TCA CYCLE

 Forthe production of ATP

through oxidative phosphorylation electro
ns are required so that they can pass
down the electron transport.
 The electrons required for oxidative
phosphorylation come from electro
carries such as NADH and FADH₂ which
are produced from the Tricarboxylic Acid
Cycle (TCA cycle).
 In this article we will discuss the TCA cycle
(also known as Kreb’s cycle).
 TheTCA cycle is a central pathway into
which many metabolites feed. It consists
of a number of reactions which generate
NADH and FADH₂ which can in turn be
used by
 theoxidative phosphorylation pathway to
generate ATP. The TCA cycle occurs in
the matrix of the mitochondria.
Steps of the TCA Cycle
 The TCA cycle takes place over eight
different steps:
 Step 1: First the acetyl CoA (a two carbon
molecule) joins with oxaloacetate (4
carbon molecule) to form citrate (6
carbon molecule).
 Step 2: The citrate is then converted
to isocitrate (isomer of citrate)
 Step 3: Isocitrate is then oxidised to alpha-
ketoglutarate (a five carbon molecule)
which results in the release of carbon
dioxide. One NADH molecule is also
formed in this step.
 The enzyme responsible for catalysing this
step is isocitrate dehydrogenase.
 This is a rate limiting step as isocitrate
dehydrogenase is an allosterically
controlled enzyme.
 Step 4: Here alpha-ketoglutarate is
oxidised to form a 4 carbon molecule
which picks up coenzyme A
forming succinyl CoA. This conversion also
forms a NADH molecule.
 Step 5: Succinyl CoA is then converted
to succinate (4 carbon molecule) and
one GTP molecule is produced.
 Step 6: Succinate is converted
into fumarate (4 carbon molecule) and a
molecule of FADH₂ is produced.
 Step 7: Fumarate is converted
to malate (another 4 carbon molecule).
 Step 8: Malate is then converted
into oxaloacetate and NADH is also
produced here.
 Itis important to be aware that whilst the
primary role of the TCA cycle is
production of NADH and FADH₂ it also
produces molecules that supply
various biosynthetic processes, which can
enter or exit the cycle at various points
depending on the demand on different
reactions.
 For
example, alpha-ketoglutarate can
leave the cycle to be converted into
amino acids or succinate can be
converted to haem.
 Each cycle produces two molecules of
carbon dioxide, three molecules of NADH,
three hydrogen ions, one molecule
of FADH₂ and one molecule of GTP.
 Assuch each molecule of glucose
produces double this
(2 carbon dioxide, 6 NADH, 6 hydrogen io
ns, 2 FADH₂ and 2 GTP).
REGULATION OF TCA CYCLE:
 The
TCA Cycle is regulated in a variety of
ways. As already mentioned isocitrate
dehydrogenase regulates step 3 of the
TCA cycle,
 making it the rate limiting step of the
cycle. In addition to this energy
availability also regulates the cycle – so
low energy signals,
 such as ADP activate the cycle and high
levels of NADH (a product of the cycle)
inhibit it.
CLINICAL IMPORTANCE:
 The most important thing to note is that
there are in fact no known defects of the
TCA cycle that are compatible with life.
This highlights the importance of this step
in ATP production for sustaining life.