TCA CYCLE

 The citric acid cycle (CAC) – also known as the tricarboxylic acid (TCA) cycle or
the Krebs cycle– is a series of chemical reactions used by all aerobic organisms to
release stored energy through the oxidation of Co derived from carbohydrates, fats,
and proteins into carbon dioxide and chemical energy in the form of adenosine
triphosphate (ATP).
 In addition, the cycle provides precursors of certain amino acids, as well as
the reducing agent NADH that are used in numerous other biochemical reactions.

An Overview of TCA cycle:

 The Citric Acid Cycle is a series of eight chemical reactions utilized by all aerobic
organisms to generate energy. The pathway uses acetyl CoA and oxaloacetate to
produce carbon dioxide, ATP, NADH, and FADH2.
 The citric acid cycle is one of the metabolic pathways involved in aerobic
respiration, an important process that produces energy for cells.
 The citric acid cycle takes place in the matrix, or inner fluid of the mitochondrion.
 The NADH and FADH2 are electron carriers that can be used by the electron
transport chain (ETC).
 In the first step of the citric acid cycle, acetyl CoA (a two-carbon molecule)
and oxaloacetate (a four-carbon molecule) are combined to form citrate (a six-
carbon molecule).
 The citrate molecule then undergoes multiple biochemical changes during
which two molecules of carbon dioxide are created before it is converted back to
oxaloacetate.
 However, before the citric acid cycle can begin, acetyl CoA must be produced. Acetyl
CoA is created from pyruvate (the end product of glycolysis) during pyruvate
oxidation.
 Pyruvate oxidation results in one molecule of acetyl CoA, one molecule of carbon
dioxide, and one molecule of NADH.
 During the first step of the citric acid cycle, the acetyl group from acetyl CoA is
transfered to oxaloacetate to form citrate.
 Citrate then undergoes four more reactions to form succinate, along with producing
two molecules of carbon dioxide, two molecules of NADH, and one ATP.
 Succinate goes through three more reactions before finally being converted back
to oxaloacetate. These reactions also produce one FADH2 molecule and one NADH.
 In Cytosol

In Mitochondria

Figure: An overview of TCA cycle

Reactions of TCA cycle:
The amphibolic nature of Citric acid cycle:
 TCA cycle is both catabolic & anabolic in nature, called as amphibolic.
 Since various compounds enter into or leave from TCA cycle, it is sometimes called
as metabolic traffic circle.
 This pathway is utilized for the both catabolic reactions to generate energy as well as
for anabolic reactions to generate metabolic intermediates for biosynthesis.
 If the CAC intermediate are used for synthetic reactions, they are replenished by
anaplerotic reactions in the cells.

Important anabolic reactions of TCA cycle are-

 Oxaloacetate is precursor for aspartate.
 α-ketoglutarate can be transaminated to glutamate.
 Succinyl CoA is used for synthesis of heme.
 Mitochondrial citrate is transported to cytoplasm & it is cleaved into acetyl CoA to
provide substrate for fatty acid synthesis.

Anaplerosis or anaplerotic reactions

 The reactions concerned to replenish or to fill up the intermediates of citric acid cycle
are called anaplerotic reactions or Anaplerosis
 Pyruvate carboxylase catalyses conversion of pyruvate to oxaloacetate.
 This is an ATP dependent carboxylation reaction.

Pyruvate+CO2+ATP Oxaloacetate + ADP + Pi

 Pyruvate is converted to malate by NADP+ dependent malate dehydrogenase (malic
enzyme).

Pyruvate + CO2 + NADPH + H+ malate + NADPH + H2O

 α- ketoglutarate can also be synthesized from glutamate by glutamate dehydrogenase.

Glutamate + NAD(P) + H2O α- ketoglutarate +NAD(P)H + H+ + NH4+

Regulation of CAC:
Rate controlling enzymes:
 Citrate synthase: Citrate synthase is inhibited by ATP, NADH, acetyl CoA & succinyl
CoA.
 Isocitrate dehydrogenase: Isocitrate dehydrogenase is activated by ADP & inhibited
by ATP and NADH.
 α‐ketoglutarate dehydrogenase: α-ketoglutarate dehydrogenase is inhibited by
succinyl CoA & NADH.
Regulation of activity by:
 Substrate availability: Availability of ADP is very important for TCA cycle to
proceed.
 Product inhibition:
 Aconitase is inhibited by fluoro-acetate.
- This is a non-competitive inhibition.
 Alpha ketoglutarate is inhibited by Arsenite.
- This is also a non-competitive.
 Succinate dehydrogenase is inhibited by malonate.
- This is competitive inhibition.
 Allosteric inhibition or activation by other intermediates