The Citric Acid Cycle:Tricarboxylic 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.]

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 endPyruvate has many fates depending upon the cellular conditions i.e.

Ethanol FermentationLactate productiongluconeogenesis

The pyruvate is shuttled into mitochondria by an antiporter which transport pyruvate in exchange of an OH- groupInside the mitochondria pyruvate is oxidatively decaroboxylated into Acetyl CoA by pyruvate dehydrogenase complexAcetyl Co A enters into the TCA cycle and produces NADH, FADH and GTP

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

UnitsThe entry point into TCA is Acetyl CoA which is the fuel of this cycle.

Acetyle CoA comes from:Glycolysis through pyruvateBreakdown of glycogenFatsMany 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 ControlledThe 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 cycleIncorporation into lipids

The activity of this enzyme complex is stringently controlledIt 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

PrecursorsAlthough TCA is primarily provides ATP for energy but it also provides intermediates for biosynthesis

It provides intermediate for synthesis of:Amino acidsFatty acids ands sterolsPurines and pyrimidinesPorphyrins, heme and chlorphyll

The Citric Acid Cycle Must Be Capable of Being Rapidly

ReplenishedBeing 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

AcetateMany bacteria and plants are able subsist on acetate or other compounds to produce acetyl CoAThey 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:

EnergyAnd biosynteses

The glycolate cycle utilizes:Two acetyl CoA molecules per cycleBypasses the two decarboxylation steps

In plants, these reactions take place in organelles called glyoxysomesBacteria and plants can synthesize acetyl CoA from acetate as well utilzing ATP