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Chapter 8: Outline1

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Glycogenesis, Glycogenolysis, Regulation of Glycogen Metabolism. Introduction ... Glycogenesis-5. Branching is accomplished by a branching enzyme. ... – PowerPoint PPT presentation

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Title: Chapter 8: Outline1


1
Chapter 8 Outline-1
  • Glycolysis
  • Reactions of the Glycolytic Pathway, Fate of
    Pyruvate
  • Energetics of Glycolysis, Regulation of
    Glycolysis
  • Gluconeogenesis
  • Reactions Substrates Regulation
  • Pentose Phosphate Pathway
  • Metabolism of Other Important Sugars
  • Fructose Galactose Manose
  • Glycogen Metabolism
  • Glycogenesis, Glycogenolysis, Regulation of
    Glycogen Metabolism

2
Introduction
  • Major pathways of carbohydrate metabolism.

Fig 8.1 3rd ed
3
8.1 Glycolysis
  • The anerobic oxidation of glucose (G) to give two
    molecules of pyruvate.
  • G 2 ADP 2 Pi 2 NAD ?2 pyruvate
  • 2 ATP 2 NADH 2 H 2 H2O

4
Glycolysis-overview
  • Glucose
  • Glucose-6-phosphate
  • Fructose-6-phosphate
  • Fructose-1,6-bisphosphate
  • Dihydroxyacetone phosphate
  • Glyceraldehyde 3-phosphate
  • Glycerate-1,3-Bisphosphate
  • Glycerate-3-Phosphate
  • Glycerate-2-Phosphate
  • Phosphoenolpyruvate
  • Pyruvate

5
Glycolysis Step 1
hexokinase, Mg2
glucose
ADP
ATP
glucose-6-phosphate
6
Glycolysis Step 2
glucose-6-phosphate
fructose-6-phosphate
7
Glycolysis Step 3
fructose-6-phosphate
phosphofructokinase-1 (PFK-1), Mg2
ATP
ADP
fructose-1,6-bisphosphate
8
Regulation by PFK-1
9
Glycolysis Step 3-b
  • The committed step! (irreversible)
  • PFK-1 is a tetrameric enzyme
  • as M4 in muscle and L4 in liver
  • allosteric effectors
  • high ATP conc. depresses rate
  • fructose-2,6-bisP activates (well see later)

10
Glycolysis Step 4
dihydroxyacetone phosphate
fructose-1,6-bisphosphate
aldolase
D-glyceraldehyde 3-phosphate
11
Glycolysis Step 4b
12
Glycolysis Step 5
13
Glycolysis Step 6
Glycerate-1,3-bisphosphate
glyceraldehyde 3-phosphate dehydrogenase
NAD HPO42-
NADH H
14
Glycolysis Step 6b
  • A phosphorylation and a two electron oxidation by
    NAD occur.
  • G-3-P NAD H2O ?
  • 3-P-glycerate - 43.1 kJ
  • 3-P-glycerate HPO42- H ?
  • glycerate-1,3-bisP 49.3 kJ

15
Step 6c1
16
Step 6c2
17
Glycolysis Step 7
phospho- glycerate kinase Mg2
ADP
ATP
Glycerate-3-phosphate
18
Glycolysis Step 8
Phosphoglycerate mutase Mg2
Glycerate-2-phosphate
19
Glycolysis Step 9
enolase Mg2
H2O
Phosphoenolpyruvate (PEP)
20
Glycolysis Step 10
pyruvate kinase Mg2
H ADP
ATP
pyruvate
21
Pyruvate Fermentation
lactate dehydrogenase
NADH H
NAD
lactate
22
Pyruvate Fermentation-2
  • This reaction produces NAD which is needed for
    further anerobic glycolysis.
  • Glyceraldehyde 3-phosphate
  • --gt glycerate-1,3-bisphosphate

23
Pyruvate Fermentation-3
pyruvate decarboxylase
TPP, Mg2
NADH H
ethanol NAD
24
Glycolysis ATP
  • Use ATP
  • glucose to glucose-6-P
  • fructose-6-P to fructose 1,6-bisP
  • Produce ATP
  • glycerate-1,3-bisP to
  • 3-P-glycerate
  • PEP to pyruvate

25
Energetics of Glycolysis
  • Evaluation of free energy changes measured in
    blood cells shows steps 1,3, and 10 have
    significantly negative DG values and are
    irreversible.
  • The rest of the steps are close to equilibrium
    and the direction of reaction can be shifted by
    changes in substrate concentrations.

26
Glycolysis Free Energy

  • kJ/mol
  • Glu 2 ADP 2 Pi NAD ?
  • 2 pyruvate 2 ATP NADH -73.3 H
  • 2 (pyruvate NADH H ?
  • lactate NAD ) -50.2
  • Net -123.5

27
Energy Efficiency
  • 2 mol ATP 61 kJ
  • Glucose to 2 lactate 184.5 kJ
  • (no ATP production)
  • Efficiency
  • 61/184.5 x 100 33

28
Regulation of Glycolysis
  • Regulation is controlled primarily by three
    allosteric enzymes hexokinase. PFK-1, and
    pyruvate kinase.

29
8.2 Gluconeogenesis
  • Synthesis of glucose from noncarbohydrate
    precursors is gluconeogenesis.
  • The three irreversible steps of glycolysis are
    bypassed.
  • Pyruvate from a variety of sources is converted
    to glucose.

30
Gluconeogenesis-overview
  • Pyruvate
  • Oxaloacetate
  • Phosphoenolpyruvate
  • Glycerate-2-Phosphate
  • Glycerate-3-Phosphate
  • Glycerate-1,3-bisphosphate
  • Triose phosphates
  • (Dihydroxyacetone phosphate)
  • (Glyceraldehyde 3-phosphate)
  • Fructose-1,6-bisphosphate
  • Fructose-6-phosphate
  • Glucose-6-phosphate
  • Glucose

31
Pyruvate to Oxaloacetate
Acetyl-CoA Biotin, Mg2
pyruvate carboxylase
ATP CO2 H2O
ADP Pi H
32
Pyruvate to Oxaloacetate 2
Biotin, which is attached to a lysine residue on
the enzyme, carries carbon dioxide.
Biotin-a one carbon carrier
33
Oxaloacetate to PEP
GTP
34
F-1,6-bP ? F-6-P
fructose-1,6-bisphosphate
fructose-1,6-bisphosphatase
fructose-6-phosphate
35
G-6-P ? Glucose
glucose-6-phosphatase
36
Gluconeogenesis Substrates
  • In the Cori cycle, lactate from skeletal muscle
    is transferred to the liver where it is converted
    to pyruvate then glucose.
  • Glycerol (fats) enters gluconeogenesis in the
    liver via glycerol-3-P then DHAP.
  • In the alanine cycle, pyruvate in muscles is
    converted to alanine which is transported to the
    liver and reconverted to pyruvate. This cycle
    also transports NH4 to the liver!!

37
Substrate Cycling
  • Substrate cycling refers to the situation where
    opposing reactions are catalyzed by different
    reactions. The Cori cycle is a good example.
  • The opposing reactions
  • Glucose?lactate??pyruvate?glucose are separated
    and occur in the muscle or liver and are
    controlled by different enzymes.

38
Substrate Cycling 2
  • Glycolysis
  • Glu 2NAD 2ADP 2Pi?
  • 2Pyv 2NADH 4H 2ATP 2H2O
  • Gluconeogenesis
  • 2Pyv 2NADH 4H 4ATP 2GTP 6H2O ?
  • Glu 2NAD 4ADP 2GDP 4Pi
  • Net
  • 2ATP 2GTP 4H2O ? 2ADP 2GDP 4Pi

39
Substrate Cycling 3
  • Hydrolysis of 2 ATP and 2 GTP is the energy
    price for the Cori cycle or the simultaneous
    control of the two opposing pathways, glycolysis
    and gluconeogenesis.

40
Regulation gluconeogenesis
  • The rate for the process is controlled by
    substrate availability, allosteric effectors, and
    hormones.
  • Insulin leads to synthesis of glucokinase, PFK-1,
    and PFK-2.
  • Glucagon leads to synthesis of PEP carboxykinase,
    fructose-1,6-bisphosphatase, and
    glucose-6-phosphatase.
  • The insulin/glucagon ratio exerts the major
    regulatory effects on carbohydrate metabolism.
  • Also, control at pyruvate kinase permits maximal
    retention of PEP.

41
Regulation gluconeogenesis-3
F-2,6-P activates
F-2,6-P deactivates
42
Regulation 4
  • Both enzyme activities are on the same dimeric
    enzyme at different sites.

43
8.3 Pentose Phosphate Pathway
  • Five carbon sugars are produced.
  • NADPH is produced for biosynthesis.
  • Reshuffling of carbons occurs to give products
    with three, four, six, and seven carbons.

44
Oxidation-1, PP Path
6-phospho-D-glucono-d-lactone
45
Oxidation-2, PP PAth
46
Oxidation-3, PP Path
47
PP Path-2
48
PP Shunt-3
49
PP Path -4
50
PP Path -5
51
Control, PP Path
  • Glycolysis PP Pathway
  • Glucose-6-phosphate ribulose-5-phosphate
  • 2 NADP CO2 2 NADPH
  • fructose-6-phosphate ribose-5-phosphate
  • fruct-1,6-bisP
  • glyceraldehyde-3-phosphate
  • dihydroxyacetone phosphate

52
Control, PP Path-2
  • If NADPH is needed, oxidative steps must occur.
  • If ribose is needed, fructose and glyceraldehyde
    phosphates react via the PP Pathway to make
    ribose.
  • Overall Oxidation
  • 6 G-6-P 12 NADP 6 H2O ?
  • 6 R-5-P 6 CO2 12 NADPH 12 H

53
Hemolytic Anemia
  • The PP Pathway supplies NADPH in red blood cells.
  • Glucose-6-phosphate deficiency leads to less
    NADPH, less reduced glutathione (a peptide needed
    to maintain sulfhydryl groups and to keep iron as
    iron(II) in hemoglobin) thus anemia develops.
  • Over 100 million people have the deficiency which
    conveys some resistance to malaria.

54
Hemolytic Anemia-2
Glutathione
Reduced form provides H to reduce protein
disulfide links.
55
8.4 Metabolism of Other Sugars
  • In the liver, fructose is converted to
    fructose-1-phosphate and then split into DHAP and
    glyceraldehyde.
  • Glyceraldehyde is then converted to
    glyceraldehyde-3-phosphate by glyceraldehyde
    kinase.
  • In muscle and fat tissue fructose is converted to
    F-6-P.

56
Other Sugars-2
  • In fetus and childhood

57
Other Sugars-3
  • Galactosemia is the result of a lack of
    galactose-1-pyrophosphate uridyltransferase.
  • Beginning in adolescence, UDP-galactose is
    produced in a reaction cartalyzed by
    UDP-galactose pyrophorylase.
  • UDP-galactose is isomerized to UDP-glucose.
  • Other Sugars-4
  • Mannose is phosphorylated to M-6-P and then
    isomerized to F-6-P.

58
8.5 Glycogen Metabolism
  • Glycogen metabolism is carefully regulated so
    that sufficient glucose is available for the
    bodys energy needs.
  • Insulin, glucagon, and epinephrine control
    glycogenesis and glycogenolysis.

59
Glycogenesis-1
  • Chain priming begins with attachment of the C-1
    OH of a glucose molecule to a specific tyrosine
    residue on the enzyme glycogenin.
  • Two glucose molecules cannot spontaneously link
    to start the glycogen polymer.
  • Chain elongation requires an activated glucose
    molecule, UDP-glucose

60
Glycogenesis-2
hexokinase
ATP, Mg2
  • Final product via 1,6-bisphosphate

61
Glycogenesis-3
UDP glucose- phosphorylase
  • Pyrophosphate hydrolyzes

UDPG
62
Glycogenesis-4
  • Glycogen synthase

63
Glycogenesis-5
  • Branching is accomplished by a branching enzyme.
    This enzyme removes about seven glucose units
    from a chain at least 11 units long and transfers
    them to make an a-1,6 branch at least four units
    away from the nearest existing branch.

64
Glycogen Breakdown
  • Glycogen phosphorylase removes glucose units
    until four are left approaching a branch point.
    The glucose is produced as glucose-1-P.
  • G-1-P isomerizes to G-6-P.
  • Note this saves one ATP molecule when glucose
    from glycogen goes through glycolysis! A net of
    three ATP are produced.
  • When the four glucose units next to a branch
    remain, another enzyme is needed.
  • When four glucose units remain, a second enzyme
    (debranching enzyme) goes into action.
  • Debranching enzyme removes three (limit branch)
    of the four units and transfers them to the end
    of another chain.
  • The glucose 1,6 bond is cleaved and glucose is
    the product, not the phosphorylated glucose.

65
Regulation
  • Glycogen metabolism is regulated primarily by
    three hormones insulin, glucagon, and
    epinephrine. The process depends on second
    messengers and a cascade reaction which will
    be discussed later.
  • Covalent modification of enzymes (primarily
    phosphorylation) is central to control of
    glycogen metabolism and is overall an important
    means of enzyme regulation.

66
Regulation-2
Cont. next slide
cAMP
67
Regulation-2b
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