Formation of pyruvic acid
(P.A.) in the body :
From oxidation of glucose (glycolysis).
From lactic acid by oxidation.
Deamination of Alanine.
Glucogenic amino acids-pyruvate
forming.
Decarboxylation of oxaloacetic acid
(OAA)
Fate of pyruvic acid (P.A.)
1
-Form
acetyl CoA
by oxidative
decarboxylation (in presence of O
2
).
2
-Forms
lactic acid
by reduction
(in absence of O
2
).
3
-Forms
alanine
by amination.
4
-Forms
glucose
(gluconeogenesis).
5
-Forms
malic acid
→ to O.A.A
(oxaloacetic acid).
6
-Forms
oxaloacetic
acid (O.A.A) by CO
2
-
fixation reaction.
(1)
Before pyruvate can enter the TCA
cycle, it must be transported into
the mitochondria via a special
pyruvate transporter that aids its
passage across the inner
mitochondrial membrane.
Within the mitochondria, pyruvate
is oxidatively decarboxylated to
acetyl-CoA
, this reaction is
catalyzed by sequentially
multienzyme complex
(pyruvate
dehydrogenase complex).
(2)
The citric acid cycle (TCA)
1-
TCA cycle (tricarboxylic acid cycle), also
known as the citric acid cycle or the Krebs
cycle, is the major
energy production
pathways in the body. The cycle occur in the
mitochondria
.
2
-
It is a cyclic process
3
-
The cycle involves a sequence of
compounds inter-related by oxidation
reduction and other reaction which finally
produces CO
2
and H
2
O.
4 -
It is the final common pathway of breakdown or
catabolism of
carbohydrates, fats
and
proteins
.
5
-
Acetyl CoA derived mainly from
oxidation of either glucose or
-oxidation of FA and partly from
certain amino acids.
6
-
By stepwise dehydrogenations and loss
of two molecules of CO
2
, accompanied by
internal re-arrangements, the citric acid is
reconverted to OAA, which again starts
the cycle by taking up another acetyl
group from acetyl-CoA.
7-
All the enzymes of the TCA cycle are in
the mitochondrial matrix, which is in the
inner mitochondrial membrane.
8-
Electrons are transferred by the
cycle to NAD
+
and FAD.
9-
As the electrons subsequently are
passed to O
2
by the electron
transport chain,
ATP
is generated by
the process of
oxidative
phosphorylation.
10-
ATP is also generated from GTP,
produced in one reaction of the cycle
by substrate level phosphorylation.
11
-
The whole process is
aerobic
,
requiring O
2
as the final oxidant of the
reducing equivalents. Absence of O
2
(
anoxia
) or partial deficiency of O
2
(
hypoxia
) causes total or partial
inhibition of the cycle.
12-
The
H atoms
removed in the
successive dehydrogenations are
accepted by corresponding coenzymes.
Reduced coenzymes transfer the
reducing equivalents to electron-transport
system, where oxidative phosphorylation
product
ATP
molecules.
(4)
There are three key enzymes in TCA
cycle:
1-Citrate synthase (1)
2- Isocitrate dehydrogenase(I.C.D) (3)
3- α-ketoglutarate dehydrogenase (4)
Function of the TCA cycle
1-
Provieds for
oxidation of acetyl CoA
to
CO
2
and
water
.
2-
Produces
NADH
and
FADH
lead to
formation of ATP as a result of oxidative
phosphorylation.
3-
Provides for synthetic reactions for
example conversion of amino acids to
glucose.
Biomedical importance of TCA cycle
:
-
Final common pathway for
carbohydrates,
proteins and fats,
through formation of 2 –
carbon unit acetyl-CoA.
- Acetyl-CoA is oxidized to CO
2
and H
2
O giving
out energy
(Catabolic role).
- Intermediates of TCA cycle play a major role
in synthesis also like heme formation,
formation of non essential amino acids, FA
synthesis, cholesterol and steroid synthesis
(
anabolic role).
TCA cycle is called
Amphibolic
in nature
because TCA cycle has dual role catabolic
and anabolic.
Energy produced by the TCA cycle
The net reaction for the oxidation of one acetyl unit is :
Acetyl - CoA + 3NAD
+
+ FAD + GDP + Pi
2CO
2
+ 3NADH + 3H
+
+ FADH
2
+ GTP +
CoA
Energy – producing reaction Number of ATP
produced
3NADH
3NAD
+
3 x 3 = 9
FADH
2
FAD 2 x 1 = 2
GDP + P
i
GTP
1 x 1 = 1
Net gain :
12 ATP
Maximal ATP Production
Overall, when 1 mole of glucose is
oxidized to CO
2
and H
2
O,
approximately(
36
moles
) of ATP are
produced if
the glycerol phosphate
shuttle is used,
or(
38 moles
)s if the
malate aspartate shuttle is used.
Note:
Assuming each high energy bond to
be equivalent to 7600 calories. Total energy
captured in ATP per mol. of glucose oxidized
= 7600× 38 =
2
88,800 calories.
Electron Transport Chain and
Oxidative Phosphorylation
-Electron Transport Chain:
This is the final
common pathway in aerobic cells by which
electrons derived from various substrates
are
transferred to oxygen.
- Electron transport chain(ETC) is a series of
highly organized oxidation-reduction
enzymes . The ETC is localized in the
mitochondria.
- Energy-rich molecules, such as glucose, are
metabolized by a series of oxidation reactions
ultimately yielding
CO
2
and water.
ATP
is generated as a result of the
energy produced when electrons
from
NADH
and
FADH
2
are passed
to molecular oxygen by a series of
electron carriers, collectively
known as the
electron transport
chain
.
The components of the chain include
FMN
(Flavin mononucleotide),
Fe-S
centers,
coenzyme Q
, and a series of
cytochromes
(b, c
1
, c and aa
3
).
The electron transport chain
in the
mitochondrial membrane has been
separated on four (4)
complexes
, their
components as follows:
1- Complex I : NADH – CoQ Reductase.
This system has two functions :
-Electron transfer.
-Acts as a proton pump.
NADH + H
+
+ FMN
FMN.H
2
+ NAD
+
•
2- Complex II : Succinate – CoQ
Reductase.
Flow of electrons from succinate to CoQ
occurs via FADH
2
.
Succinate + CoQ
Fumarate + CoQ.H
2
3- Complex III : CoQ – Cyt.C Reductase.
Function as :
Proton pump, and
Catalyzes transfer of electrons.
Fe
+3
accepts electron and is oxidized to
Fe
+2
The energy change permits
ATP formation
.
Co.Q.H
2
+ 2 Cyt.C (Fe
+3
)
Co.Q + 2 Cyt.C (Fe
+2
) + 2H
+
4
-
Complex IV : Cyt.C oxidase
.
The system functions :
As proton pump.
Catalyzes transfer of electrons from Cyt.C to
molecular O
2
to form H
2
O via Cyt.a, Cu
+2
ions
and Cyt. a
3
.
4Cyt.C (Fe
+2
) + 4H
+
+ O
2
4 Cyt.C (Fe
+3
) + 2H
2
O
The flow of electrons is as follows :
Cyt. C
Cyt. a
Cu
+2
Cyt. a
3
O
2
The energy change permits ATP formation
between Cyt. a
3
and molecular O
2
.
(6)
-
The energy
derived from the transfer of
electrons through the electron transport
chain is used
to pump protons across the
inner mitochondrial membrane
from the
matrix
to the
cytosolic
side.
-
An electrochemical gradient is generated
,
consisting of a proton gradient and a
membrane potential.
-
Protons
moves back into the matrix
through the
ATP synthase complex
, causing
ATP
to be produced from ADP and inorganic
phosphate.
-
ATP
is transported from the mitochondrial
matrix to the cytosol in exchange for ADP
(the
ATP-ADP antiport system
).
(7)
-The oxidation of NADH generates
approximately( 3 ATP), while the
oxidation of one FADH
2
generates
approximately ( 2 ATP).
-Because energy generated by
transfer of electrons through the
electron transport chain to
O
2
is
used in the production of ATP, the
overall process is known as
oxidative phosphorylation.
(8)
Electron transport and ATP
production occur
simultaneously and are tightly
coupled.
-
NADH
and
FADH
2
are oxidized
only if
ADP
is available for
conversion to
ATP
.
(9)
(10)
-
The energy transformation
occurring during oxidative
phosphorylation may be
summarized as follows:
Electron transport
energy
proton gradient
ATP
synthesis
(11)
Clinical correlations :
Cyanide poisoning :
Cyanide binds to
Fe
+3
in
cytochrome
aa
3
.
As a result,
O
2
can not receive electrons,
respiration is inhibited
,
energy production is halted,
and death occurs
rapidly
.
-
Acute myocardial infarction
Coronary arteries frequently become
narrow because of atherosclerotic plaques.
If coronary occlusions occur, regions of
heart muscle may be deprived of blood flow
and, therefore, of oxygen for prolonged
periods of time.
Lack of oxygen causes inhibition of
the processes of electron transport
and oxidative phosphorylation, which
results in
a decreased production of
ATP.
•
Heart muscle
, suffering from a lack
of energy required for contraction and
maintenance of membrane integrity,
becomes
damaged
.
Enzymes from the damaged cells
(including the MB fraction of creatine
kinase)
leak into the blood
.
If the damage is relatively
mild
, the
person may recover. If heart function
is severely compromised, death may
result.