Transcript An Overview of the Citric Acid Cycle

Roundabouts, or traffic circles, function as hubs to facilitate traffic flow. The citric acid
cycle is the biochemical hub of the cell, oxidizing carbon fuels, usually in the form of acetyl
CoA, as well as serving as a source of precursors for biosynthesis. [(Above) Chris
Warren/International Stock.]
The Citric Acid Cycle:
Tricarboxylic Acid Cycle
Dr. M. Zeeshan Hyder
Chapter 17
Biochemistry, Lubert Stryer, 5th Edition
An Overview of the Citric Acid Cycle
The citric acid cycle is the central metabolic hub of the cell.
It is the gateway to the aerobic metabolism of any molecule that can be
transformed into an
acetyl group or
dicarboxylic acid.
The cycle is also an important source of precursors for:
the storage forms of fuels
the building blocks of many other molecules
amino acids,
nucleotide bases
cholesterol, and porphyrin (the organic component of heme).
An Overview of the Citric Acid Cycle
The glycolysis produces pyruvate in the end
Pyruvate has many fates depending upon the
cellular conditions i.e.
Ethanol Fermentation
Lactate production
gluconeogenesis
The pyruvate is shuttled into mitochondria by an
antiporter which transport pyruvate in exchange of
an OH- group
Inside the mitochondria pyruvate is oxidatively
decaroboxylated into Acetyl CoA by pyruvate
dehydrogenase complex
Acetyl Co A enters into the TCA cycle and produces
NADH, FADH and GTP
An Overview of the Citric Acid Cycle
The NADH and FADH2 produced during the TCA cycle are then utilized
through electron transport chain to harvest energy.
The energy generated by TCA cycle in association with ETC provides most of
the energy.
The TCA cycle is strictly aerobic process as NAD+ and FAD+ need to be
regenerated through ETC to carry on this process
The function of the citric acid cycle is the harvesting of high energy
electron from carbon fuels
The Citric Acid Cycle Oxidizes
Two-Carbon Units
The entry point into TCA is Acetyl CoA which is the fuel of this cycle.
Acetyle CoA comes from:
Glycolysis through pyruvate
Breakdown of glycogen
Fats
Many amio acids
Oxidative Decarboxylation of pyruvate for form Acetyl CoA by pyruvate dehydrogenase
complex is the link between Glycolysis and TCA
Pyruvate Dehydrogenase Complex is a multienzyme complex each composed of several
polypeptide chains, and five coenzymes: thiamine pyrophosphate (TPP), lipoic acid, and
FAD serve as catalytic cofactors
pyruvate dehydrogenase component (E1), (decarboxylation activity)
Dihydrolipoyl transacetylase (E2) (transfer the acetyl group from acetyllipoamide
to CoA to form acetyl CoA).
dihydrolipoyl dehydrogenase (E3) (Regenerate the the oxidized form of lipoamide).
The activity of Pyruvate Dehydrogenase Complex is regulated to control the TCA cycle.
Stoichiometry of the Citric Acid Cycle
1. Two carbon atoms enter the cycle in the condensation of an acetyl unit
(from acetyl CoA) with oxaloacetate. Two carbon atoms leave the cycle in the
form of CO2 in the successive decarboxylations catalyzed by isocitrate
dehydrogenase and a-ketoglutarate dehydrogenase.
2. Four pairs of hydrogen atoms leave the cycle in four oxidation reactions.
Two molecules of NAD+ are reduced in the oxidative decarboxylations of
isocitrate and a -ketoglutarate, one molecule of FAD is reduced in the oxidation
of succinate, and one molecule of NAD+ is reduced in the oxidation of malate.
3. One compound with high phosphoryl transfer potential, usually GTP, is
generated from the cleavage of the thioester linkage in succinyl CoA.
4. Two molecules of water are consumed: one in the synthesis of citrate by the
hydrolysis of citryl CoA and the other in the hydration of fumarate.
Recall also that NADH is generated in the formation of acetyl CoA from
pyruvate by the pyruvate dehydrogenase reaction.
Entry to the Citric Acid Cycle and
Metabolism Through It Are
Controlled
The TCA cycle is the final common pathway for the aerobic
oxidation of fuels molecules
TCA is also a good source of building blocks and
intermediate metabolites
Therefore TCA is rigorously regulated for its:
Entry point
For its pace
The pyruvate Dehydrogenase Complex is Regulated
Allosterically and by Reversible Phosphorylation
The formation of Acetyl Co A from pyruvate is an
irreversible step in animals and commits it to two principal
fates:
Oxidation to CO2 by TCA cycle
Incorporation into lipids
The activity of this enzyme complex is stringently
controlled
It is allosterically inhibited by its own products
NADH (inhibit dihydrolipoyl dehydrogenease E3)
Acetyl Co A (Inhibit transacetylase component E2)
The enzyme complex is regulated by reversible
phosphorylation by specific kinase and phosphatase which
regulate pyruvate dehydrogenase component E1
Kinase (adds phosphate group and inhibit the activity)
Phosphatase (removes phosphate group and activate
the enzyme)
Activity is inhibited by increase in:
NADH,
Acetyl Co A
ATP
While activity is stimulated by:
Pyruvate
ADP
The pyruvate dehydrogenase is switched off when the energy
charge is high and biosynthetic intermediates are abundant.
The Citric Acid Cycle is Controlled at
Several Points
The rate of citric acid cycle is precisely
adjusted to meet an anime cells need for
ATP
The primary allostertic control points are :
Isocitrate Dehydrogenase
Activated by ADP
ATP and NADH inhibits it
α-ketoglutarate Dehydrogenase
Inhibited by succinyl Co A, NADH
and ATP
The Citric Acid Cycle Is a Source of
Biosynthetic Precursors
Although TCA is primarily provides ATP for energy but it also
provides intermediates for biosynthesis
It provides intermediate for synthesis of:
Amino acids
Fatty acids ands sterols
Purines and pyrimidines
Porphyrins, heme and chlorphyll
The Citric Acid Cycle Must Be Capable of Being
Rapidly Replenished
Being producer of intermediatory metabolitesf TCA cycle should be
replenished if
The intermediates are used for biosynthesis
As TCA is a cyclic conversion it can be replenished by the production of any
intermediate theoretically.
In TCA oxaloacetate functions cayalytically
To replenish the TCA oxaloacetate is regenrated from pyruvate by the action
of pyruvate carboxylase; an enzyme involved in gluconeogenesis
The activity of pyruvate carboxylase is stimulated when actyle CoA is
present meaning need for more oxaloacetate
If the energy charge is high, oxaloaccetate is converted into glucose
When energy charge is low, oxaloacetate replensihs the citric acid
cycle
The Glyoxylate Cycle Enables Plants and
Bacteria to Grow on Acetate
Many bacteria and plants are able subsist on acetate or other compounds
to produce acetyl CoA
They utilize another pathway which is absent in most of the organisms
that coverts two-carbon unit acetyl units into four carbon units (succinate)
to produce:
Energy
And biosynteses
The glycolate cycle utilizes:
Two acetyl CoA molecules per cycle
Bypasses the two decarboxylation steps
In plants, these reactions take place in organelles called glyoxysomes
Bacteria and plants can synthesize acetyl CoA from acetate as well utilzing
ATP