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Citric Acid Cycle/Krebs Cycle
citric acid cycle is used to harvest high energy electrons from
carbon fuel.
the central metabolic hub of the cell
produces intermediates which are precursors for fatty acids,
amino acids, nucleotide bases, and cholesterol
named after Hans Krebs who was largely responsible for
elucidating its pathways in the 1930s.
Summary of the citric acid cycle
acetyl CoA combines with oxaloacetate to form citrate.
Ultimately, the oxaloacetate is recycled and the acetate is broken
down to CO2.
Each cycle produces 1 ATP, 3 NADH, and 1 FADH, per acetyl
CoA.
For each acetyl CoA which enters the cycle:
(1) Two molecules of CO2 are released
(2) Coenzymes NAD+ and FAD+ are reduced
(3) One GDP is phosphorylated
(4) The initial acceptor molecule (oxaloacetate) is reformed
“All roads lead to Rome”
To extract energy from nutrients:
break down of large molecules into smaller ones
Who?
degradation by
final products
Polysaccarides
Specific enzymes
ex amylases
sugar monomers
Proteins
proteases
amino acids
Fats
(triacylglycerols)
lipases
glycerol to fatty acids then
eventually acetyl-CoA
“All roads lead to Rome”
Mille viae ducunt homines per saecula Romam: A thousand roads lead men forever to Rome
To extract energy from nutrients:
break down of large molecules into smaller ones
final products sugar monomers, amino acids fatty acids, acetyl-CoA
“delivered” into CA cycle!!
Catabolic pathways feed into CA cycle cross into mitochondria
Just as “All roads lead to Rome”.. All pathways lead to CA cycle!
PS opposite is true!!!
“All roads lead to Rome”
Catabolic pathways feed into CA cycle cross into mitochondria
Just as “All roads lead to Rome”.. All pathways lead to CA cycle!
ALL METABOLIC PATHWAYS ARE RELATED, AND ALL
OPERATE SIMULTANEOUSLY!
CA cycle... Generate energy from our food, and generate intermediates
for our cellular processes.. Metabolic “hub” of our cells!!
gluconeogenesis
GLUCOSE
glycolysis
alanine
aminotransferase
Alanine
lactate
PYRUVATE dehydrogenase
pyruvate
carboxylase
pyruvate
dehydrogenase
lipogenesis
Oxaloacetate
Acetyl CoA
Fatty acids
-oxidation
citric acid
cycle
CO2
Lactate
ketogenesis
(liver only)
ketone
oxidation
Ketone bodies
cholesterol
synthesis
Cholesterol
steroid
hormones
(endocrine glands)
The Citric Acid Cycle Can Be a Multistep-Catalyst
Oxaloacetate is regenerated
The cycle is a mechanism for oxidizing acetyl CoA to CO2 by
NAD+ and FAD
The cycle itself is not a pathway for a net degradation of any
cycle intermediates
Cycle intermediates can be shared with other pathways,
which may lead to a re-supply or net decrease in cycle
intermediates
Fates of carbon atoms in the cycle
Carbon atoms from acetyl CoA (red) are
not lost in the first turn of the cycle
Citric Acid Cycle/Krebs Cycle
citric acid cycle is used to harvest high energy electrons from
carbon fuel.
the central metabolic hub of the cell
produces intermediates which are precursors for fatty acids,
amino acids, nucleotide bases, and cholesterol
The citric acid cycle may seem like an elaborate way to oxidize
acetate into carbon dioxide, but there is chemical logic to the
cycle.
Citric Acid Cycle/Krebs Cycle
The citric acid cycle may seem like an elaborate way to oxidize
acetate into carbon dioxide, but there is chemical logic to the
cycle.
In order to directly oxidize acetate into two molecules of CO2 a
C—C bond must be broken.
Under the mild conditions found in cells, there is insufficient
energy to break the bond.
Cells often break C—C bonds between
carbon atoms α and β to a carbonyl
called  cleavage
Enzymes that catalyze:
aldolases and transaldolases
Another common type of C—C cleavage is α-cleavage of an αhydroxy-ketone carried out by ketolases and decarboxylases.
Since neither of these common strategies for cleavage of C—C
O
bonds is available to acetate, the acetate is activated
in the form
acetyl-CoA, condensed
with oxaloacetate to form
citrate and then
C CH3
Coenzyme A-SH + HO
a β-cleavage is carried out in subsequent acetic
steps.
acid
O
Coenzyme A-S
C
acetyl-CoA
CH3 + H2O
1. Citrate Synthase
Citrate formed from acetyl CoA and oxaloacetate
Only cycle reaction with C-C bond formation
a synthase is an enzyme which catalyzes a synthesis process; makes covalent bonds
Stereo views of citrate synthase
(a) Open conformation
(b) Closed conformation
Product citrate (red)
2. Aconitase
catalyses the stereo-specific isomerization of citrate to isocitrate via
cis-aconitate
Elimination of H2O from citrate to form C=C bond of cisaconitate
Stereospecific addition of H2O to cis-aconitate to form 2R,3SIsocitrate
3. Isocitrate Dehydrogenase
dehydrogenase is an enzyme that oxidizes a substrate by
transferring one or more hydrides to an acceptor, NAD or FAD
Oxidative decarboxylation of isocitrate to
a-ketoglutarate (a-kg) (a metabolically irreversible reaction)
One of four oxidation-reduction reactions of the cycle
Hydride ion from the C-2 of isocitrate is transferred to NAD+ to
form NADH
Oxalosuccinate is decarboxylated to a-kg
Isocitrate dehydrogenase reaction
4. The a-Ketoglutarate Dehydrogenase Complex
5. Succinyl-CoA Synthetase
Free energy in thioester bond of succinyl CoA is conserved
as GTP (or ATP in plants, some bacteria)
GDP + Pi
GTP
Synthetase is an enzyme that catalyzes the linking together of two molecules especially
by using the energy derived from the concurrent splitting off of a pyrophosphate group
from a triphosphate (as ATP)— now called ligase
6. The Succinate Dehydrogenase (SDH) Complex
Located on the inner mitochondrial membrane (other
components are dissolved in the matrix)
Dehydrogenation is stereospecific; only the trans isomer is
formed
Substrate analog malonate is a competitive inhibitor of the
SDH complex
Reaction of the succinate
dehydrogenase complex
7. Fumarase
Stereospecific trans addition of water to the
double bond of fumarate to form L-malate
8. Malate Dehydrogenase
Citric acid cycle inputs and outputs per glucose
molecule
Inputs:
Outputs:
2 acetyl groups
6 NAD+
2 FAD
2 ADP + 2 P
4 CO2
6 NADH
2 FADH2
2 ATP
Energy conservation by the cycle
Energy is conserved
in the reduced
coenzymes NADH,
QH2 and one GTP
NADH, QH2 can be
oxidized to produce
ATP by oxidative
phosphorylation
Reduced Coenzymes Fuel the Production
of ATP
Each acetyl CoA entering the cycle nets:
(1) 3 NADH
(2) 1 QH2
(3) 1 GTP (or 1 ATP)
Oxidation of each NADH yields 2.5 ATP
Oxidation of each QH2 yields 1.5 ATP
Complete oxidation of 1 acetyl CoA = 10 ATP
Fig. 19-8, p.526
3 control points in CA cycle
PDH.. Covered
Isocitrate dehydronase
ADP/NAD+ allosteric activators
a-ketogluterate dehydrogenase complex
Guess who inhibits???? (same as always: ATP/NADH say No!)