16.3 Regulation of the Citric Acid Cycle
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Transcript 16.3 Regulation of the Citric Acid Cycle
The Energy of Oxidations in the Cycle
is Efficiently Conserved
4 Oxidation steps
Released
energy
Conserved in NDAH and FADH2
ATP generation from NADH or FADH2 by oxidative phosphorylation
NADH : 2.5 ATP
FADH2 : 1.5 ATP
The Energy of Oxidations in the Cycle
is Efficiently Conserved
ATP generation from 1 glucose
Total : 30-32 ATP
32 X 30.5 kJ/mol = 976 kJ/mol
34% of the maximum of ~2,840 kJ/mol available from the complete
oxidation of glucose
65% efficiency within cells considering DG of ATP hydrolysis
Roles of citric acid cycle
Oxidation of acetyl group
Hub of intermediary metabolism
Entry of 4- or 5-C products from
catabolic process “fuel”
Providing precursors for
biosynthesis
Incomplete citric acid cycle in
anaerobic bacteria
Production of biosynthetic
precursors
Citric acid Cycle for Biosynthesis
Amphibolic pathway
Anaplerotic Reactions Replenish Citric
Acid Cycle Intermediates
Anaplerotic Reactions
Generation of OAA or malate from pyruvate or PEP
Constant maintenance of citric acid cycle intermediates
Pyruvate carboxylase in liver and kidney
Allosteric stimulation by acetyl-CoA
Biotin cofactor
PEP carboxylase in plant, yeast, bacteria
Activation by Fru 1,6-bisphosphate
Biological Tethers
Flexible tethers
Movement of reaction
intermediates from one to another
active sites (w/o dissociation)
Lipoate
Biotin
High affinity with avidin in egg
white
Biotin-avidin interaction
Useful researche tools in
biochemistry and cell biology
Pantothenate
16.3 Regulation of the Citric Acid Cycle
- Avoiding wasteful overproduction
- Keeping the cell in stable steady state
Regulation of the Citric Acid Cycle
Regulation of the Citric Acid Cycle
1. Pyruvate dehydrogenase complex rxn
2. Citrate synthase rxn
3. Isocitrate dehydrogenase rxn
4. a-Ketoglutarate dehydrogenase rxn
Three factors for the rate of flux through the cycle
1. Substrate availability
2. Inhibition by accumulating products
3. Allosteric feedback inhibition
Regulation mechanisms
1. Allosteric regulation
2. Covalent modification
Regulation of the Citric Acid Cycle
Regulation of PDH Complex in Mammals
Allosteric regulation
High ratio of [ATP]/[ADP],
[NADH]/[NAD+],
[acetyl-CoA]/[CoA]
Allosteric inhibition
Covalent modification
(by regulatory kinase & phophatase)
Reversible -lation on Ser in E1
High [ATP] allosteric activation of
specific kinase inactivation of E1 by
-lation
Regulation of the Citric Acid Cycle
Regulation of 3 exergonic steps
Citrate synthase
Isocitrate dehydrogenase
a-Ketoglutarate dehydrogenase
complex
Substrate availability
; OAA, acetyl-CoA, NAD+
Feedback inhibition
; succinyl-CoA, citrate, ATP
Ca2+ in muscle tissue
; allosteric activation
“Substrate Channeling
Through Multienzyme
Complexes May Occur in the
Citric Acid Cycle”
Metabolons
Multienzyme complexes
ensuring efficient passage of the
product of one enzyme reaction
to the next enzyme
substrate channeling
In citric acid cycle
Associated together as
supramolecular complexes
Association with the inner
mitochondrial membrane
16.4 The Glyoxylate Cycle
Glyoxylate Cycle
Conversion of acetate to carbohydrate
In organisms other than vertebrates
Net conversion of acetate to succinate
or other 4-C intermediates of citric
acid cycle
2 Acetyl-CoA + NAD+ + 2 H2O
succinate + 2 CoA + NADH + H+
Enzymes specific for glyoxylate
cycle
Isocitrate lyase
Malate synthase
Not in vertebrates
Glyoxylate Cycle in Germinating Seeds
Glyoxysome (in plant)
Specialized peroxisome
Organelles containing enzymes for
glyoxylate cycle & fatty acid degradation
Developed in lipid-rich seeds during
germination
Regulation of Citric Acid Cycle and
Glyoxylate Cycle
Regulation of isocitrate dehydrogenase
- Isocitrate (sharing common intermediate)
- Covalent modification
Reversible -lation (specific kinase or
phosphatase)
Intermediates of citric acid cycle and
glycolysis, AMP, ADP
Allosteric regulation
Activation of isocitrate dehydrogenase
via inactivation of specific kinase
activation of citric acid cycle
Inactivation of isocitrate lyase
inhibition of glyoxylate cycle