Overview of Citric Acid Cycle The citric acid cycle operates under aerobic conditions only The...
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Transcript of Overview of Citric Acid Cycle The citric acid cycle operates under aerobic conditions only The...
Overview of Citric Acid Cycle• The citric acid cycle operates
under aerobic conditions only
• The two-carbon acetyl group in acetyl CoA is oxidized to CO2
• It produces reduced coenzymes NADH and FADH2 and one ATP directly
• In the citric acid cycle:- acetyl (2C) bonds to oxaloacetate (4C) to form citrate (6C)- oxidation and decarboxylation convert citrate to oxaloacetate- oxaloacetate bonds with another acetyl to repeat the cycle
Reaction 1: Formation of Citrate
• Oxaloacetate combines with the two-carbon acetyl group to form citrate
citrateoxaloacetate
+ HS-CoA + H+
COO-
CH2
CHO COO-
CH2
COO-
+ CH3 C
O
SCoA
COO-
C
CH2
COO-
O
acetyl CoA
Reaction 2: Isomerization to Isocitrate
• Citrate isomerizes to isocitrate
• The tertiary –OH group in citrate is converted to a secondary –OH that can be oxidized
Citrate
COO-
CH2
CHO COO-
CH2
COO-
COO-
CH2
C COO-
CH
COO-
COO-
CH2
C COO-
C
COO-
H
HO H
H2O H2O
Aconitase Aconitase
Aconitate Isocitrate
Reaction 3: Oxidative Decarboxylation 1
• A decarboxylation removes a carbon as CO2 from
isocitrate
• The –OH group is oxidized to a ketone releasing H+ and 2e- that form reduced coenzyme NADH
COO-
CH2
C COO-
C
COO-
H
HO H
Isocitrate
+ NAD+
COO-
CH2
C H
C
COO-
H
O + CO2 + NADH
Isocitratedehydrogenase
Reaction 4: Oxidative Decarboxylation 2
• In a second decarboxylation, a carbon is removed as CO2
from -ketoglutarate
• The 4-carbon compound bonds to coenzyme A providing H+ and 2e- to form NADH
+ NAD+
COO-
CH2
CH2
C
COO-
O
+ CO2 + NADH
COO-
CH2
CH2
C
S
O
CoA
Succinyl CoA
+ CoASH
-Ketoglutarate
Reaction 5: Hydrolysis of Succinyl CoA
• The hydrolysis of the thioester bond releases energy to add phosphate to GDP and form GTP, a high energy compound
+ GTP + CoA-SH+ GDP + Pi
Succinyl CoA
CH2
CH2
COO-
COO-
Succinyl CoA synthetase
CH2
CH2
C
COO-
O
S CoA
Succinate
Reaction 6: Dehydrogenation of Succinate
• In this oxidation, two H are removed from succinate to form a double bond in fumarate
• FAD is reduced to FADH2
+ FAD
Succinate Fumarate
+ FADH2
C
C
COO-
COO-
H
HCH2
CH2
COO-
COO-
Succinatedehydrogenase
Reaction 7: Hydration of Fumarate
• Water is added to the double bond in fumarate to form malate
Fumarase
C
C
COO-
COO-
H
H
Fumarate Malate
COO-
CHO H
C
COO-
HHH2O+
Reaction 8: Dehydration of Malate
• Another oxidation forms a C=O double bond
• The hydrogens from the oxidation form NADH + H+
+ H++ NAD+COO-
CHO H
C
COO-
HH
Malate Oxaloacetate
NADH+
Malatedehydrogenase
C
CH2
O
COO-
COO-
Summary of Products from Citric Acid CycleIn one turn of the citric acid cycle:
• Two decarboxylations remove two carbons as 2CO2
• Four oxidations provide hydrogen for 3NADH and one FADH2
• A direct phosphorylation forms GTP which is used to form ATP
• Overall reaction of citric acid cycle:
Acetyl CoA + 3NAD+ + FAD + GDP + Pi + 2H2O
2CO2 + 3NADH + 2H+ + FADH2 + HS-CoA + GTP
Regulation of the Citric Acid Cycle
The citric acid cycle:
• Increases its reaction rate when low levels of ATP or NAD+ activate isocitrate dehydrogenase to formation of acetyl CoA for the citric acid cycle
• Slows when high levels of ATP or NADH inhibit citrate synthetase (first step in cycle), decreasing the formation of acetyl CoA
Electron Carriers
• The electron transport chain consists of electron carriers that accept H+ ions and electrons from the reduced coenzymes NADH and FADH2
• The H+ ions and electrons are passed down a chain of carriers until in the last step they combine with oxygen to form H2O
• Oxidative phosphorylation is the process by which the energy from transport is used to synthesize ATP
Oxidation and Reduction of Electron Carriers
• Electron carriers are continuously oxidized and reduced as hydrogen and/or electrons are transferred from one to the next
• The energy produced from these redox reactions is used to synthesize ATP
electron carrier AH2(reduced)
electron carrier BH2(reduced)
electron carrier B(oxidized)
electron carrier A(oxidized)
FMN (Flavin Mononucleotide)
• FMN coenzyme is derived from riboflavin (vitamin B2)
- it contains flavin, ribitol,and a phosphate
- it accepts 2H+ + 2e- to form reduced coenzyme FMNH2
Iron-Sulfur (Fe-S) Clusters
• Fe-S clusters are groups of proteins containing iron ions and sulfide
• They accept electrons to reduce Fe3+ to Fe2+, and lose electrons to re-oxidize Fe2+ to Fe3+
Coenzyme Q (CoQ or Q)
• Coenzyme Q (Q or CoQ) is a mobile electron carrier derived from quinone
• It is reduced when the keto groups accept 2H+ and 2e-
Cytochromes (Cyt)• Cytochromes (cyt) are proteins containing heme groups with
iron ions.• In a cytochrome, Fe3+ accepts an electron to form Fe2+
(reduction), and the Fe2+ is oxidized back to Fe3+ when it passes an electron to the next carrier: Fe3+ + e- Fe2+
• They are abbreviated as cyt a, cyt a3, cyt b, cyt c, and cyt c1
Electron Transport System
• The electron carriers in the electron transport system are attached to the inner membrane of the mitochondrion
They are organized into four protein complexes:
Complex I NADH dehydrogenase
Complex II Succinate dehydrogenase
Complex III CoQ-Cytochrome c reductase
Complex IV Cytochrome c Oxidase
Complex I: NADH Dehydrogenase
• At Complex I, hydrogen and electrons are transferred:
- from NADH to FMN:
FMN + NADH + H+ FMNH2 + NAD+
- from FMNH2 to Fe-S clusters and Q, which reduces Q to
QH2 and regenerates FMN
Q + FMNH2 QH2 + FMN
- to complex I to Complex III by Q (QH2), a mobile carrier
Complex II: Succinate Dehydrogenase
• At Complex II, hydrogen and electrons are transferred:
- from FADH2 to Complex II, which is at a lower energy
level than Complex I
- from FADH2 to coenzyme Q, which reduces Q and
regenerates FAD
Q + FADH2 QH2 + FAD
- from complex II to Complex III by Q(QH2), a mobile
carrier
Complex III: Coenzyme Q-Cytochrome c Reductase
• At Complex III, electrons are transferred:
- from QH2 to two Cyt b, which reduces Cyt b and
regenerates Q
2Cyt b (Fe3+) + QH2 2Cyt b (Fe2+) + Q + 2H+
- from Cyt b to Fe-S clusters and to Cyt c, the second
mobile carrier
2Cyt c (Fe3+) + 2Cyt b (Fe2+) 2Cyt c (Fe2+) + 2Cyt b (Fe3+)
Complex IV: Cytochrome c Oxidase
• At Complex IV, electrons are transferred:
- from Cyt c to Cyt a
2Cyt a (Fe3+) + 2Cyt c (Fe2+) 2Cyt a (Fe2+) + 2Cyt c (Fe3+)
- from Cyt a to Cyt a3, which provides the electrons to
combine H+ and oxygen to form water
4H+ + O2 + 4e- (from Cyt a3) 2H2O
Oxidative Phosphorylation and the Chemiosmotic Model• In the chemiosmotic model, complexes I, III, and IV pump
protons into the intermembrane space, creating a proton gradient• Protons must pass through ATP synthase to return to the matrix• The flow of protons through ATP synthase provides the energy for
ATP synthesis (oxidative phosphorylation): ADP + Pi + Energy ATP
ATP Synthase• In ATP synthase protons flow back to the matrix through
a channel in the F0 complex
• Proton flow provides the energy that drives ATP synthesis by the F1 complex
ATP Synthase F1 Complex• In the F1 complex of ATP synthase, a center subunit () is surrounded
by three protein subunits: loose (L), tight (T), and open (O)• Energy from the proton flow through F0 turns the center subunit (),
which changes the shape (conformation) of the three subunits• As ADP and Pi enter the loose L site, the center subunit turns,
changing the L site to a tight T conformation• ATP is formed in the T site where it remains strongly bound• Energy from proton flow turns the center subunit, changing the T site
to an open O site, which releases the ATP
Electron Transport and ATP Synthesis
• In electron transport, the energy level decreases for electrons:
• Oxidation of NADH (Complex I) provides sufficient energy
for 3ATPs
NADH + 3ADP + 3Pi NAD+ + 3ATP
• Oxidation of FADH2 (Complex II), which enters the chain as
a lower energy, provides sufficient energy for only 2ATPs
FADH2 + 2ADP + 2Pi FAD + 2ATP
ATP from and Regulation of Electron Transport• Low levels of ADP, Pi, oxygen, and NADH decrease
electron transport activity• High levels of ADP activate electron transport• As the electrons flow through decreasing energy levels, three
of the transfers provide enough energy for ATP synthesis