Transcript chapt05_lecture

Chapter 05
Lecture Outline
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I.
Glycolysis and the Lactic Acid
Pathway
A. Introduction
1. Metabolism
a. All of the reactions in the body that require
energy transfer. Can be divided into:
1) Anabolism: requires the input of energy to
synthesize large molecules
2) Catabolism: releases energy by breaking
down large molecules into small molecules
2. Catabolism Drives Anabolism
a. The catabolic reactions that break down glucose,
fatty acids, and amino acids serve as energy
sources for the anabolism of ATP.
b. Involves many oxidation-reduction reactions.
c. Complete catabolism of glucose requires oxygen
as the final electron acceptor.
1) Called aerobic cellular respiration.
2) Breaking down glucose requires many
enzymatically catalyzed steps, the first of
which are anaerobic.
3. Aerobic respiration of glucose
a. Occurs in three steps
1) Glycolysis – occurs in the cytoplasm;
anaerobic
2) Citric acid (Krebs) cycle – occurs in the matrix
of the mitochondria; aerobic
3) Electron transport – occurs on cristae of
mitochondria inner membrane; aerobic
b. C6H12O6 + O2  6 CO2 + 6 H2O + ATP
Overview of Energy Metabolism
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Glycogen
in liver
Glucose
from digestive tract
Glucose
from liver
Capillary
Glucose
in blood plasma
Interstitial fluid
Plasma membrane
Glucose
in cell cytoplasm
Glycolysis
Pyruvic acid
Anaerobic
Cytoplasm
Lactic
acid
Metabolism
in skeletal muscle
into mitochondrion
Citric acid
cycle
Electron
transport
Aerobic
CO2 + H2O
Respiration
Mitochondrion
B. Glycolysis
1. First step in catabolism of glucose
2. Occurs in the cytoplasm of the cell
3. Glucose is split into two pyruvic acid molecules
a. 6-carbon sugar  2 molecules of 3-carbon
pyruvic acid
b. C6H12O6  2 molecules C3H4O3
4. Note loss of 4 hydrogen ions. These were used
to reduce 2 molecules of NAD.
a. 2NAD + 4H+  2NADH + H+ (2NADH)
5. Net Energy Gain in Glycolysis
a. Glycolysis is exergonic, so some energy is
produced and used to drive the reaction
ADP + Pi  ATP
b. 4 ATP are generated.
c. Glucose requires activation at the beginning
provided by 2 Pi stripped from 2 ATP molecules.
d. This phosphorylates the glucose so that it can
not diffuse back through the plasma membrane
e. Net gain in glycolysis = 2 ATP
Use and Expenditure of
Energy in Glycolysis
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1
ATP
ADP
ATP
2 NADH
ADP
2 NAD
Free energy
Glucose
2
2 ATP
2 ADP + 2 Pi
3
2 ATP
2 ADP + 2 Pi
Pyruvic acid
6. Reactants and Products of Glycolysis
Glucose + 2 NAD + 2 ADP + 2 Pi 
2 pyruvic acid + 2 NADH + 2 ATP
Glycolysis Pathway
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Glucose (C6H12O6)
ATP
1
ADP
Glucose 6-phosphate
2
Fructose 6-phosphate
ATP
3
ADP
Fructose 1,6-biphosphate
4
3–Phosphoglyceraldehyde
Dihydroxyacetone
phosphate
3–Phosphoglyceraldehyde
Pi
Pi
NADH
5
NADH
2H
5
2H
NAD
NAD
1,3–Biphosphoglyceric acid
ATP
1,3–Biphosphoglyceric acid
ATP
6
ADP
6
ADP
3–Phosphoglyceric acid
3–Phosphoglyceric acid
7
2–Phosphoglyceric acid
7
2–Phosphoglyceric acid
8
Phosphoenolpyruvic acid
ATP
8
Phosphoenolpyruvic acid
ATP
9
ADP
9
ADP
Pyruvic acid (C3H4O3)
Pyruvic acid (C3H4O3)
C. Lactic Acid Pathway
1. When there is no oxygen to complete the
breakdown of glucose, NADH has to give its
electrons to pyruvic acid. This results in the
reformation of NAD and the conversion of
pyruvic acid to lactic acid.
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NADH + H+
H
H
O
C
C
N AD
O
C
H
OH
H
Pyruvic acid
LDH
H
OH
C
C
O
C
OH
H
H
Lactic acid
Lactic Acid Pathway, cont
2. Also called anaerobic metabolism or lactic acid
fermentation (Similar to how yeast ferments
glucose into alcohol)
3. Still yields a net gain of 2 ATP
a. Muscle cells can survive for awhile without
oxygen by using lactic acid fermentation.
b. RBCs can only use lactic acid fermentation
because they lack mitochondria.
II.
Aerobic Respiration
A. Introduction
1. Equation: C6H12O6 + O2  6 CO2 + 6 H2O
2. Similar to combustion except energy is released
in small, enzymatically controlled steps, not in
large amounts of heat
3. Begins with glycolysis, which produces:
a. 2 molecules pyruvic acid, 2 NADH, and 2 ATP
b. The pyruvic acid will be used in a metabolic pathway
called the citric acid cycle, and the NADH will be
oxidized to make ATP.
4. The fate of pyruvic acid
a. Pyruvic acid leaves the cytoplasm and enters the
interior matrix of the mitochondria.
b. Carbon dioxide is removed to form acetic acid.
c. Acetic acid is combined with coenzyme A to form
acetyl CoA.
d. 1 glucose  2 molecules acetyl CoA + 2 CO2
The Fate of Pyruvic Acid
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H
H
NAD
H
C
H
C
O
H
+
S
H
CoA
C
HO
NADH + H+
C
H
C
O
S
CoA
O
Pyruvic acid
Coenzyme A
Acetyl coenzyme A
+ CO2
B. Citric Acid Cycle
1. Also called the citric acid cycle or the TCA
(tricarboxylic acid) cycle
2. Acetyl CoA combines with oxaloacetic acid to
form citric acid.
3. Citric acid starts the citric acid cycle.
a. It is a cycle because citric acid moves through
a series of reactions to produce oxaloacetic
acid again.
4. Important Events in the Citric Acid Cycle
a. One guanosine triphosphate (GTP) is produced,
which donates a phosphate group to ADP to
form ATP.
b. Three molecules NAD are reduced to NADH.
c. One molecule FAD is reduced to FADH2.
d. These events occur for each acetic acid, so it
happens twice for each glucose molecule.
Simplified Diagram of the Citric Acid Cycle
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Glycolysis
C3
Pyruvic acid
CYTOPLASM
NAD
CO2
Mitochondrial matrix
CoA
NADH + H+
C2 Acetyl CoA
Oxaloacetic acid C
4
CO2
Citric acid
cycle
α-Ketoglutaric acid
C5
CO2
C6
Citric acid
3 NADH + H+
1 FADH2
1 ATP
The Complete Citric Acid Cycle
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H
H
O
C
C
COOH
HS – CoA
S
CoA
+ H2 O
H
COOH
Acetyl CoA (C2)
H
C
O
C
H
H2 O
H
C
H
HO
C
COOH
H
C
H
1
H2 O
COOH
2
H
COOH
Citric acid (C6)
COOH
C
H
C
COOH
C
H
COOH
Oxaloacetic acid (C4)
H2 O
COOH
3
cis-Aconitic acid (C6)
8
COOH
NADH
H
C
OH
H
C
H
H
C
H
H
C
COOH
H
C OH
+ H+
COOH
2H
Isocitric acid (C6)
NAD
COOH
NADH
+ H+
4
2H
Malic acid (C4)
NAD
7
H2 O
H
COOH
C
C
HOOC
FADH2
H
2H
Fumaric acid (C4)
CO2
FAD
6
ATP
COOH
H
C
H
H
C
H
COOH
ADP
NADH
GDP
NAD
COOH
C
H
C
H
C
O
+ H+
2H
GTP
H
CO2
H
COOH
α-Ketoglutaric acid (C5)
Succinic acid (C4)
5
H2 O
5. Products of the Citric Acid Cycle
For each glucose:
a. 6 NADH
b. 2 FADH2
c. 2 ATP
d. 4 CO2
C. Electron Transport & Oxidative
Phosphorylation
1. In the folds or cristae of the mitochondria are
molecules that serve as electron transporters.
a. Include FMN, coenzyme Q, and several
cytochromes
b. These accept electrons from NADH and
FADH2. The hydrogens are not transported
with the electrons.
c. Oxidized FAD and NAD are reused.
2. Electron Transport Chain
a. Electron transport molecules pass the electrons
down a chain, with each being reduced and then
oxidized.
b. This is an exergonic reaction, and the energy
produced is used to make ATP from ADP.
1) ADP is phosphorylated.
2) This process is called oxidative
phosphorylation.
c. Process is not 100%; difference is released as
heat
Electron Transport Chain
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NADH
FMN
NAD
FMNH2
2 H+
Electron energy
FADH2
FAD
2 e–
Oxidized
Fe2+
CoQ
Cytochrome b
Reduced
Fe3+
2 e–
Fe2+
Cytochrome
c1 and c
Cytochrome a
Fe3+
Fe2+
Fe3+
2 e–
Fe2+
H2O
Cytochrome a3
Fe3+
2 e–
2
H+
1
+ – O2
2
D. Coupling of electron transport to ATP
production
1. Chemiosmotic Theory
a. Electron transport fuels proton pumps, which pump
H+ from the mitochondrial matrix to the space
between the inner and outer membranes.
b. This sets up a huge concentration gradient between
the membranes.
c. H+ can only move through the inner membrane
through structures called respiratory assemblies
d. Movement of H+ across the membrane provides
energy to the enzyme ATP synthase, which converts
ADP to ATP.
Oxidative Phosphorylation
Figure 5.9 The steps of oxidative phosphorylation
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Outer mitochondrial
membrane
Inner mitochondrial
membrane
2
H+
Intermembrane
space
Third
pump
Second
pump
H+
H+
1
2 H+
ATP
synthase
H2O
First pump
4H+
e–
1
4 H+
3
2 H + 1 /2 O2
ADP
+
Pi
H+
ATP
NAD+
Matrix
NADH
2. The Function of Oxygen
a. Final electron acceptor. Without a final acceptor,
the whole process would come to a halt.
b. The citric acid cycle and electron transport
require oxygen to continue.
c. Water is formed in the following reaction:
O2 + 4 e- + 4 H+  2 H2O
E. ATP Balance Sheet
1. Direct (substrate-level) phosphorylation in
glycolysis and the citric acidcycle yields 4 ATP.
a. These numbers are constant.
2. Oxidative phosphorylation in electron transport
yields varying amounts of ATP, depending on
the cell and conditions.
a. Theoretically, each NADH yields 3 ATP and
each FADH2 yields 2 ATP.
b. Theoretical ATP yield is 36-38 per glucose.
3. Actual ATP yield
a. NADH yields 2.5 ATP and FADH2 yields 1.5 ATP
b. Energy is needed to move the ATP out of the
mitochondria into the cell cytoplasm
c. One glucose will actually yield 30-32 ATP
Detailed Accounting
III. Interconversion of Glucose, Lactic
Acid, and Glycogen
A. Glycogenesis and Glycogenolysis
1. Glycogenesis
a. Cells can’t store much glucose because it will pull
water into the cell via osmosis.
b. Glucose is stored as a larger molecule called
glycogen in the liver, skeletal muscles, and
cardiac muscles.
c. Glycogen is formed from glucose via
glycogenesis.
1) Glucose is phosphorylated, then isomerized
2) Glycogen synthase removes the phosphate
and joins glucose together
2. Glycogenolysis
a. When the cell needs glucose, it breaks glycogen
down again.
b. Produces glucose 1-phosphate (see Fig 5.10)
c. Glycogen phosphorylase is the catalyst
Glycogenolysis
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GLYCOGEN
Pi
Pi
1
2
Glucose 1-phosphate
Pi
Glucose
(blood)
ADP
ATP
Glucose 6-phosphate
Liver
only
Many
tissues
Fructose 6-phosphate
GLYCOLYSIS
Glucose
(blood)
d. Glycogenolysis in the Liver
1) Glucose from glycogen is in the form glucose 1phosphate, so cannot leave muscle or heart
cells.
2) The liver has an enzyme called glucose 6phosphatase that removes the phosphate so
glucose can reenter the bloodstream.
C. Cori Cycle
1. Some lactic acid can be used in cellular
respiration to produce carbon dioxide and water.
Skeletal muscles make too much, so it is
shipped to the liver.
2. The liver has the enzyme lactic acid
dehydrogenase, which converts lactic acid to
pyruvic acid and NADH.
The Cori Cycle, cont
3. The liver can convert pyruvic acid to glucose 6phosphate.
a. This can be used to make glycogen or
glucose in a reverse of glycolysis.
b. Pyruvic acid  Glucose = gluconeogenesis
(making “new” glucose from noncarbohydrate
molecules)
c. The glucose can return to the muscle cells,
which completes the Cori Cycle.
The Cori Cycle
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Skeletal muscles
Liver
Glycogen
Glycogen
Exercise
1
Rest
9
Blood
Glucose 6-phosphate
Glucose 6-phosphate
Glucose
8
7
6
2
Pyruvic acid
Pyruvic acid
5
3
Lactic acid
Blood
4
Lactic acid
Common Metabolic Process Terms
IV. Metabolism of Lipids and Proteins
A. Introduction
1. Lipids and proteins can also be used for energy
via the same pathways used for the metabolism
of pyruvic acid.
2. When more food energy is taken into the body
than is needed to meet energy demands, we
can’t store ATP for later. Instead, glucose is
converted into glycogen and fat, and ATP
production is inhibited
Conversion of glucose into
glycogen and fat
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Glycogen
Glucose 1-phosphate
Glucose
Glucose 6-phosphate
Fructose 6-phosphate
Fructose 1,6-biphosphate
Glycerol
Fat
3-Phosphoglyceraldehyde
Pyruvic acid
Fatty acids
Acetyl CoA
C6
C4
Oxaloacetic acid Citric acid
Citric acid
cycle
C5
-Ketoglutaric acid
B. Lipid Metabolism
1. As ATP levels rise after an energy-rich meal,
production of ATP is inhibited:
a. Glucose doesn’t complete glycolysis to form
pyruvic acid, and the acetyl CoA already
formed is joined together to produce a variety
of lipids, including cholesterol, ketone bodies,
and fatty acids.
b. Fatty acids combine with glycerol to form
triglycerides in the adipose tissue and liver =
lipogenesis.
Acetyl CoA  Lipids
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Bile acids
Steroids
Cholesterol
Ketone bodies
Acetyl CoA
Citric acid
(Krebs cycle)
Fatty acids
Triacylglycerol
(triglyceride)
Phospholipids
CO2
2. White Adipose Tissue (White Fat)
a. Fat stored in adipose tissue as triglycerides
b. Great way to store energy: 1 gram fat = 9 kcal energy.
1) In a nonobese 155-pound man, 80-85% of his stored
energy is in fat. (140,000 calories)
c. Lipolysis: breaking triglycerides down into fatty acids and
glycerol using the enzyme lipase.
1) Fatty acids can then enter the blood as blood-borne
energy carriers and be used for energy elsewhere.
2) Glycerol is taken up by the liver and converted to
glucose through gluconeogenesis
d. Fatty Acids as an Energy Source
1) β-oxidation: Enzymes remove acetic acid
molecules from fatty acids to form acetyl CoA.
a) For every 2 carbons on the fatty acid chain, 1
acetyl CoA can be formed.
b) A 16-carbon fatty acid  8 acetyl CoA
c) Each acetyl CoA  10 ATP + 1 NADH + 1
FADH2
d) A 16-carbon fatty acid  80 ATP + 28 in
electron transport = 108 ATP!!!
β-oxidation of Fat
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Fatty acid
β

H
H
C
C
H
H
O
C
OH
CoA
1
ATP
AMP + PPi
Fatty acid
H
H
O
C
C
C
H
H
CoA
FAD
2
FADH2
H
H
O
C
C
C
Fatty acid
1.5 ATP
CoA
H
H2O
3
CoA
HO
H
O
C
C
C
H
H
Fatty acid
Fatty acid now
two carbons shorter
CoA
NAD
4
NADH
O
H
O
C
C
C
Fatty acid
5
2.5 ATP
+ H+
CoA
Acetyl CoA
Citric
acid
cycle
10 ATP
3. Brown Adipose Tissue (Brown Fat)
a. Stored in different cells
b. Involved in thermogenesis (heat production),
especially in newborns
c. Adults also have some brown fat that contributes
to calories and heat production
d. Sympathetic release of norepinephrine causes
brown fat to form an uncoupling protein called
UCPI; H+ leaks out of inner mitochondrial
membrane, less ATP is formed, which leads to
use of fatty acids for more heat generation
4. Ketone Bodies
a. When the rate of lipolysis exceeds the rate of
fatty acid utilization (as in dieting, starvation, or
diabetes), the concentration of fatty acids in the
blood increases.
b. Liver cells convert the fatty acids into acetyl CoA
and then into ketone bodies.
c. These are water-soluble molecules that circulate
in the blood.
d. Build-up in the blood can cause ketosis
C. Amino Acid Metabolism
1. Proteins provide nitrogen for the body
2. Amino acids from dietary proteins are needed to
replace proteins in the body.
3. If more amino acids are consumed than are
needed, the excess amino acids can be used for
energy or converted into carbohydrates or fat.
4. Our bodies can make 12 of the 20 amino acids
from other molecules. Eight of them (9 in
children) must come from the diet and are called
essential amino acids.
Essential Amino Acids
5. Transamination
a. Pyruvic acid and several citric acid cycle
intermediates (called keto acids) can be
converted to amino acids by adding an amine
group (NH2).
1) Usually obtained from other amino acids
2) Called transamination
3) Requires vitamin B6 as a coenzyme
4) Each transamination requires a specific
enzyme
Transamination
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OH
O
HO
C
O
O
OH
C
O
OH
C
C
H
H
N
C
H
C
O
+
H
H
C
H
H
C
H
C
H
C
H
C
HO
+
H
C
H
H
C
H
C
H
H
C
H
C
HO
O
C
O
Glutamic acid
OH
N
H
O
C
HO
O
AST
HO
α-Ketoglutaric acid
Oxaloacetic acid
O
OH
C
O
O
O
OH
C
Aspartic acid
O
OH
C
C
H
H
N
C
H
H
C
O
C
H
+
H
C
H
H
C
H
H
H
ALT
C
O
H
C
H
H
C
H
C
HO
Glutamic acid
+
N
C
H
H
C
H
H
H
C
HO
O
Pyruvic acid
O
-Ketoglutaric acid
Alanine
6. Oxidative Deamination
a. If there are more amino acids than needed, the
amine group from glutamic acid can be stripped and
excreted as urea in the urine.
b. Oxidative deamination sometimes forms pyruvic
acid or another citric acid cycle intermediates.
1) These can be used to make energy or converted
to glucose or fat.
2) The formation of glucose from amino acids is
called gluconeogenesis and occurs in the Cori
cycle.
3) The main substrates are 3-carbon molecules –
alanine, lactic acid, and glycerol
Oxidative Deamination
Amino Acids as Energy
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Alanine, cysteine,
glycine, serine,
threonine, tryptophan
NH3
Pyruvic acid
Urea
Leucine,
tryptophan,
isoleucine
NH3
Acetyl CoA
Urea
Asparagine,
aspartate
Arginine, glutamate,
glutamine, histidine,
proline
Citric acid
Urea
NH3
Oxaloacetic acid
–Ketoglutaric acid
NH3
Citric acid cycle
Phenylalanine,
tyrosine
Urea
NH3
Isoleucine,
methionine,
valine
Fumaric acid
Succinic acid
NH3
Urea
Urea
D. Uses of different energy sources
1. Glucose and ketone bodies come from the liver
2. Fatty acids come from adipose tissue
3. Lactic acid and amino acids come from muscle
Different Energy Sources
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Glycogen
Glucose
Phosphoglyceraldehyde
Glycerol
Triacylglycerol
(triglyceride)
Lactic acid
Pyruvic acid
Acetyl CoA
Fatty acids
Amino acids
Protein
Urea
Ketone
bodies
C4
Citric
acid
cycle
C5
C6
Relative importance of different energy
sources to different organs