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CHAPTER 16: The Citric Acid Cycle - Coggle Diagram
CHAPTER 16:
The Citric Acid Cycle
基本概念
Conversion of Pyruvate
to Acetyl-CoA
Net reaction:
oxidative decarboxylation of pyruvate
first carbons of glucose to be fully oxidized
Catalyzed by the pyruvate
dehydrogenase complex
requires 5 coenzymes
TPP, lipoyllysine, and FAD are prosthetic groups.
NAD+ and CoA-SH are co-substrates.
Structure of Coenzyme A
Coenzymes are not a permanent part of the enzymes’ structure.
– They associate, fulfill a function, and dissociate.
The function of CoA is to accept and carry acetyl groups.
In Eukaryotes, Stages 2 and 3 Are
Localized to the Mitochondria
Glycolysis occurs in the cytoplasm.
Citric acid cycle occurs in the mitochondrial matrix†.
Oxidative phosphorylation occurs in the inner membrane.
Except succinate dehydrogenase, which is located in the inner membrane
Structure of Lipoyllysine
Prosthetic groups are strongly bound to the protein.
The lipoic acid is covalently linked to the enzyme via a lysine residue
Respiration: Stages
Pyruvate Dehydrogenase Complex (PDC)
PDC is a large (up to 10 MDa) multienzyme complex.
pyruvate dehydrogenase (E1)
dihydrolipoyl transacetylase (E2)
dihydrolipoyl dehydrogenase (E3)
Advantages of multienzyme complexes:
The short distance between catalytic sites allows channeling of substrates from one catalytic site to another.
Channeling minimizes side reactions.
The regulation of activity of one subunit affects the entire complex.
Cellular Respiration
Process in which cells consume O2 and produce CO2
Provides more energy (ATP) from glucose than glycolysis
Also captures energy stored in lipids and amino acids
Evolutionary origin: developed about 2.5 billion years ago
Used by animals, plants, and many microorganisms
Occurs in three major stages:
acetyl CoA production
acetyl CoA oxidation
electron transfer and oxidative phosphorylation
Overall Reaction of PDC
Only a Small Amount of Energy Available in Glucose Is Captured in Glycolysis
Sequence of Events in Oxidative Decarboxylation of Pyruvate
Enzyme2
Step 3: Formation of acetyl-CoA (product 1)
Enzyme3
Step 4: Reoxidation of the lipoamide cofactor
Step 5: Regeneration of the oxidized FAD cofactor
‒ forming NADH (product 2)
Enzyme1
Step 1: Decarboxylation of pyruvate to an aldehyde
Step 2: Oxidation of aldehyde to a carboxylic acid‒ Electrons reduce lipoamide and form a thioester.
其他
Regulation of Pyruvate Dehydrogenase
PDH kinase and PDH phosphorylase are part of
mammalian PDH complex.
Regulation of PDH is somewhat similar to regulation of the glycogen synthase/glycogen phosphorylase complex.
Also regulated by reversible phosphorylation of E1
phosphorylation: inactive
dephosphorylation: active
Kinase is activated by ATP.
high ATP => phosphorylated PDH => less acetyl-CoA
low ATP => kinase is less active and phosphorylase removes phosphate from PDH => more acetyl-CoA
Regulation of the Citric Acid Cycle
Regulated at highly thermodynamically favorable and irreversible steps
– PDH, citrate synthase, IDH, and KDH
General regulatory mechanism
activated by substrate availability
inhibited by product accumulation
Overall products of the pathway
are NADH and ATP.
affect all regulated enzymes in the cycle
inhibitors: NADH and ATP
activators: NAD+ and AMP
CAC Intermediates Are Amphibolic
Anaplerotic Reactions
Intermediates in the citric acid cycle can be used in biosynthetic pathways (removed from cycle).
Must replenish the intermediates in order for the cycle and central metabolic pathway to continue
4-carbon intermediates are formed by carboxylation of 3-carbon precursors.
Direct and Indirect ATP Yield
The Citric Acid Cycle (CAC)
Step 5
Generation of GTP Through Thioester: Substrate-Level Phosphorylation by Succinyl-CoA Synthetase
Step 6
Oxidation of an Alkane to Alkene
by Succinate Dehydrogenase
Step 4
Final Oxidative Decarboxylation by
α-Ketoglutarate Dehydrogenase
Step 7
Hydration Across a Double Bond: Fumarase
Step 3
Oxidative Decarboxylation by Isocitrate Dehydrogenase
Step 8
Oxidation of Alcohol to a Ketone and Regeneration of Oxaloacetate by Malate Dehydrogenase
Step 2
Isomerization by Dehydration/Rehydration
One Turn of the Citric Acid Cycle
Step 1
C-C Bond Formation by Condensation
of Acetyl-CoA and Oxaloacetate
Net Result of the Citric Acid Cycle
Net oxidation of two carbons to CO2
equivalent to two carbons of acetyl-CoA
but NOT the exact same carbons
Energy captured by electron transfer to NADH and FADH2
Generates 1 GTP, which can be converted to ATP
Completion of cycle
Sequence of Events in the Citric Acid Cycle
Step 1: C-C bond formation between acetate (2C) and oxaloacetate (4C) to make citrate (6C)
Step 2: Isomerization via dehydration/rehydration
Steps 3–4: Oxidative decarboxylations to give 2 NADH
Step 5: Substrate-level phosphorylation to give GTP
Step 6: Dehydrogenation to give FADH 2
Step 7: Hydration
Step 8: Dehydrogenation to give NADH