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Chapter 14 Glycolysis, gluconeogenesis, and the pentose phosphate pathway

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Title: Chapter 14 Glycolysis, gluconeogenesis, and the pentose phosphate pathway


1
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  • Chapter 14 Glycolysis, gluconeogenesis, and the
    pentose phosphate pathway
  • Chapter 15 Principles of metabolic regulation
    Glucose and glycogen
  • Chapter 16 The citric acid cycle
  • Chapter 19 Oxidative phosphorylation

2
To remind you..
  • Class schedule
  • Exam

3
GlycolysisGluconeogenesisPentose phosphate
pathway
  • Chapter 14

4
Metabolism Catabolism Anabolism
  • Catabolic pathways converge to a few end products
  • Anabolic pathways diverge to synthesize many
    biomolecules
  • Some pathways serve both in catabolism and
    anabolism, such pathways are amphibolic

5
Outline
  • 14.1 Glycolysis
  • First Phase of Glycolysis (preparatory phase)
  • Second Phase of Glycolysis (lysis phase)
  • 14.2 Feeder pathways for glycolysis
  • 14.3 Fates of pyruvate under anaerobic
    conditions Fermentation
  • 14.4 Glucogenesis
  • 14.5 Pentose phosphate pathway of glucose
    oxidation

6
14.1 Glycolysis
Why glucose? 1. Complete oxidation yields 2,840
KJ/mol 2. low cytosolic osmolarity 3. capable of
supplying a huge array of metabolic intermediates
for biosynthetic reactions
7
Glycolysis ?? The Embden-Meyerhof (Warburg)
Pathway
1. Consume 2 ATP in 1st phase, produce 4 ATP in
2nd phase net gain 4 - 2 2 ATP 2.
Glucose(6C) ? 23C (pyrurate) 3. Pyruvate is
used in 3 ways
8
Alcohol fermentation
Lactate fermentation
O2
9
Hexokinase
Phosphohexose isomerase
Phospho- Fructosekinase-1
Aldolase
Triose phosphate isomerase
10
Glyceraldehyde 3-phosphate Dehydrogenase Phospho
- Glycerate Kinase Phospho- Glycerate Mutase Eno
lase Pyruvate kinase
11
Glycolytic enzyme ?? (1)
Kinase??ATP??or ?????enzyme (2) Mutase(
??)?Transfer functional group from one position
to another in the same molecule, ?P?C3???C2??
(3) Isomerase??Aldose
Ketose (4) Aldolase??????-Aldose???ketose?? (5)
Enolase???enol form ??
-CC-
alcohol
?Mutase is a subclass of isomerase
12
First Phase of Glycolysis
  • The first reaction - phosphorylation of glucose
  • Hexokinase or glucokinase
  • This is a priming reaction - ATP is consumed here
    in order to get more later
  • ATP makes the phosphorylation of glucose
    spontaneous

13
Reaction 1 Phosphorylation of glucose
spontaneous and irreversible
14
Hexokinase is allosterically inhibited by its
reaction product
  • Hexokinase
  • Km 0.1 mM
  • So hexokinase is normally active!
  • Inhibited by G6P reversibly
  • Glucose, mannose.
  • Glucokinase
  • Km 10 mM
  • only turns on when cell is rich in glucose
  • Not inhibited by G6P
  • Exist in liver
  • Specific for glucose

15
Reaction 2 Phosphohexose isomerase
(phosphoglucose isomerase) Reaction 3
Phosphofructose kinase (PFK-1)---- 2nd priming
step
Irreversible
16
Reaction 4 Fructose 1,6-bisphosphate Aldolase
In erythrocyte 0.23kJ/mol
17
Reaction 5 DHAP?Glyceraldehyde 3-P by
triose-phosphate isomerase
18
Glycolysis - Second Phase
  • Metabolic energy produces 4 ATP
  • Net ATP yield for glycolysis is two ATP
  • Second phase involves two very high energy
    phosphate intermediates
  • .
  • 1,3 BPG
  • Phosphoenolpyruvate

19
Reaction 6 Glyceraldehyde-3-phosphate
dehydrogenase
1.Addition of a phosphate group to G3P 2.e-
transfer from G3P to NAD (hydride H-) 3.No ATP
or ADP is involved
20
Reaction 7 Phosphoryl transfer from 1,3
bisphosphoglycerate to ADP
Pay off
21
Substrate-level phosphorylation
  • The formation of ATP by phosphoryl transfer from
    a substrate such as 1,3 BPG is referred as a
    substrate-level phosphorylation. It involves
    soluble proteins and chemical intermediates.

Respiration-linked (oxidative) phosphorylation (??
???) involves membrane-bound enzymes and
transmembrane gradients of protons.
22
Reaction 8 Conversion of 3-phosphoglycerate to 2
phosphoglycerate Reaction 9 Dehydration of 3-
to 2- phosphoenolpyruvate by enolase(????)
???
23
Reaction 10 Transfer of the phosphoryl group
from phosphoenolpyruvate to ADP
This is referred to as "substrate-level
phosphorylation
Payoff
24
SUMMARY 14.1 Glycolysis
  • Glycolysis is a near-universal pathway by which a
    glucose molecule is oxidized to two molecules of
    pyruvate, with energy conserved as ATP and NADH.
  • 2. All ten glycolytic enzymes are in the cytosol,
    and all ten intermediates are phosphorylated
    compounds of three or six carbons.

25
SUMMARY 14.1 Glycolysis
  • 3. In the preparatory phase of glycolysis, ATP is
    invested to convert glucose to fructose
    1,6-bisphosphate. The bond between C-3 and C-4 is
    then broken to yield two molecules of triose
    phosphate.

26
SUMMARY 14.1 Glycolysis
  • 4. In the payoff phase, each of the two molecules
    of glyceraldehyde 3-phosphate derived from
    glucose undergoes oxidation at C-1 the energy of
    this oxidation reaction is conserved in the
    formation of one NADH and two ATP per triose
    phosphate oxidized. The net equation for the
    overall process is

Glucose2NAD2ADP2Pi ? 2pyruvate2NADH2H
2ATP2H2O
27
SUMMARY 14.1 Glycolysis
  • 5. Glycolysis is tightly regulated in
    coordination with other energy-yielding pathways
    to assure a steady supply of ATP. Hexokinase,
    PFK-1, and pyruvate kinase are all subject to
    allosteric regulation that controls the flow of
    carbon through the pathway and maintains constant
    levels of metabolic intermediates.

28
14.2 Feeder pathways for glycolysis
Glycogen and starch Maltose, lactose, trehalose,
sucrose Fructose, mannose, galactose
29
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30
Fig. 14-11Conversion of galactose to glucose
1-phosphate
31
Galactosemia
Mutation Symptoms
Galactokinase- deficient (high galactose conc. is found in the blood and urine) Cataracts cause by deposition of galactose metabolite galactitol in the lens
Transferase-deficient Poor growth of children, speech abnormality, mental deficiency, and liver damage even when galactose is withheld from the diet (more severe!)
Epimerase-deficient Same as above but is less severe when dietary galactose is carefully controlled.
32
Catabolism of glycogen
  • Cellular glycogen
  • Dietary glycogen

33
Catabolism of cellular glycogen
Glycogen phosphorylase catalyzes an attack by Pi
on the (a1?4) glycosidic linkage that joins the
last two glucose residues at a nonreducing end,
generating glucose 1-phosphate and a polymer one
glucose unit shorter.
14-10
34
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35
  • Glucose 1-phosphate produced by glycogen
    phosphorylase is converted to glucose 6-phosphate
    by phosphoglucomutase, which catalyzes the
    reversible reaction

Glycolysis Pentose phosphate pathway
36
Dietary polysaccharides and disaccharides are
hydrolyzed to monosaccharides by various enzymes
a-amylase Salivary---digest to short
polysaccharide fragment or oligosaccharides Pa
ncrease---digest to disaccharides (maltose),
trisaccharides (maltotrioses) and dextrins
37
Intestine secrects enzymes to digest dextrin and
disaccharides
38
Catabolism of dietary and cellular glycogen
Cellular Dietary (saliva) Dietary (pancrease)
Enzyme Glycogen phosphorylase and debranching enzyme a-amylases a-amylases
End product glucose-1-P Short polysaccharides fragment or oligosaccharides Di-saccharides and dextrins
39
Lactose intolerance?????
Lack lactase Diarrhea and discomfort
Undigested lactose and its metabolites increase
the osmolarity of the intestinal contents,
favoring the retention of water in the intestine.
40
Anaerobic Metabolism and tooth decay
(??)
Sucrose ?Plaque (polysaccharide) Products of
anaerobic glycolysis carried out by bacteria
?lactate and pyruvate ?tooth decay
41
SUMMARY 14.2 Feeder Pathways for Glycolysis
  • 1. Glycogen and starch, polymeric storage forms
    of glucose, enter glycolysis in a two-step
    process. Phosphorolytic cleavage of a glucose
    residue from an end of the polymer, forming
    glucose-1 phosphate, is catalyzed by glycogen
    phosphorylase or starch phosphorylase.
    Phosphoglucomutase then converts the glucose
    1-phosphate to glucose 6-phosphate, which can
    enter glycolysis.

42
SUMMARY 14.2 Feeder Pathways for Glycolysis
  • 2. Ingested polysaccharides and disaccharides are
    converted to monosaccharides by intestinal
    hydrolytic enzymes, and the monosaccharides then
    enter intestinal cells and are transported to the
    liver or other tissues.

43
SUMMARY 14.2 Feeder Pathways for Glycolysis
  • 3. A variety of D-hexoses, including fructose,
    galactose, and mannose, can be funneled into
    glycolysis. Each is phosphorylated and converted
    to either glucose 6-phosphate or fructose
    6-phosphate.

44
SUMMARY 14.2 Feeder Pathways for Glycolysis
  • 4. Conversion of galactose 1-phosphate to glucose
    1-phosphate involves two nucleotide derivatives
    UDP-galactose and UDP-glucose. Genetic defects in
    any of the three enzymes that catalyze conversion
    of galactose to glucose 1-phosphate result in
    galactosemias of varying severity.

45
14.3 Fates of Pyruvate under Anaerobic
Conditions Fermentation
O2
46
Anaerobic pathways
??
yeast
muscle
Fetal Alcohol syndrome
47
Thiamine Pyrophosphate Carries Active
Acetaldehyde Groups
  • Thiamine pyrophosphate (TPP), a coenzyme derived
    from vitamin B1.
  • Lack of vitamin B1 in the human diet leads to the
    condition known as beriberi.
  • Thiamine pyrophosphate plays an important role in
    the cleavage of bonds adjacent to a carbonyl
    group, such as the decarboxylation of -keto
    acids, and in chemical rearrangements in which an
    activated acetaldehyde group is transferred from
    one carbon atom to another

48
Thiamine Pyrophosphate Carries Active
Acetaldehyde Groups
49
Replenishment of NAD
1. under anaerobic condition Lactic acid
fermentation 2. under anaerobic condition
Alcoholic fermentation 3. under aerobic
condition Mitochondria oxidation of each
NADH to yield 2.5 (1.5) ATP
50
Oxygen debt
Cori cycle
51
SUMMARY 14.3 Fates of Pyruvate under anaerobic
conditions Fermentation
  • 1. The NADH formed in glycolysis must be recycled
    to regenerate NAD, which is required as an
    electron acceptor in the first step of the payoff
    phase. Under aerobic conditions, electrons pass
    from NADH to O2 in mitochondrial respiration.

52
SUMMARY 14.3 Fates of Pyruvate under anaerobic
conditions Fermentation
  • 2. Under anaerobic or hypoxic conditions, many
    organisms regenerate NAD by transferring
    electrons from NADH to pyruvate, forming lactate.
    Other organisms, such as yeast, regenerate NAD by
    reducing pyruvate to ethanol and CO2.

53
Regulation of carbohydrate catabolism
Cellular energy level and intermediate
concentration Glycogen phosphorylase,
hexokinase, phosphofructokinase, pyruvate kinase
1. At branching point 2. Large and negative free
energy
54
Regulation of PFK-1
FIGURE 1518 Phosphofructokinase-1 (PFK-1) and
its regulation.
55
??ATP?PFK-1 ?????inhibitor?
?ATP?,?ADP??Low energy charge?glycolysis ?ATP
?,?ADP??High energy charge?glycolysis

-
ATP??,ADP??allosteric site ?activator,
ATP??active site? substrate ATP??,ATP??alloster
ic site ? inhibitor
FIGURE 626 Subunit interactions in an allosteric
enzyme, and interactions with inhibitors and
activators.
56
14.4 gluconeogenesis
  • Synthesis of "new glucose" from common
    metabolites
  • Humans consume 160 g of glucose per day
  • 75 of that is in the brain
  • Body fluids contain only 20 g of glucose
  • Glycogen stores yield 180-200 g of glucose
  • So the body must be able to make its own glucose

57
Fig. 6-29
58
  • Substrates pyruvate, lactate, glycerol, amino
    acids (except Lys and Leu)
  • Active in liver and kidney supply glucose to
    brain and muscle
  • Seven of ten glycolytic steps in reverse
  • Three steps not reversal of glycolysis for two
    reasons
  • energetics
  • regulation

59
  • Occurs mainly in liver and kidneys
  • Not the mere reversal of glycolysis for 2
    reasons
  • Energetics must change to make gluconeogenesis
    favorable (delta G of glycolysis -74 kJ/mol
  • Reciprocal regulation must turn one on and the
    other off - this requires something new!

60
  • Something Borrowed, Something New
  • Seven steps of glycolysis are retained
  • Steps 2 and 4-9
  • Three steps are replaced
  • Steps 1, 3, and 10 (the regulated steps!)
  • The new reactions provide for a spontaneous
    pathway (?G negative in the direction of sugar
    synthesis), and they provide new mechanisms of
    regulation

61
Glycolysis
Gluconeogenesis
62
Three unique gluconeogenesis steps First bypass
  • Pyruvate to PEP
  • Pyruvate carboxylase converts pyruvate to
    oxaloacetate
  • Biotin-dependent enzyme
  • ATP bicarbonate to carbonylphosphate
    intermediate to carboxybiotin intermediate
  • Allosteric activation by acetyl CoA
  • Localized in mitochondria
  • Oxaloacetate to malate and back (if PEP
    carboxykinase is localized in cytosol)
  • PEP carboxykinase converts oxaloacetate to PEP
  • Decarboxylation drives reactions
  • GTP or ATP supplies Pi and drives reaction
  • Localized in mitochondria or in cytosol

63
Synthesis of PEP from pyruvate
Overall reaction Pyruvate ATP GTP HCO3-
? phosphenolpyruvate ADP GDP Pi CO2
64
PEP carboxykinase- Rabbit liver
mitochondria Rat liver cytosolic Human liver
both
65
Three unique gluconeogenesis steps Second bypass
  • Fructose-1,6 bisphosphate to fructose 6 phosphate
  • Hydrolysis
  • Fructose-1,6-bisphosphatase
  • Acetyl CoA or citrate stimulates
  • fructose-2,6-bisphosphate inhibits
  • AMP inhibits

66
Three unique gluconeogenesis steps Third bypass
  • Glucose-6-phosphate to glucose
  • Hydrolysis
  • Glucose-6-phosphatase
  • Release product into ER lumen
  • Enzyme expressed in liver and kidney (not in
    muscle or brain)
  • High Km for G6P substrate-level control

67
  • FIGURE 156 Hydrolysis of glucose 6-phosphate by
    glucose 6-phosphatase of the ER. The catalytic
    site of glucose 6-phosphatase faces the lumen of
    the ER. A glucose 6-phosphate (G6P) transporter
    (T1) carries the substrate from the cytosol to
    the lumen, and the products glucose and Pi pass
    to the cytosol on specific transporters (T2 and
    T3). Glucose leaves the cell via the GLUT2
    transporter in the plasma membrane.

68
Pentose phosphate pathway of glucose oxidation
69
14.5 Pentose Phosphate Pathway
  • aka phosphogluconate pathway, hexose
    monophosphate shunt
  • Provides NADPH for biosynthesis
  • Produces ribose-5-P
  • Two oxidative processes followed by five
    non-oxidative steps
  • Operates mostly in cytoplasm of liver and adipose
    cells
  • NADPH is used in cytosol for fatty acid synthesis

70
Oxidative Steps
  • of the Pentose Phosphate Pathway
  • Glucose-6-P Dehydrogenase
  • Irreversible 1st step - highly regulated!
  • Gluconolactonase
  • Uncatalyzed reaction happens too
  • 6-Phosphogluconate Dehydrogenase
  • An oxidative decarboxylation (in that order!)
  • Phosphopentose isomerase
  • converts ketose to aldose

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72
The Nonoxidative Steps
  • Phosphopentose Epimerase
  • epimerizes at C-3
  • Transketolase (TPP-dependent)
  • transfer of two-carbon units
  • Transaldolase (Schiff base mechanism)
  • transfers a three-carbon unit

73
???
74
04172005
75
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76
Clinical aspects of PPP --???
  • G6P dehydrogenase deficiency
  • G-S-S-G NADPH H ? 2G-SH NADP (by
    glutathione reductase)
  • 2G-SH H2O2 ? G-S-S-G 2H2O (by gluthathione
    peroxidase)
  • increase rate of oxidation of hemoglobin
  • Susceptible to oxidants (antimalarial primaquine,
    aspirin, or sulfonamides), or fava beans

77
SUMMARY 14.5 Pentose Phosphate Pathway
ofGlucose Oxidation
  • 1. NADPH provides reducing power for biosynthetic
    reactions, and ribose 5-phosphate is a precursor
    for nucleotide and nucleic acid synthesis.
    Rapidly growing tissues and tissues carrying out
    active biosynthesis of fatty acids, cholesterol,
    or steroid hormones send more glucose 6-phosphate
    through the pentose phosphate pathway than do
    tissues with less demand

78
SUMMARY 14.5 Pentose Phosphate Pathway
ofGlucose Oxidation
  • 2. The first phase of the pentose phosphate
    pathway consists of two oxidations that convert
    glucose 6-phosphate to ribulose 5-phosphate and
    reduce NADP to NADPH. The second phase comprises
    nonoxidative steps that convert pentose
    phosphates to glucose 6-phosphate, which begins
    the cycle again.

79
SUMMARY 14.5 Pentose Phosphate Pathway
ofGlucose Oxidation
  • 3. Entry of glucose 6-phosphate either into
    glycolysis or into the pentose phosphate pathway
    is largely determined by the relative
    concentrations of NADP and NADPH.
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