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Chapter 8
Chem 341
Suroviec Fall 2016
I. Overview
•
Metabolism – overall process through which living system acquire and
use free energy to carry our various functions
I. Overview
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Catabolism
•
Anabolism
A. Tropic Strategies
•
Autotropic – synthesize all their
cellular constituents from
simpler molecules
– Chemolithotrophs
– Photoautotrophs
•
Heterotrophs - Obtains free
energy through oxidation of
organic compounds
II. Food, Fuel and Storage
A. Intake of proteins, nucelic acids, polysaccharides and triacylglycerols
•
Digestion takes place by:
– Salivary amylase
– Gastric and pancreatic proteases
– lipases
II. Food, Fuel and Storage
B. Cells
– Take up digestion products through intestine
C.
Storage
–
Depends on monomer if stored or used immediately
II. Food, Fuel and Storage
D.
Mobilization
–
Metabolic fuels
–
Broken down by processes that make free energy available
II. Food, Fuel and Storage
E. Adipose tissue mobilization
F. Amino acid mobilization
II. Food, Fuel and Storage
G. Common Intermediates
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Many steps required to break down monomeric compounds/build them up 
metabolic pathways
II. Food, Fuel and Storage
H. Small Molecules
• NAD to NADH
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FAD to FADH2
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Coenzyme A
Images from Wikipedia
III. Thermodynamic Requirements
1.
2.
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Reactions need to be specific
The entire set of reactions needs to be the thermodynamically favored
Enzymes that catalyze near-equilibrium reactions tend to
– act quickly
– restore equilibrium concentrations
– net rates of such reactions are effectively regulated by the relative
concentration of substrates and products
IV. ATP
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Acts as energy conduit between
high and low energy compounds
•
ATP is special for several
reasons
–
Drives thermodynamically
unfavorable reactions by
cleavage of high energy
bonds
–
Why is large amount of free
energy released?
IV. ATP
A. How is ATP consumed
•
Early stages of nutrient breakdown
•
During physiological processes using ATP to drive reactions
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Additionally in endergonic reaction the PPi to Pi + Pi
B. Regenerate ATP
•
Catabolism – carbon in full molecules oxidized to CO2
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Anabolism – use O2
•
Redox reactions are linked
V. CAC Overview
•
Glycolysis converts to two C3 units. The free energy released in this
process is harvested to synthesize ATP from ADP and Pi
V. Overview
A.
Some pathways are irreversible
B.
Catabolic and anabolic pathways
MUST differ
C. Every metabolic pathway has a 1st committed step
II. Glucose
A. Glucose
•
•
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6 carbon sugar with aldehyde group
 form: OH group of the anomeric C is on OPPOSITE side of ring from CH2OH
 form: OH group of the anomeric C is on SAME side of ring from CH2OH
II. Glucose
C. Glycogenolysis
– Only liver can make glucose available to the liver at large
VI. Glycolysis
•
Stage I. Energy investment
–
•
Glucose is phosphorylated and
cleaved
– Uses 2 ATP
Stage II. Energy recovery
– 2 molecules of glyceraldehyde-3phosphate converted to pyruvate
– Produces 4 ATP
VII. Reactions of Glycolysis
A.
Hexokinase
Metabolically irreversible reaction
B. Phosphoglucose Isomerase
•
Conversion of G6P to F6P
C. Phosphofrutokinase
•
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PFK phosphorylates FBP
Operates similar to hexokinase
•
•
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Tetrameric enzyme
R and T states in equilibrium
ATP is both a substrate and and allosteric
inhibitor
C. PFK
•
•
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Each PFK has 2 binding site
– Substrate site
– Inhibitor site
Inhibitor site binds ATP only in T state
Shifts equilibrium in favor of T at high
ATP concentrations
D. Aldolase
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Catalyzes cleavage of FBP to form GAP and
DHAP
E. Triose Phosphate Isomerase
•
•
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GAP continues down the glycolytic pathway
DHAP and GAP are ketose-aldose isomers
Final reaction Stage I
F. Glyceraldehyde-3-Phosphate Dehydrogenase
•
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Exergonic reaction
Synthesis of high energy 1,3-BPG
G. Phosphoglycerate Kinase
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Bilobal with Mg2+
1,3-BPG common intermediate whose consumption pulls reaction
forward
H. Phosphoglycerate Mutase
•
•
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3PG is converted to 2PG
Phosphorylated His is needed to complete reaction
2,3-BPG allosteric inhibitor of deoxyhemoglobin
I. Enolase
•
•
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2PG dehydrated to PEP
Needs Mg2+
F- inhibitor of reaction
J. Pyruvate Kinase
•
•
•
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PEP is cleaved via PK to form
pyruvate
Forms ATP
Step 1: ADP nucleophilically attacks
the PEP, forms ATP
Step 2: Enolpyruvate tautomerizes
to pyruvate
3 products of glycolysis
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•
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ATP
– Investment of 2 ATP per glucose
– Generation of 4 ATP
NADH
– Glucose oxidized
– 2 NAD+ reduced to NADH
– Electron transport
Pyruvate
– 2 molecules are produced
– Complete oxidation to CO2 done in
citric acid cycle
VIII. Fermentation
•
Pyruvate
– Aerobic conditions
• completely oxidized to CO2 and H2O
– Anaerobic conditions
• converted to reduced end product to reoxidize NADH
A. Homolactic Fermentation
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Demand for ATP high
Supply of oxygen is low
B. Alcoholic Fermentation
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Forms CO2, ethanol and NAD+
TPP is essential cofactor of
pyruvate decarboxylase
IX. Control of Glycolysis
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•
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Glycolysis operates continuously in
most tissues
Flux must vary to meet needs
How do we determine to flux control
mechanisms?
One 3 reactions of glycolysis
potentially control it:
– Hexokinase
– Phosphofrucokinase
– Pyrivate kinase
X. Gluconeogenesis
Gluconeogenesis is the formation of new glucose
molecules from precursors in the liver
Precursor molecules include lactate, pyruvate, and
-keto acids
Gluconeogenesis Reactions
Reverse of glycolysis except the three irreversible
reactions
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
X. Gluconeogenesis
Figure 8.11 Carbohydrate Metabolism: Gluconeogenesis and Glycolysis
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
X. Gluconeogenesis
Figure 8.11 Carbohydrate Metabolism: Gluconeogenesis and Glycolysis
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Section 8.2: Gluconeogenesis
Gluconeogenesis Reactions Continued
Three bypass reactions:
1. Synthesis of phosphoenolpyruvate (PEP)
2. Conversion of fructose-1,6-bisphosphate to fructose6-phosphate
3. Formation of glucose from glucose-6-phosphate
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
X. Gluconeogenesis
Gluconeogenesis Substrates
Three of the most important substrates for gluconeogenesis are:
1. Lactate
2. Glycerol
Alanine
Figure 8.12 Cori Cycle
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
X. Gluconeogenesis
Gluconeogenesis
Regulation
Substrate availability
Hormones (e.g., cortisol
and insulin)
Figure 8.14 Allosteric Regulation of
Glycolysis and Gluconeogenesis
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
X. Gluconeogenesis
Gluconeogenesis
Regulation Continued
Allosteric enzymes
(pyruvate carboxylase,
pyruvate
carboxykinase,
fructose-1,6bisphosphatase, and
glucose-6-phosphatase)
+
Figure 8.14 Allosteric Regulation of
Glycolysis and Gluconeogenesis
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
XI. Pentose Phosphate Pathway
Glucose-6-phosphate
dehydrogenase
Pentose Phosphate
Pathway
Gluconolactonase
Figure 8.15a The Pentose Phosphate Pathway (oxidative)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
XI. Pentose Phosphate Pathway
6-phosphogluconate
dehydrogenase
Pentose Phosphate
Pathway: Oxidative
Figure 8.15a The Pentose Phosphate Pathway (oxidative)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
XI. Pentose Phosphate Pathway
Pentose Phosphate
Pathway: Nonoxidative
Figure 8.15b The Pentose Phosphate
Pathway (nonoxidative)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
X. Pentose Phosphate Pathway
Pentose Phosphate
Pathway
Figure 8.16 Carbohydrate
Metabolism: Glycolysis
and the Phosphate
Pathway
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Metabolism of Other Important Sugars
Figure 8.17 Carbohydrate Metabolism:
Galactose Metabolism
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press
Metabolism of Other Important Sugars
Figure 8.17 Carbohydrate Metabolism:
Other Important Sugars
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press