Download 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