ee–– pair eventually transferred to mitochondrial pair eventually transferred to mitochondrial
matrix NADmatrix NAD++, so ATP yield is 2.5/, so ATP yield is 2.5/ ee–– pairpair6
GOP-DHAP shuttleGOP-DHAP shuttle main shuttle in brain & skeletal musclemain shuttle in brain & skeletal muscle net reactionnet reaction
NADHNADHcytcyt + +
HH++ + + EE-FAD-FAD
↓↓
NADNAD++cytcyt + +EE-FADH-FADH22
yieldsyields1.5 ATP 1.5 ATP per eper e–– pair pair
Fig. 18.37
‚
7 e–s from complex II, others
Regeneration of NADRegeneration of NAD++: 2. reduction of pyruvate: 2. reduction of pyruvate conditions limiting electron shuttles:conditions limiting electron shuttles:
• mitochondria scarce (“fast” muscle) or absent (RBC)mitochondria scarce (“fast” muscle) or absent (RBC)• limited Olimited O22 supply (ischemia) supply (ischemia)• high demand for ATP causes glycolysis rate > shuttle ratehigh demand for ATP causes glycolysis rate > shuttle rate
ee–– pair is transferred to pyruvate: pair is transferred to pyruvate:
as a result, glycolysis can occur without net oxidation: as a result, glycolysis can occur without net oxidation: anaerobicallyanaerobicallyfermentationfermentation: any anaerobic process: any anaerobic process
NAD + H+ +H NAD+ +
pyruvate L-lactate
lactateDHase
C HOHCH3
CO O
COCH3
CO O
_ _
11. oxidation-11. oxidation- reduction reduction
8
Glycolysis stoichiometriesGlycolysis stoichiometriesAerobic glycolysis:Aerobic glycolysis: ATPATP
yield yieldsteps 1-10 steps 1-10 glc + 2 NADglc + 2 NAD++ →→ 2 pyruvate + 2 NADH + 4H 2 pyruvate + 2 NADH + 4H++ 2 2
Regen. of NADRegen. of NAD++: GOP shuttle + ox phos: GOP shuttle + ox phos2 H2 H++ + 2 NADH + O + 2 NADH + O22 →→ 2 NAD 2 NAD++ + 2 H + 2 H22OO 3 3**
glc + Oglc + O22 → 2 pyruvate + 2 H → 2 pyruvate + 2 H++ + 2 H + 2 H22O O 55
Anaerobic glycolysis:Anaerobic glycolysis:steps 1-10steps 1-10 glc + 2 NAD glc + 2 NAD++ →→ 2 pyruvate + 2 NADH + 4 H 2 pyruvate + 2 NADH + 4 H++ 2 2
step 11step 11 2 pyruvate +2 NADH + 2H 2 pyruvate +2 NADH + 2H++ →→ 2 lactate +2 NAD 2 lactate +2 NAD++
(steps 1-11)(steps 1-11) glc → 2 lactate + 2 H glc → 2 lactate + 2 H++ 22
** 5 if malate-aspartate shuttle used 5 if malate-aspartate shuttle used
9
Effect of glycolysis products (pyruvate/lactate):Effect of glycolysis products (pyruvate/lactate):acidificationacidification stoichiometry of both aerobic & anaerobic glycolysis stoichiometry of both aerobic & anaerobic glycolysis
shows production of 2 Hshows production of 2 H++// glcglc unlike phosphate-containing metabolites,unlike phosphate-containing metabolites,
lactate & pyruvate permeant to most cell membraneslactate & pyruvate permeant to most cell membranes(as protonated forms: lactic acid & pyruvic acid)(as protonated forms: lactic acid & pyruvic acid)• microorganismsmicroorganisms: :
their environment becomes acidictheir environment becomes acidic e.g.e.g., plaque bacteria on enamel surface ferment carbs, plaque bacteria on enamel surface ferment carbs
low pH increases solubility of Ca phosphate mineralslow pH increases solubility of Ca phosphate minerals repeated acid attacks produce carious lesionrepeated acid attacks produce carious lesion
• skeletal muscle during exerciseskeletal muscle during exercise::[lactate], [pyruvate] & [H[lactate], [pyruvate] & [H++] rise] rise10
Fate of pyruvate/lactateFate of pyruvate/lactatepyruvatepyruvate has a number of alternative fates has a number of alternative fates
•e.g.e.g., oxidized further in mitochondria (, oxidized further in mitochondria (next lecturenext lecture))•diffusion out of cell (efflux)diffusion out of cell (efflux)
lactatelactate has only 1 metabolic fate: oxidation back to pyruvate has only 1 metabolic fate: oxidation back to pyruvate•if oxidation limited, efflux occursif oxidation limited, efflux occurs
blood distributes theseblood distributes theseliver converts them liver converts them
back to glc by back to glc by gluconeogenesis gluconeogenesis ((next lecturenext lecture))
combination of muscle combination of muscle glycolysis & liver glycolysis & liver gluconeogenesis: gluconeogenesis:
Cori cycleCori cycle
11
LIVERLIVER MUSCLEMUSCLE
glucose glucose glucose glucose6 ATP 6 ATP 2 ATP 2 ATP outout
pyruvate pyruvate bloodblood pyruvatepyruvate lactate lactate lactate lactate
gluconeogenesisgluconeogenesis glycolysisglycolysis
Net effect is transfer of energy Net effect is transfer of energy from liver to musclefrom liver to muscle
The Cori cycle
stepstep enzymeenzyme inhibitorinhibitor activatoractivator
1 1 hexokinasehexokinase glc 6-Pglc 6-P 33 phosphofructokinase phosphofructokinase ATP, ATP, AMP,AMP,
citrate* citrate* ADPADP
mechanism of control:mechanism of control:
both kinases have allosteric sites to whichboth kinases have allosteric sites to whichactivators/inhibitors bind activators/inhibitors bind
Control of glycolysisControl of glycolysis
* provides coordination with Krebs (citric acid) cycle* provides coordination with Krebs (citric acid) cycle12
Next time:Next time:
4. 4. GluconeogenesisGluconeogenesis Pyruvate oxidationPyruvate oxidation