is the primary site of the
oxidation of carbon atoms derived from food.
called the "final common
pathway" because all carbon atoms
from food are oxidized here.
OVERVIEW OF THE KREBS CYCLE:
AKA tricarboxylic acid cycle, citric acid cycle.
Major function is the oxidation of carbon atoms.
All reactions of the Krebs cycle
Acetyl CoA + 3NAD+ + FAD + GDP + Pi +H2O
2CO2 + 3 NADH +
+ CoA-SH + GTP
CoA is made from pyruvate by
REACTIONS OF THE KREBS CYCLE
1) Formation of citrate:
CoA + à
Oxaloacetate (OAA) CoA-SH
Catalyzed by: Citrate synthase
The hydrolysis of the thiolester
releases energy used to form citrate.
Citrate is a tri-carboxylic acid,
‘tricarboxylic acid cycle’ (TCA Cycle).
Being the first enzyme in
synthase is a major regulatory enzyme
Both reactions catalyzed by: Aconitase
Isocitrate + NAD+ àα-keto glutarate +
CO2 + NADH + H+
Catalyzed by: Isocitrate dehydrogenase (dh).
a major regulatory enzyme
4) Formation of thiolester:
Glutarate + à
Succinyl-CoA + CO2
CoA-SH + NAD+ NADH + H+
Catalyzed by: α-Keto Glutarate Dehydrogenase
This reaction is analogous to the
It has the same three parts.
It has the same five cofactors.
This is the third important
the Krebs cycle (more later).
5) Formation of GTP:
Succinate + GTP +
GDP + Pi CoA-SH
Catalyzed by Succinic Thiokinase
The hydrolysis of the thiolester
CoA yields the energy needed to produce GTP:
This is another
of substrate level
6) FAD-linked oxidation of succinate:
Succinate + FAD à Fumarate + FADH2
Catalyzed by: Succinic Dehydrogenase
This enzyme is bound to the inner
mitochondrial membrane, and is
actually part of the electron
transport system (ETS).
Thus, the electrons on the FADH2
can enter the ETS directly, and
their energy can be used
to produce ATP.
This is a fourth regulatory step in the
Krebs cycle (more later).
Fumarate + H2O à Malate
Catalyzed by: Fumarase
8) NAD+-linked oxidation of malate:
NADH + H+
Catalyzed by: Malate dehydrogenase.
This reaction forms oxaloacetate (OAA),
one of the precursors, so this
pathway is a cycle!
INPUT/OUTPUT RELATIONSHIPS OF THE
Acetyl CoA 2 CO2
3 NAD+ 3 NADH + 3 H+
1 FAD 1 FADH2
GDP + Pi GTP
Note: No ATP is produced in the
However, Using the nucleotide kinase
the GTP can be used to produce ATP:
GTP + ADP ßà ATP + GDP
REGULATION OF THE KREBS CYCLE
regulated by the cell’s need for
both Energy and Carbon.
by the availability of oxygen
There are four regulatory steps in the cycle:
Inhibited by citrate, succinyl-CoA, NADH, ATP.
Activated by ADP.
Inhibited by ATP and NADH
Activated by ADP,
NAD+, and calcium ions
(signal for muscle contraction).
α-keto Glutarate dehydrogenase:
Inhibited by NADH,
Succinyl CoA, ATP,
Activated by calcium ions.
Inhibited by OAA.
Activated by Succinate, ADP, and Pi.
The Krebs cycle and Glycolysis
tandem, so that under most conditions, only as
much pyruvate and acetyl CoA are produced
from glycolysis as are needed to supply
the Krebs cycle.
This is accomplished by the
of PFK by ATP and NADH, which are signals
of the energy supply, and by feedback inhibition
by citrate, which is a signal of the substrate needs.
AMPHIBOLIC NATURE OF THE TCA CYCLE
The Krebs cycle has both
functions, and therefore is amphibolic.
Acetyl CoA and other inter-
mediates derived from other pathways:
α-Keto Glutarate, Succinyl CoA, OAA.
Formation of high energy intermediates:
NADH + H+, FADH2, and GTP.
cycle intermediates to make
Citrate: part of fatty acid synthesis pathway.
OAA: part of gluconeogenesis and
amino acid synthesis.
α-KG: part of amino acid synthesis.
Succinyl CoA: part of heme and
ANAPLEROTIC REACTIONS OF TCA CYCLE
Due to the amphibolic nature of
sometimes the supply of intermediates can
Remember than when we add 2
as Acetyl CoA, 2 carbons come out as
CO2, and thus we can’t add to the carbon
pool of the Krebs cycle with Acetyl CoA.
A corollary to this is that we
glucose from Acetyl-groups.
There are three reactions that
to the Krebs cycle:
(‘anaplerotic’ means ‘to fill up’)
1. Pyruvate carboxylase (liver and kidney):
Pyruvate + CO2 + ATP ßà
OAA + ADP + Pi
This enzyme is allosterically
Thus, when the supply of Acetyl
high, more OAA is made so that it can
enter the cycle(this will be important later).
As with most carboxylases, this
requires biotin as a cofactor.
(heart and skeletal muscle):
PEP + CO2 + GDP ßà OAA + GTP
3. Malic enzyme (widely
Pyruvate + NADPH + H+ ßà
Malate + NADP+