Citric Acid Cycle

Citric Acid Cycle (tricarboxylic acid (TCA) cycle or the Krebs cycle (after its discoverer, Hans Krebs)
• Respiration refers to a multicellular organism’s uptake of O2 and release of CO2.

• The pyruvate produced by glycolysis is further oxidized to H2O and CO2. This aerobic phase of catabolism is called
respiration.
• Three fate of pyruvate: 1. enter in CAC as acetyl-CoA for fuel,

2. starting material for fatty acid and sterol synthesis and
3. precursor for amino acid synthesis.
• The molecular processes by which cells consume O2 and produce
CO2—processes more precisely termed cellular respiration.
Three stages of cellular respiration
1. Stage 1: oxidation of fatty acids, glucose, and some amino acids
yields acetyl-CoA.
2. Stage 2: oxidation of acetyl groups in the citric acid cycle
includes four steps in which electrons are abstracted.
3. Stage 3: electrons carried by NADH and FADH2 are funneled into
a chain of mitochondrial (or, in bacteria, plasma membrane–
bound) electron carriers—the respiratory chain—ultimately
reducing O2 to H2O.
This electron flow drives the production of ATP
Pyruvate dehydrogenase (PDH) complex
Five Coenzymes (Prosthetic group)

1. Thiamine pyrophosphate (TPP)
2. Flavin adenine dinucleotide(FAD)
3. Coenzyme A (CoA/CoA-SH)
4. Nicotinamide adenine dinucleotide (NAD)
5. Lipoate.
Three different enzymes:
1. Pyruvate dehydrogenase (E1),
2. Dihydrolipoyl transacetylase (E2)
3. Dihydrolipoyl dehydrogenase (E3)
Production acetyl-CoA
• The overall reaction catalyzed by the pyruvate dehydrogenase complex is an oxidative decarboxylation, an irreversible
oxidation process in which the carboxyl group is removed from pyruvate as a molecule of CO2 and the two remaining
carbons become the acetyl group of acetyl-CoA.
• The NADH formed in this reaction gives up a hydride ion (:H2) to the respiratory chain, which carries the two electrons to
oxygen or, in anaerobic microorganisms, to an alternative electron acceptor such as nitrate or sulfate.
• The transfer of electrons from NADH to oxygen ultimately generates 2.5 molecules of ATP per pair of electrons.
The five coenzymes participating in this reaction, and the three enzymes that make up the enzyme complex,
• Coenzyme A (CoA). A hydroxyl group of pantothenic acid • Lipoic acid (lipoate) in amide linkage with a Lys residue. The
is joined to a modified ADP moiety by a phosphate ester lipoyllysyl moiety is the prosthetic group of dihydrolipoyl
bond, and its carboxyl group is attached to β- transacetylase (E2 of the PDH complex). The lipoyl group
mercaptoethylamine in amide linkage. occurs in oxidized (disulfide) and reduced (dithiol) forms and
• The hydroxyl group at the 3’ position of the ADP moiety acts as a carrier of both hydrogen and an acetyl (or other
has a phosphoryl group not present in free ADP. The — acyl) group
SH group of the β-mercaptoethylamine moiety forms a
thioester with acetate in acetyl-coenzyme A (acetyl-
CoA).
Oxidative decarboxylation of pyruvate to acetyl-CoA by the PDH complex
Step 1 pyruvate reacts with the bound thiamine pyrophosphate (TPP) of pyruvate dehydrogenase (E1), undergoing
decarboxylation to the hydroxyethyl derivative.
Step 2, the transfer of two electrons and the acetyl group from TPP to the oxidized form of the lipoyllysyl group of the
core enzyme, dihydrolipoyl transacetylase (E2), to form the acetyl thioester of the reduced lipoyl group.
Step 3 is a transesterification in which the —SH group of CoA replaces the —SH group of E2 to yield acetyl-CoA and the
fully reduced (dithiol) form of the lipoyl group.
Step 4 dihydrolipoyl dehydrogenase (E3) promotes transfer of two hydrogen atoms from the reduced lipoyl groups of
E2 to the FAD prosthetic group of E3, restoring the oxidized form of the lipoyllysyl group of E2.
Step 5 the reduced FADH2 of E3 transfers a hydride ion to NAD+, forming NADH. The enzyme complex is now ready for
another catalytic cycle.
Citric Acid Cycle (CAC)
C-C bond formation to
Dehydrogenation to give NADH make citrate
Isomerization via
Hydration dehyd/rehydration
Dehydrogenation to give reduced

to give FADH2
Oxidative decarboxylation to
Substrate level phosphorylation give 2 NADH
to give GTP
Products of one turn of the citric acid cycle
At each turn of the cycle,
• 3 NADH
• 1 FADH2
• 1 GTP (or ATP)
• 2CO2
are released in oxidative decarboxylation reactions.
• Biosynthetic precursors produced by an incomplete citric
acid cycle in anaerobic bacteria.
• These anaerobes lack a-ketoglutarate dehydrogenase and
therefore cannot carry out the complete citric acid
cycle. a-Ketoglutarate and succinyl-CoA serve as precursors
in a variety of biosynthetic pathways.
Anaplerotic Reactions
A biochemical pathway that serves both anabolic and catabolic processe.
As intermediates of the citric acid cycle are serve as biosynthetic precursors, they are replenished by anaplerotic reactions.
CAC components are important Biosynthetic intermediates
• The citric acid cycle is an amphibolic pathway, which

serves in both catabolic and anabolic processes.
• Besides its role in the oxidative catabolism of
carbohydrates, fatty acids, and amino acids, the cycle
provides precursors for many biosynthetic pathways.
• α-Ketoglutarate and oxaloacetate serve as precursors
of the amino acids aspartate and glutamate and other
amino acids as well as purine and pyrimidine
nucleotides.
• Oxaloacetate is converted to glucose in
gluconeogenesis.
• Succinyl-CoA is a central intermediate in the synthesis
of the porphyrin ring of heme groups, which serve as
oxygen carriers (in hemoglobin and myoglobin) and
electron carriers (in cytochromes)
• Citrate produced in some organisms is used
commercially for a variety of purposes
Regulation of CAC
• The production of acetyl-CoA for the citric acid cycle by the

PDH complex is inhibited allosterically by metabolites that
signal a sufficiency of metabolic energy (ATP, acetyl-CoA,
NADH, and fatty acids) and stimulated by metabolites that
indicate a reduced energy supply (AMP, NAD1, CoA)
• The overall rate of the citric acid cycle is controlled by the
rate of conversion of pyruvate to acetyl-CoA and by the flux
through citrate synthase, isocitrate dehydrogenase, and a-
ketoglutarate dehydrogenase.
• These fluxes are largely determined by the concentrations
of substrates and products: the end products ATP and
NADH are inhibitory, and the substrates NAD1 and ADP
are stimulatory.
Glyoxylate cycle
• Vertebrates cannot convert fatty acids, or the acetate derived from them, to carbohydrates.
PEP → pyruvate → acetyl-CoA irreversible reaction.
• If a cell cannot convert acetate into PEP, so acetate cannot serve as the starting material for the gluconeogenic pathway.
• Without this capacity a cell is unable to convert fuels or metabolites that are degraded to acetate (fatty acids and certain
amino acids) into carbohydrates.
Anaplerotic reactions
Oxaloacetate + GTP → PEP + CO2 + GDP
• In many organisms other than vertebrates, the glyoxylate cycle serves as a mechanism for converting acetate to
carbohydrate
Glyoxylate cycle
• In plants, certain invertebrates, and some microorganisms
(including E. coli and yeast) acetate can serve both as an
energy-rich fuel and as a source of PEP for carbohydrate
synthesis. So enzymes of the glyoxylate cycle catalyze the net
conversion of acetate to succinate or other four-carbon
intermediates of the citric acid cycle:
2 Acetyl-CoA + NAD + 2H2O → succinate + 2CoA + NADH + H+
• In plants, the enzymes of the glyoxylate cycle are present in

glyoxysomes, which are specialized peroxisomes.
• Those enzymes common to the citric acid and glyoxylate cycles
have two isozymes, one specific to mitochondria, the other to
glyoxysomes.
In germination seeds, Acetyl-CoA formed from lipid breakdown is converted to Relationship
succinate via the glyoxylate cycle, and the succinate is exported to between the
mitochondria, where citric acid cycle enzymes transform it to malate. glyoxylate and CAC.
A cytosolic isozyme of malate dehydrogenase oxidizes malate to oxaloacetate,
a precursor for gluconeogenesis.
Germinating seeds can therefore convert the carbon of stored lipids into
glucose.
The oxaloacetate from the CAC (in the mitochondrion) is carried to the
glyoxysome in the form of aspartate. Aspartate is converted to oxaloacetate,
which condenses with acetyl-CoA derived from fatty acid breakdown.
Four different pathways participate in these conversions:

1. fatty acid breakdown to acetyl-CoA (in glyoxysomes),
2. the glyoxylate cycle (in glyoxysomes),
3. the citric acid cycle (in mitochondria),
4. gluconeogenesis (in the cytosol)
Coordinated regulation of glyoxylate and citric acid cycles
Isocitrate dehydrogenase is regulated by covalent modification:

• A specific protein kinase phosphorylates dehydrogenase and
thereby inactivates the dehydrogenase.
• This inactivation shunts isocitrate to the glyoxylate cycle, where it
begins the synthetic route toward glucose.
• A phosphoprotein phosphatase removes the phosphoryl group
from isocitrate dehydrogenase, reactivating the enzyme
and sending more isocitrate through the energy-yielding
CAC. The regulatory protein kinase and phosphoprotein
phosphatase are separate enzymatic activities of a single
polypeptide.

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Citric Acid Cycle (tricarboxylic acid (TCA) cycle or the Krebs cycle (after its discoverer, Hans Krebs)

• Respiration refers to a multicellular organism’s uptake of O2 and release of CO2.

• Three fate of pyruvate: 1. enter in CAC as acetyl-CoA for fuel,

Five Coenzymes (Prosthetic group)

Dehydrogenation to give reduced

• The citric acid cycle is an amphibolic pathway, which

• The production of acetyl-CoA for the citric acid cycle by the

2 Acetyl-CoA + NAD + 2H2O → succinate + 2CoA + NADH + H+

• In plants, the enzymes of the glyoxylate cycle are present in

Four different pathways participate in these conversions:

Isocitrate dehydrogenase is regulated by covalent modification:

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