Transcript Introduction to Physiology: The Cell and General Physiology

Adenosine triphosphate (ATP) - the central link between
energy-producing and energy-using systems of the body
Figure 67-1; Guyton & Hall
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ATP Structure
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Phosphate Terminology
• Kinase
– adds a phosphate
• phosphatase
– removes a phosphate
• phosphorylase
– splits a compound by adding a phosphate
(analagous to hydrolysis, but uses phosphate
instead of water)
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Glucose Transport Into Most Cells
• Down a concentration gradient by
facilitated diffusion,
– i.e. a carrier is required but energy is not
• There are many different carriers. The
most important and commonly studied are
– GLUT-1, does not require insulin
• note that most post-absorptive glucose uptake by
cells does not require insulin
– GLUT-4, insulin dependent
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Glycolysis
2 ATP
Glucose
Dihydroxyacetone
Phosphate (DHAP)
Fructose 1,6diphosphate
(PP)
4 ADP
Glyceraldehyde
3-phosphate (GA 3-P)
2 NAD+
2
Pyruvic Acid
Net Output:
2 pyruvate
2 NADH + H (4
H’s)
2 ATP
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4 ATP
2 NADH + 2H
Go from 3-C
pyruvate to ...
O
O
H3 C - C - C
Pyruvic Acid
Formation of
Acetyl CoA from
Pyruvic Acid
OH
Transport into
Mitochrondrion
HS - CoA
CO2
CO2
NADH + H
... a 2-C
Acetyl CoA
O
H3C - C - S - CoA
Acetyl CoA
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Remember, there
are 2 pyruvates per
glucose molecule!
Acetyl CoA
Remember... 2 of these
per molecule of glucose,
so double the outputs of
the TCA shown here.
O
H3C - C - S - CoA
Citrate
(6-C)
O
O
O
C-C-C-C
NADH + H
HO
NADH + H
OH
Oxaloacetate (4-carbon)
NADH + H
ATP
FADH2
CO2
CO2
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One molecule of glucose yields...
• Glycolysis
– 2 NADH
– 2 ATP
• Pyruvate to Acetyl CoA conversion
– 2 NADH (because there are 2 pyruvates)
• Citric Acid cycle (numbers are for 2 pyruvates going through)
– 6 NADH
– 2 FADH2
– 2 ATP
• Total: 10 NADH, 2 FADH2, and 4 ATP
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Electron Transport, Making ATP
• Each NADH + H yields 2 electrons
– Electron transport along the cytochrome chain enables
establishment of an electrochemical H+ gradient along the inner
mitochondrial membrane.
• Hydrogen movement down this gradient, through
the ATP synthetase, provides the energy for
conversion of ADP to ATP.
• Each electron pair from each NADH + H can
provide enough energy for production of 3 ATP
– electron pair from FADH2 yield 2 ATP
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Chemiosmosis
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ATP Synthase
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One molecule of glucose yields...
• Glycolysis
– 2 NADH + 2H 6 ATP
– 2 ATP
• Pyruvate to Acetyl CoA conversion
– 2 NADH + 2H 6 ATP
• Citric Acid cycle
– 6 NADH + 6H 18 ATP
– 2 FADH2 4 ATP
– 2 ATP
• Total: 38 ATP, which yields ~ 456 kcal
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galactokinase
Galactose
Galactose-1-P
Glucose-1-P
glucokinase (liver)
Glucose
Glucose-6-P
hexokinase
Fructose-6-P
Fructose-1,6-PP
Fructose
DHA-P
Fructose-1-P
fructokinase
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GA 3-P
Because the liver has this enzyme, it can convert the other
monosaccharides into glucose for export. (Renal tubular and
intestinal epithelial cells also have this enzyme)
Galactose
Glucose-1-P
glucose-6-phosphatase
Glucose
Glucose-6-P
Fructose-6-P
Fructose
Phosphorylation of the monosaccharides upon entering cells of the
body “traps” it there for use. The G-6-P enzyme is needed for tissues
that send glucose to other parts of the body.
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Glycogenesis &
Glycogenolyis
Glycogen
UDP -Glucose
Glycogenolysis
Glycogenesis
Glucose 1-P
From the Blood
From
Gluconeogenesis
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Glucose
Glucose 6-P
Glycolysis
The Lactate Story
• The NADH formed from oxidizing glucose
eventually gets oxidized back to NAD+ in the
mitochondria.
– (the result of giving the electrons to electron transport chain)
• NAD+ is needed to keep oxidizing glucose.
• In exercise (once the anaerobic threshold is
crossed), NAD+ isn’t re-formed fast enough, so low
levels threaten to stop glycolysis and ATP
production.
• The main reason to form lactate is to regenerate the
NAD+ needed to continue oxidizing glucose.
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GLYCOLYSIS
Glyceraldehyde - 3 - P
Lactate
NAD+
(oxidized)
oxidation
reaction
reduction
reaction
NADH
(reduced)
1,3 - Diphosphoglycerate
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Pyruvate
The Fate of Lactate
• Lactate is transported to the liver for conversion back
to pyruvate and then, via gluconeogenesis, to glucose.
– Why would muscle transport lactate to the liver for conversion back to
pyruvate? NAD+ is needed for that step, and the point of making
lactate in the first place was because NAD+ was too low.
• Lactate is in a sense a “storage form” of NADH,
because when it gets oxidized back to pyruvate,
NADH is formed.
• The glucose is released and taken up by the active
muscle.
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More on Lactate
• Reconversion of Lactic Acid: Why does excess ATP cause
excess pyruvate to be converted back to glucose?
– This is because high ATP levels inhibit glycolysis and actually
promote the reverse, i.e. gluconeogenesis.
• Lactic Acid and the Heart
– The very high blood flow and O2 levels mean no shortage of NAD+
so any lactate that is formed can be oxidized readily to pyruvate.
– Significant lactic acid is formed in the heart only during ischemia.
– Lactate Dehydrogenase (LD) has a very low affinity for pyruvate in the
heart, also explaining why little lactate is formed normally. However,
cardiac LD has high affinity for lactate, hence the ability of the heart to
utilize lactate from the circulation during exercise.
• in “white” skeletal muscle, LD has a high affinity for pyruvate.
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Control of Glucose Oxidation
fructose 1,6-diphosphate
fructose 6-P
Phosphofructokinase
+
glucagon
ATP
citrate
Mitochondrion
Pyruvate
kinase
NADH
citrate formation
(+ other steps)
Pyruvate
pyruvate dehydrogenase
Acetyl CoA
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PEP
ADP
Pyruvate
Effects of Epinephrine and Glucagon
Glycogen
Phosphorylase a
active P
Glucose-1-P
Activates this by adding P
Epinephrine/
Glucagon
“Glucose”
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+ cAMP-dependent
protein kinase
Inactivates this by adding P
Glycogen Synthase
INACTIVE (D) P
Glycogen
Epinephrine and Glucagon stimulate glycogen breakdown
ultimately by adding a P to and activating glycogen phosphorylase
(phosphorylase a).
Epinephrine/
Glucagon
cAMP
cAMP-dependent
protein kinase
Phosphorylates and
activates this enzyme
P
active phosphorylase b kinase
Phosphorylase b
inactive
P
Glycogen
Phosphorylase a
P
active
Phosphorylase Phosphatase
Glucose-1- P
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Final Enzymes for Glycogen -esis and -olysis
Glycogenolysis
Glycogen
Phosphorylase a
active P
(Phosphorylase b is
the inactive form)
Glucose-1-P
Note that the enzyme for glycogenolysis is activated when it
is phosphorylated (i.e. has a phosphate added P ), but the
enzyme for glycogenesis is inhibited by phosphorylation.
“Glucose”
Glycogen Synthase
active (I)
Glycogen
Glycogenesis
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