CORI'S CYCLE OR LACTIC ACID CYCLE
It is a process in which glucose is converted to lactate in the muscle; and
in the liver this lactate is re-converted into glucose. In an actively
contracting muscle, pyruvate is reduced to lactic acid which may tend to
accumulate in the muscle. The muscle cramps, often associated with
strenuous muscular exercise, are thought to be due to lactate
accumulation. To prevent the lactate accumulation, this lactic acid from
muscle diffuses into the blood. Lactate then reaches liver, where it is
oxidized to pyruvate. Thus, it is channeled to gluconeogenesis.
Regenerated glucose can enter into blood and then to muscle. This cycle
is called Cori's cycle .
Cori's cycle
Tricarboxylic acid cycle (TCA cycle, also called the
Krebs cycle or the citric acid cycle)
It is the final pathway where the oxidative metabolism of carbohydrates,
amino acids, and fatty acids converge, their carbon skeletons being
converted to CO2 and H2O. This oxidation provides energy for the
production of the majority of ATP in most animals, including humans.
The cycle occurs totally in the mitochondria.
Intermediates of the TCA cycle can also be synthesized by the catabolism
of some amino acids. Therefore, this cycle should not be viewed as a
1
closed circle, but instead as a traffic circle with compounds entering and
leaving as required.
Reactions of the citric acid cycle.
Oxidative decarboxylation of pyruvate
Pyruvate, the end-product of aerobic glycolysis, must be transported into
the mitochondrion before it can enter the TCA cycle. This is
accomplished by a specific pyruvate transporter that helps pyruvate cross
the inner mitochondrial membrane. Once in the matrix, pyruvate is
converted to acetyl CoA by the pyruvate dehydrogenase complex, which
is a multienzyme complex. [Note: The irreversibility of the reaction
precludes the formation of pyruvate from acetyl CoA, and explains why
2
glucose cannot be formed from acetyl CoA via gluconeogenesis.] Strictly
speaking, the pyruvate dehydrogenase complex is not part of the TCA
cycle proper, but is a major source of acetyl CoA— the two-carbon
substrate for the cycle
The Pyruvate Dehydrogenase Complex Requires Five Coenzymes—
thiamine pyrophosphate (TPP), flavin adenine dinucleotide (FAD),
coenzyme A (CoA, sometimes denoted CoA-SH), nicotinamide adenine
dinucleotide (NAD), and lipoate. Four different vitamins required in
human nutrition are vital components of this system: thiamine (in TPP),
riboflavin (in FAD), niacin (in NAD), and pantothenate (in CoA).
Clinical application:
Pyruvate dehydrogenase deficiency: A deficiency in the pyruvate
dehydrogenase complex is the most common biochemical cause of
congenital lactic acidosis. This enzyme deficiency results in an inability
to convert pyruvate to acetyl CoA, causing pyruvate to be shunted to
lactic acid via lactate dehydrogenase .This causes particular problems for
the brain, which relies on the TCA cycle for most of its energy, and is
particularly sensitive to acidosis.
1. Condensation (Synthesis of citrate from acetyl CoA and
oxaloacetate )
The condensation of acetyl CoA and oxaloacetate to form citrate is
catalyzed by citrate synthase.
2 +
Citrate synthase is allosterically activated by Ca
and ADP, and
inhibited by ATP, NADH, succinyl CoA, and fatty acyl CoA derivatives
However, the primary mode of regulation is also determined by the
availability of its substrates, acetyl CoA and oxaloacetate. [Note: Citrate,
in addition to being an intermediate in the TCA cycle, provides a source
of acetyl CoA for the cytosolic synthesis of fatty acids. Citrate also
inhibits phosphofructokinase (PFK), the rate-limiting enzyme of
3
glycolysis, and activates acetyl CoA carboxylase (the rate-limiting
enzyme of fatty acid synthesis)
2. Isomerization of citrate
Citrate is isomerized to isocitrate by aconitase
3. Oxidation and decarboxylation of isocitrate
Isocitrate dehydrogenase catalyzes the
decarboxylation of isocitrate, yielding the
molecules produced by the cycle, and the first
one of the rate-limiting steps of the TCA
irreversible oxidative
first of three NADH
release of CO2. This is
cycle. The enzyme is
++
allosterically activated by ADP (a low-energy signal) and Ca , and is
inhibited by ATP and NADH, whose levels are elevated when the cell
has abundant energy stores.
4. Oxidative decarboxylation of α-ketoglutarate
The conversion of α-ketoglutarate to succinyl CoA is catalyzed by the
α-ketoglutarate dehydrogenase complex. The mechanism of this
oxidative decarboxylation is very similar to that used for the
conversion of pyruvate to acetyl CoA. The reaction releases the
4
second CO2 and produces the second NADH of the cycle. The
coenzymes required are thiamine pyrophosphate, lipoic acid, FAD,
NAD+, and coenzyme A. The equilibrium of the reaction is far in the
direction of succinyl CoA—a high-energy thioester similar to acetyl
CoA. a-Ketoglutarate dehydrogenase complex is inhibited by ATP,
.
GTP, NADH, and succinyl CoA, and activated by Ca++.
5. Cleavage of succinyl CoA
Succinate thiokinase (also called succinyl CoA synthetase) cleaves the
high-energy thioester bond of succinyl CoA. This reaction is coupled
to phosphorylation of GDP to GTP. GTP and ATP are energetically
interconvertible by the nucleoside diphosphate kinase reaction .The
generation of GTP by succinate thiokinase is another example of
substrate-level phosphorylation.
6. Oxidation of succinate
Succinate is oxidized to fumarate by succinate dehydrogenase, producing
the reduced coenzyme FADH .Succinate dehydrogenase is inhibited by
oxaloacetate.
5
7. Hydration of fumarate
Fumarate is hydrated to malate in a freely reversible reaction catalyzed
by fumarase (also called fumarate hydratase).
8. Oxidation of malate
Malate is oxidized to oxaloacetate by malate dehydrogenase. This
reaction produces the third and final NADH of the cycle.
REGULATION OF THE TCA CYCLE
A. Regulation by activation and inhibition of enzyme activities
TCA cycle is controlled by the regulation of several enzyme activities .
The most important of these regulated enzymes are citrate synthase,
isocitrate dehydrogenase, and ketoglutarate dehydrogenase complex.
B. Regulation by the availability of ADP
1. Effects of elevated ADP: Energy consumption as a result of
muscular contraction, biosynthetic reactions, or other processes
results in the hydrolysis of ATP to ADP and the resulting increase in
the concentration of ADP accelerates the rate of reactions that use
ADP to generate ATP, most important of which is oxidative
phosphorylation . Production of ATP increases until it matches the
rate of ATP consumption by energy-requiring reactions.
6
2. Effects of low ADP:
ADP (or Pi) is present in limiting concentration, the formation of
ATP by oxidative phosphorylation decreases as a result of the lack of
phosphate acceptor (ADP) or inorganic phosphate.
The rate of oxidative phosphorylation is proportional to
[ADP][Pi]/[ATP]; this is known as respiratory control of energy
production. The oxidation of NADH and FADH2 by the electron transport
chain also stops if ADP is limiting. This is because the processes of
oxidation and phosphorylation are tightly coupled and occur
simultaneously .As NADH and FADH2 accumulate, their oxidized forms
become depleted, causing the oxidation of acetyl CoA by the TCA cycle
to be inhibited as a result of a lack of oxidized coenzymes.
AMPHIBOLIC PATHWAY
All other pathways such as beta oxidation of fat or glycogen synthesis are
either catabolic or anabolic. But TCA cycle is truly amphibolic (both
catabolic and anabolic) in nature. Citric Acid Cycle components are
important biosynthetic intermediates in aerobic organisms; the citric acid
cycle is an amphibolic pathway, one that serves in both catabolic and
anabolic processes. Besides its role in the oxidative catabolism of
carbohydrates, fatty acids, and amino acids, the cycle provides precursors
for many biosynthetic pathways, Ketoglutarate and oxaloacetate can, for
example, serve as precursors of the amino acids aspartate and glutamate
by simple transamination .Through aspartate and glutamate, the carbons
of oxaloacetate and -ketoglutarate are then used to build other amino
acids, as well as purine and pyrimidine nucleotides. Oxaloacetate is
converted to glucose in gluconeogenesis. SuccinylCoA is a central
intermediate in the synthesis of the porphyrin ring of heme groups, which
serve as oxygen carriers (in hemoglobin and myoglobin) and electron
carriers (in cytochromes).
7
Amphibolic pathway of the citric acid cycle
Influx of TCA cycle intermediates
8
Efflux of TCA cycle intermediates
Anaplerotic Reactions
Anaplerotic Reactions replenish Citric Acid Cycle Intermediates as
intermediates of the citric acid cycle are removed to serve as biosynthetic
precursors; they are replenished by anaplerotic reactions. Under normal
circumstances, the reactions by which cycle intermediates are siphoned
off into other pathways and those by which they are replenished are in
dynamic balance, so that the concentrations of the citric acid cycle
intermediates remain almost constant.
Anaplerotic Reactions are:
9