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Krebs’ Cycle Intermediates
by Ward Dean, MD and Jim English
Production and management of sustainable biological energy resources
is of vital concern for everyone. Disruptions in the normal production
of mitochondrial energy can contribute to a wide range of metabolic
disturbances and symptoms, including fatigue, immune system dysfunction,
dementia, depression, behavioral disturbances, attention deficiency,
muscle weakness and pain, angina, heart disease, diabetes, skin
rashes, and hair loss. These symptoms of metabolic impairment are
also present in persons suffering from acquired diseases, such as
Alzheimer’s disease and Chronic Fatigue Syndrome (CFS), and
in those with inherited mitochondrial diseases, such as mitochondrial
myopathy.
As these conditions share a common link in mechanisms
of metabolic energy production, they may also benefit from nutritional
strategies that optimize energy production and metabolic pathways.
All cells must produce energy to survive. Hans A. Krebs first elucidated
the process of cells converting food into energy, the Citric Acid
Cycle, in 1937. Krebs proposed a specific metabolic pathway within
the cells to account for the oxidation of the basic components of
food — carbohydrates, protein and fats — for energy.
The Krebs’ cycle takes place inside the mitochondria or 'power
plant' of cells and provides energy required for the organism to
function.
Mitochondria are found in all cells in the human
body, with the exception of mature red blood cells. The primary
function of these tiny organelles (each cell contains between 500
and 2,000 mitochondria) is to convert energy found in nutrient molecules
and store it in the form of adenosine triphosphate (ATP). ATP is
the universal energy-yielding molecule used by enzymes to perform
a wide range of cellular functions. Humans cannot survive, even
for a second, without a constant supply of ATP.
In order to carry out energy conversion, mitochondria
require oxygen. The purpose of our respiratory and circulatory systems
is to deliver oxygen to the tissues for use by mitochondria, and
to eliminate carbon dioxide. The consumption of oxygen by mitochondria
is called cellular respiration.
In simple terms, the Krebs’ cycle metabolizes
acetyl coenzyme A into citric acid and then runs through a complex
series of biological oxidations, producing free hydrogen ions. A
net of two molecules of ATP is created at this stage in the Krebs’
cycle. The hydrogen ions then enter a biochemical chain, known as
oxidative phosphorylation, which is a highly efficient aerobic energy
generator. Oxidative phosphorylation generates 36 molecules of ATP
during a sequence of steps that combine hydrogen electrons to molecular
oxygen to form water. Therefore, each molecule of citric acid that
rotates through the Krebs’ cycle, generates 38 molecules of
ATP for tissue fuel.1
There are different points where metabolites enter
the Krebs’ cycle. Most of the products of protein, carbohydrates
and fat metabolism are reduced to the molecule acetyl coenzyme A
that enters the Krebs’ cycle. Glucose, the primary fuel in
the body, is first metabolized into pyruvic acid and then into acetyl
coenzyme A. The breakdown of the glucose molecule forms two molecules
of ATP for energy in the Embden Meyerhof pathway process of glycolysis.
On the other hand, amino acids and some chained fatty acids can
be metabolized into Krebs intermediates and enter the cycle at several
points.
When oxygen is unavailable or the Krebs’
cycle is inhibited, the body shifts its energy production from the
Krebs’ cycle to the Embden Meyerhof pathway of glycolysis,
a very inefficient way of making energy.
As well as producing far less energy, glycolysis
also produces lactic acid as a byproduct. Increased lactic acid
is a common acidotic condition that can be caused by a variety of
metabolic problems. Accumulation of lactic acid in muscle tissue
produces the pain and inflammation we experience after exercising.
While untrained individuals have a low lactate threshold, highly
trained, elite athletes are extremely efficient at converting lactate
to glucose and therefore have lower lactate levels. 2, 3
Step 1 The acetic acid subunit
of acetyl CoA is combined with oxaloacetate to form a molecule of
citrate. Acetyl coenzyme A acts only as a transporter of acetic
acid from one enzyme to another. After Step 1, the coenzyme is released
by hydrolysis to combine with another acetic acid molecule and begin
the Krebs’ Cycle again.
Step 2 The citric acid molecule
undergoes an isomerization. A hydroxyl group and a hydrogen molecule
are removed from the citrate structure in the form of water. The
two carbons form a double bond until the water molecule is added
back. Only now, the hydroxyl group and hydrogen molecule are reversed
with respect to the original structure of the citrate molecule.
Thus, isocitrate is formed.
Step 3 The isocitrate molecule
is oxidized by a NAD molecule. The NAD molecule is then reduced
by the hydrogen atom and the hydroxyl group. The NAD binds with
a hydrogen atom and carries off the other hydrogen atom leaving
a carbonyl group. This structure is very unstable, so a molecule
of CO2 is released, creating alpha-ketoglutarate.
Step 4 In this step, coenzyme
A, returns to oxidize alpha-ketoglutarate. A molecule of NAD is
reduced again to form NADH and leaves with another hydrogen. This
instability causes a carbonyl group to be released as carbon dioxide
and a thioester bond is formed in its place between the former alpha-ketoglutarate
and coenzyme A to create a molecule of succinyl-coenzyme A complex.
Step 5 A water molecule sheds
its hydrogen atoms to coenzyme A. Then, a free-floating phosphate
group displaces coenzyme A and forms a bond with the succinyl complex.
The phosphate is then transferred to a molecule of ADP to produce
an energy molecule of ATP. It leaves behind a molecule of succinate.
Step 6 In this step, succinate
is oxidized by a molecule of FAD (Flavin Adenine Dinucleotide).
The FAD removes two hydrogen atoms from the succinate and forms
a double bond between the two carbon atoms to create fumarate.
Step 7 An enzyme adds water to
the fumarate molecule to form malate. The malate is created by adding
one hydrogen atom to a carbon atom and then adding a hydroxyl group
to a carbon next to a terminal carbonyl group.
Step 8 In this final step, the
malate molecule is oxidized by a NAD molecule. The carbon that carried
the hydroxyl group is now converted into a carbonyl group. The end
product is oxaloacetate which can then combine with acetyl-coenzyme
A and begin the Krebs’ Cycle all over again.
Amino acids can be converted via the Krebs’ cycle to glucose
for energy or for storage as glycogen and fat. During times of increased
stress due to trauma, exercise, starvation and disease states, amino
acids can be catabolized into intermediates to produce energy for
muscular contraction. This is why taking free form amino acids can
boost energy levels and help to prevent hypoglycemia. Additionally,
low levels of particular Krebs’ cycle factors may diminish
amino acid availability and require supplementation to generate
energy and correct metabolic dysfunction.4-6
Under normal conditions all the reactions in the Krebs’ cycle
proceed smoothly and ATP is generated without the excessive production
of any harmful byproducts. However, different conditions can alter
Krebs’ cycle chemistry, causing it to shut down normal energy
production. For example, ifcatabolic pathwayssuch as stress, illness,
or the synthesis of amino acids consume vital intermediary substances,
then the Krebs’ cycle can come to a grinding halt. Interconversions
of Krebs’ cycle intermediates are controlled by enzymes that
often require vitamin-derived cofactors and minerals to operate.
For example, pyruvate is the anaerobic breakdown product of glucose.
Its further conversion to acetyl-CoA requires cofactors derived
from thiamin, riboflavin, niacin, lipoic acid, and pantothenic acid.
When these nutrients are deficient, problems result that disrupt
mitochondrial energy production.7
In some individuals, a deficiency in the enzyme
activity of the Krebs’ cycle may occur when Krebs’ cycle
enzymes are bound up by various xenobiotics or endotoxins. The inability
of pyruvic acid to enter into the cycle for energy production can
shut down the second half of the Krebs’ cycle and create a
lactic acid buildup. With increased acidification comes a localized
decrease in oxygenation of the tissues, leading to muscle fatigue
and other characteristic symptoms.
Researchers have concluded that prolonged exercise
to fatigue results in carbohydrate and glycogen depletion that reduces
levels of three-carbon compounds from glycolysis. This produces
an energy deficiency as the Krebs’ cycle shuts down and lowers
aerobic capacity. 8
A deficiency in one or more Krebs’ cycle intermediates and
an inhibition of normal energy production may cause a wide range
of metabolic disturbances and symptoms. A deficiency of malic acid
and fumaric acid is linked to chronic fatigue and psoriasis. Disturbances
in mitochondrial energy production contribute to a variety of neurological
and physical problems. Impaired oxidative and energy metabolism
are indicators of Alzheimer’s disease. These disturbances
of energy production can create abnormal spilling of Krebs’
cycle byproducts into the urine. 9-13
Chronic Fatigue Syndrome (CFS) represents a condition
of debilitating fatigue. Some neurological symptoms of CFS are poor
attention, memory loss, lack of concentration and depression. An
underlying cause of CFS may be an impairment in the production of
mitochondrial adenosine triphosphate (ATP), the fundamental cellular
energy source. Studies have found that CFS patients have elevated
blood levels of lactate, indicating suboptimal aerobic ATP production
that can lead to fatigue and muscle aches.
Studies have shown administering specific Krebs’
cycle amino acid precursors and intermediates to stimulate energy
production significantly reduce symptoms of CFS. Therefore supplying
a complete range of Krebs’ cycle factors and lactic acid-buffering
agents may be of great benefit to the sufferers of CFS. 14, 15
Intense exercise involves an anaerobic component that can lead to
a significant reduction of ATP, a buildup of lactic acid, and an
increase in tissue acidity. Acidity can normally be buffered by
the body, but high levels of physical stress can rapidly produce
large quantities of lactic acid and overwhelm the body. The resulting
excess acidity may lead to premature muscle fatigue.47 A buildup
of lactic acid occurs whenever inadequate supplies of oxygen create
a hypoxic condition, preventing the complete aerobic metabolism
of glucose. As a result, ATP cannot be generated in adequate amounts,
causing skeletal muscles to weaken, become fatigued and less efficient
at contracting.
In addition, the accumulation of large amounts
of metabolic anaerobic byproducts can lower intracellular pH, inhibit
muscle contraction, and may cause acidosis. The accumulation of
metabolic byproducts, like hydrogen ions, interferes with muscle
contractions and ATP energy release. Metabolic fatigue from exercise
occurs when the muscle’s need for ATP has outstripped production
capacity. Chronic acidosis in muscle tissue causes a negative nitrogen
balance and loss of muscle protein. 16-23, 48-54
There are several ways to counteract metabolic fatigue. One approach
is to increase the production of ATP by eating correctly and taking
supplements that stimulate the pathways that make ATP. There are
three pathways used by the body to produce energy: (1) the immediate
energy-producing ATP-PC system; (2) the short-term anaerobic energy
system of glycolysis; and (3) the long-term aerobic energy system
of oxygen. Creatine supplements stimulate the ATP-PC system. The
Krebs’ cycle factors, their precursor amino acids and food
metabolites enhance glycolysis and aerobic energy production.
An entirely different way to relieve fatigue is by buffering hydrogen
ions and lactic acid. Buffers can prevent intracellular acidosis
from producing fatigue and muscle breakdown. The intracellular
buffers that have been shown to improve buffering capacity and
enhance sports
performance are phosphates, carnosine and bicarbonates. While bicarbonate
is the main blood buffer, it plays a minor role in muscle tissue
buffering. Phosphates and the amino acid carnosine account for
90% of muscle buffering. 24, 55
The alkaline salts of phosphor act as buffers to improve athletic
performance in several ways. First, they reduce lactic acid
buildup
and intracellular acidosis to delay muscle fatigue. Secondly,
phosphate supplements increase the concentration of 2,3-DPG
(diphosphoglycerate)
in red blood cells which speeds the release of oxygen from hemoglobin
to muscles. Lastly, phosphate supplements help in the phosphorylation
of creatine to creatine phosphate to reform ATP and increase
energy.
Numerous studies spanning decades have demonstrated
the benefits of phosphate blood buffer supplements on improving
athletic performance. The early use of phosphates to improve physical
performance began with Embden (of the Embden Meyerhof pathway) during
World War I. German soldiers were given sodium acid phosphate to
reduce battle fatigue. East German researchers found that taking
1 to 3 grams of phosphates one hour prior to workouts improved psychomotor
performance and prevented muscle fatigue. More recently researchers
at the University of Memphis found that phosphates lead to a 10%
increase in VO2max, a 10% increase in maximal oxygen uptake and
a 9% increase in power output at anaerobic threshold. 25-30, 56-61
These acids are intermediate compounds that are found in the Krebs’
cycle and are necessary to generate cellular energy for tissue fuel.
Supplementing these essential Krebs’ cycle acids in the presence
of nutrient cofactors can enable a partially completed Krebs’
cycle to go to completion. They can prevent and remove the harmful
byproducts that are generated from abnormal energy production in
the mitochondria. And they can stimulate a high yield of ATP from
the mitochondria for tissue energy.
Supplementing these Krebs’ cycle fuel sources
may be advisable for different purposes. They can help correct certain
metabolic disorders that result from abnormal mitochondria energy
production. They can provide an ergogenic edge in athletic performance
by generating muscle energy, increasing aerobic capacity and preventing
fatigue. They may be even more helpful for improving athletic performance
when used in conjunction with alkalizers that buffer lactic acid
build-up in muscle tissue and improve tissue oxygenation.
Alpha-ketoglutaric acid plays a vital role in the Krebs’ cycle
production of energy. As a precursor of the amino acid, glutamic
acid, AKG stabilizes blood glucose levels during exercise. Alpha-ketoglutaric
acid benefits the athlete by supporting protein synthesis, allowing
for longer, more intense workouts, and by promoting healthy nitrogen
balance.
Studies of patients given supplemental alpha-keto-glutarate
following surgery found a nitrogen-sparing effect and a reduction
in loss of lean body mass. Alpha-ketoglutaric acid helps reduce
ammonium levels that may interfere with exercise performance. Studies
have demonstrated that ammonia formed in the muscle, kidney and
brain combines with alpha-ketoglutarate and L-glutamate to reduce
ammonia toxicity. 31-33, 16-18
Malic acid acts as a catalyst in the Krebs’ cycle to increase
energy production from the burning of pyruvic acid. Malic acid also
aids in exercise recovery by counteracting the buildup of lactic
acid. Supplementation of malic acid has been reported to be beneficial
in Chronic Fatigue Syndrome by reducing symptoms of persistent fatigue,
muscular myalgia and arthritic-like pains.
Fumaric acid is the trans-isomer of malic acid that enters the citric
acid cycle. It’s a byproduct at certain stages in the arginine-urea
cycle and purine biosynthesis. In healthy individuals, fumaric acid
is formed in the skin from exposure to sunlight. A deficiency of
fumaric acid leads to the accumulation of metabolic half-products
that may be responsible for causing the skin lesions of psoriasis.
Sufferers of psoriasis have a biochemical defect in which they do
not produce enough fumaric acid, requiring prolonged exposure to
the sun. Administration of fumaric acid to individuals suffering
from psoriasis has caused a gradual elimination of the symptoms.
40-47, 25-32
Succinic acid, like other Krebs’ cycle intermediates, is an
entry pathway for other metabolites into the cycle and is involved
in a variety of important biological actions. In addition to its
enzyme activity, it combines with protein to rebuild muscle fiber
and nerve endings, and helps fight infection. Individuals with Chronic
Fatigue Syndrome have shown low levels of succinic acid in their
urine.
Several amino acids are metabolized into succinic acid, providing
a source of anaerobic and aerobic energy. Amino acids that are metabolized
into succinic acid have been shown to be important in supplying
the heart with fuel for myocardium contractions under low oxygen
conditions. The amino acid GABA can either be oxidized to succinic
acid for cellular energy production, or reduced to GHB, depending
on the metabolic needs of the body.48-50, 33-35
Citric acid, a natural organic acid present to some extent in all
plant and animal tissues, occupies a pivotal location in the Krebs’
cycle. After proteins, fats, carbohydrates and amino acids have
been oxidized into acetyl coenzyme A, the acetic acid subunit of
acetyl CoA is combined with oxaloacetate to form a molecule of citrate.
The acetyl coenzyme A acts as a transporter of acetic acid from
one enzyme to another.
First isolated by the German biochemist, Karl
Wilhelm Steele in 1784, today citric acid is widely respected for
relieving conditions of fatigue, poor digestion, cold and flu infections,
asthma, hypertension and cholesterol deposits in blood vessels.
Pyruvic acid is a three-carbon ketoacid produced in the end stages
of glycolysis. In the mitochondria, pyruvic acid is either reduced
to lactate in the cytoplasm, or oxidized to acetyl CoA.
Research has shown that taking pyruvate (the salt
of pyruvic acid) can increase muscle endurance and promote fat loss.
Pyruvic acid also appears to increase the amount of glucose that
enters muscle cells from the circulating blood. This ability of
pyruvic acid leads to increases in immediate available energy, as
well as increasing stored muscle glycogen levels for future energy.
Research has shown that pyruvic acid increases muscle endurance
and improves cardiac efficiency.
In one study pyruvic acid was found to increase
glucose extraction by almost 300% and muscle glycogen by 50% after
one hour of exercise. The researchers found that arm endurance increased
by 150% and leg endurance by 60%. Another study conducted at the
University of Pittsburgh School of Medicine found that pyruvic acid
produced a significant amount of weight loss and fat loss in obese
women on a low calorie liquid diet. Two potential mechanisms by
which pyruvic acid enhances both fat and weight loss are through
increasing both resting metabolic rate and fat utilization. 51-56,
36-41
Vitamin B5 is required for the synthesis of coenzyme A. Supplementation
of panthenine (pantothenate bound to cysteamine) has been shown
to reduce elevated blood lipids in humans. It is postulated that
this action is due to the accelerated synthesis of coenzyme A. It
has also produced an anti-arrhythmic effect in animal hearts by
increasing ATP synthesis. A study of elite distance runners who
were given two grams of pantothenic acid daily for two weeks found
a 17% reduction in lactic acid buildup and a seven percent reduction
in oxygen consumption during prolonged, strenuous exercise.57-61,
42-46
The Krebs’ cycle is an eloquent and essential system designed
to generate large amounts of cellular energy required for life.
Disruption of the Krebs’ cycle, whether caused by deficiencies
in energy substrates, acquired or inherited disease states, or physical
stress, leads to an inhibition of normal energy production and contributes
to a wide range of metabolic disturbances and symptoms.
The use of supplemental Krebs’ cycle acids
and anti-fatigue buffers can assist in the management of mitochondrial
energy substrates and increase cellular energy production. Such
a nutritional approach can be of benefit to athletes, anyone who
is aging, as well as those suffering from metabolic disturbances
caused by inherited mitochondrial diseases or acquired diseases,
such as Alzheimer’s disease and Chronic Fatigue Syndrome (CFS).
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