Al-Farabi University College

‫كـلية الفـــارابي الجامــعة‬

Department of Dentistry
‫قسم طـــب االسنان‬
Second Stage
‫المرحلة الثــانية‬
Subject: biochemistry
‫ الكيمياء الحياتية‬: ‫المــادة‬

Embden - Meyerhof - Parnas & Gluconeogenesis pathways

biochemistry :Subject

Prepared by
‫زهراء فاضل اجبير فعيل‬

Supervisor:
‫م احمد محمد‬.‫م‬
‫د علي محمد علي‬.‫م‬
Introduction
Embden - Meyerhof - Parnas Pathway (E.M.P Pathway) it the most type
of glycolysis, which was discovered by Gustav Embden, Otto Meyerhof,
and Jakub Karol Parnas. Glycolysis splits a 6-carbon sugar, glucose, into
two molecules of 3-carbon pyruvate in a series of steps, each catalyzed by
a particular enzyme. Glycolysis takes place in the cytoplasm (cytosol) of
all living cells, not in mitochondria, and does not require the presence of
oxygen. Therefore, glycolysis is also known as cytoplasmic respiration
The Embden-Meyerhof-Parnas (EMP) pathway allows the metabolic use
of glucose to generate ATP, NADH, and several biosynthetic precursors
such as 3-phosphoglycerate or pyruvate. The EMP pathway can occur
both anaerobically (leading to one or several fermentation pathways) and
aerobically through the conversion of pyruvate to acetyl CoA and the
connection with the tricarboxylic acids (TCA) cycle. The classical
version of the EMP pathway is present in bacteria and eukaryotes
whereas several modified versions are present in anaerobic archaea. The
second half of the pathway is almost universal, and thus, it could
represent the oldest part of the pathway, related to a primordial origin of
gluconeogenesis.

Glycolysis for (glucose + -lysis degradation) is the metabolic pathway

that converts glucose C6H12O6, into pyruvate, CH3COCOO− (pyruvic
acid), and a hydrogen ion, H+. The free energy released in this process is
used to form the high-energy molecules ATP (adenosine triphosphate)
and NADH (reduced nicotinamide adenine dinucleotide).[2][3][4]
Glycolysis is a sequence of ten enzyme-catalyzed reactions. Most
monosaccharides, such as fructose and galactose, can be converted to one
of these intermediates. The intermediates may also be directly useful
rather than just utilized as steps in the overall reaction. For example, the
intermediate dihydroxyacetone phosphate (DHAP) is a source of the
glycerol that combines with fatty acids to form fat.
The glycolysis pathway can be separated into two phases:[3]
The Preparatory (or Investment) Phase – wherein ATP is consumed.
The Pay Off Phase – wherein ATP is produced.
Glucose is a six- memebered ring molecule found in the blood and is
usually a result of the breakdown of carbohydrates into sugars. It enters
cells through specific transporter proteins that move it from outside the
cell into the cell’s cytosol. All of the glycolytic enzymes are found in the
cytosol.
The Preparatory (or Investment) Phase
The first five steps of Glycolysis are regarded as the preparatory (or
investment) phase, since they consume energy to convert the glucose into
two three-carbon sugar phosphates [3] (G3P)
Step 1: Hexokinase
The first step in glycolysis is the conversion of D-glucose into glucose-6-
phosphate. The enzyme that catalyzes this reaction is hexokinase.

Details:
The glucose ring is phosphorylated. Phosphorylation is the process of
adding a phosphate group to a molecule derived from ATP. As a result, at
this point in glycolysis, 1 molecule of ATP has been consumed.
The reaction occurs with the help of the enzyme hexokinase, an enzyme
that catalyzes the phosphorylation of many six-membered glucose-like
ring structures. Atomic magnesium (Mg) is also involved to help shield
the negative charges from the phosphate groups on the ATP molecule.
The result of this phosphorylation is a molecule called glucose-6-
phosphate (G6P), thusly called because the 6′ carbon of the glucose
acquires the phosphate group.
Step 2: Phosphoglucose Isomerase
The second reaction of glycolysis is the rearrangement of glucose 6-
phosphate (G6P) into fructose 6-phosphate (F6P) by glucose phosphate
isomerase (Phosphoglucose Isomerase)

Details:
The second step of glycolysis involves the conversion of glucose-6-
phosphate to fructose-6-phosphate (F6P). This reaction occurs with the
help of the enzyme phosphoglucose isomerase (PI). As the name of the
enzyme suggests, this reaction involves an isomerization reaction.
The reaction involves the rearrangement of the carbon-oxygen bond to
transform the six-membered ring into a five-membered ring. To
rearrangement takes place when the six-membered ring opens and then
closes in such a way that the first carbon becomes now external to the
ring.
Step 3: Phosphofructokinase
Phosphofructokinase, with magnesium as a cofactor, changes fructose 6-
phosphate into fructose 1,6-bisphosphate.

Details:
In the third step of glycolysis, fructose-6-phosphate is converted to
fructose- 1,6-bisphosphate (FBP). Similar to the reaction that occurs in
step 1 of glycolysis, a second molecule of ATP provides the phosphate
group that is added on to the F6P molecule.
The enzyme that catalyzes this reaction is phosphofructokinase (PFK).
As in step 1, a magnesium atom is involved to help shield negative
charges.
Step 4: Aldolase
The enzyme Aldolase splits fructose 1, 6-bisphosphate into two sugars
that are isomers of each other. These two sugars are dihydroxyacetone
phosphate (DHAP) and glyceraldehyde 3-phosphate (GAP).

Details:
This step utilizes the enzyme aldolase, which catalyzes the cleavage of
FBP to yield two 3-carbon molecules. One of these molecules is called
glyceraldehyde-3-phosphate (GAP) and the other is called
dihydroxyacetone phosphate (DHAP).
Step 5: Triosephosphate isomerase
The enzyme triosephosphate isomerase rapidly inter- converts the
molecules dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-
phosphate (GAP). Glyceraldehyde phosphate used in next step of
Glycolysis.

Details:
GAP is the only molecule that continues in the glycolytic pathway. As a
result, all of the DHAP molecules produced are further acted on by the
enzyme Triosephosphate isomerase (TIM), which reorganizes the
DHAP into GAP so it can continue in glycolysis. At this point in the
glycolytic pathway, we have two 3-carbon molecules, but have not yet
fully converted glucose into pyruvate.
Pay-off phase

The second half of glycolysis is known as the pay-off phase,

characterised by a net gain of the energy-rich molecules ATP and
NADH.

Step 6: Glyceraldehyde-3-phosphate Dehydrogenase

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) dehydrogenates

and adds an inorganic phosphate to glyceraldehyde 3-phosphate,
producing 1,3-bisphosphoglycerate.

Details:

In this step, two main events take place:

1) glyceraldehyde-3-phosphate is oxidized by the coenzyme

nicotinamide adenine dinucleotide (NAD);

2) The molecule is phosphorylated by the addition of a free phosphate

group. The enzyme that catalyzes this reaction is glyceraldehyde-3-
phosphate dehydrogenase (GAPDH).

The enzyme GAPDH contains appropriate structures and holds the

molecule in a conformation such that it allows the NAD molecule to pull
a hydrogen off the GAP, converting the NAD to NADH. The phosphate
group then attacks the GAP molecule and releases it from the enzyme to
yield 1,3 bisphoglycerate, NADH, and a hydrogen atom.
Step 7: Phosphoglycerate Kinase

Phosphoglycerate kinase transfers a phosphate group from 1,3-

bisphosphoglycerate and ADP to form ATP and 3-phosphoglycerate.

Details:

In this step, 1,3 bisphoglycerate is converted to 3-phosphoglycerate by

the enzyme phosphoglycerate kinase (PGK). This reaction involves the
loss of a phosphate group from the starting material. The phosphate is
transferred to a molecule of ADP that yields our first molecule of ATP.
Since we actually have two molecules of 1,3 bisphoglycerate (because
there were two 3-carbon products from stage 1 of glycolysis), we actually
synthesize two molecules of ATP at this step. With this synthesis of ATP,
we have cancelled the first two molecules of ATP that we used, leaving
us with a net of 0 ATP molecules up to this stage of glycolysis

Again, we see that an atom of magnesium is involved to shield the

negative charges on the phosphate groups of the ATP molecule.
Step 8: Phosphoglycerate Mutase

The enzyme phosphoglycero mutase relocates the P from 3-

phosphoglycerate from the 3rd carbon to the 2nd carbon to form 2-
phosphoglycerate.

Details:

This step involves a simple rearrangement of the position of the

phosphate group on the 3 phosphoglycerate molecule, making it 2
phosphoglycerate. The molecule responsible for catalyzing this reaction
is called phosphoglycerate mutase (PGM). A mutase is an enzyme that
catalyzes the transfer of a functional group from one position on a
molecule to another.

The reaction mechanism proceeds by first adding an additional phosphate

group to the 2′ position of the 3 phosphoglycerate. The enzyme then
removes the phosphate from the 3′ position leaving just the 2′ phosphate,
and thus yielding 2 phsophoglycerate. In this way, the enzyme is also
restored to its original, phosphorylated state.
Step 9: Enolase
The enzyme enolase removes a molecule of water from 2-
phosphoglycerate to form phosphoenolpyruvic acid (PEP).

Details:
This step involves the conversion of 2 phosphoglycerate to
phosphoenolpyruvate (PEP). The reaction is catalyzed by the enzyme
enolase. Enolase works by removing a water group, or dehydrating the
2 phosphoglycerate. The specificity of the enzyme pocket allows for the
reaction to occur through a series of steps too complicated to cover here.
Step 10: Pyruvate Kinase
The enzyme pyruvate kinase transfers a P from phosphoenolpyruvate
(PEP) to ADP to form pyruvic acid and ATP Result in step 10.

Details:
The final step of glycolysis converts phosphoenolpyruvate into
pyruvate with the help of the enzyme pyruvate kinase. As the enzyme’s
name suggests, this reaction involves the transfer of a phosphate group.
The phosphate group attached to the 2′ carbon of the PEP is transferred to
a molecule of ADP, yielding ATP. Again, since there are two molecules
of PEP, here we actually generate 2 ATP molecules.
Steps 1 and 3 = – 2ATP
Steps 7 and 10 = + 4 ATP
Net “visible” ATP produced = 2.
Immediately upon finishing glycolysis, the cell must continue respiration
in either an aerobic or anaerobic direction; this choice is made based on
the circumstances of the particular cell. A cell that can perform aerobic
respiration and which finds itself in the presence of oxygen will continue
on to the aerobic citric acid cycle in the mitochondria. If a cell able to
perform aerobic respiration is in a situation where there is no oxygen
(such as muscles under extreme exertion), it will move into a type of
anaerobic respiration called homolactic fermentation. Some cells such as
yeast are unable to carry out aerobic respiration and will automatically
move into a type of anaerobic respiration called alcoholic fermentation.

Importance of glycolysis
Glycolysis is the principal route for carbohydrate metabolism. The ability
of glycolysis to provide ATP in the absence of oxygen is especially
important, because this allows skeletal muscle to perform at very high
levels of work output when oxygen supply is insufficient, and it allows
tissues to survive anoxicep eisodes. However, heart muscle, which is
adapted for aerobic performance, has relatively low glycolytic activity and
poor survivalnder conditions of ischemia. Diseases in which enzymes of
glycolysis (eg, pyruvate kinase) are deficient are mainly seen as hemolytic
anemias or, if the defect affects skeletal muscle (eg, phosphofructokinase),
as fatigue. In fast-growing cancercells, glycolysis proceeds at a high rate,
forming large amounts of pyruvate, which is reduced to lactate and
exported. This produces a relatively acidic local environment in the tumor,
which may have implications for cancer therapy.
Overview on cictric acide cycle

The citric acid cycle is a key metabolic pathway that connects

carbohydrate, fat, and protein metabolism. The reactions of the cycle are
carried out by eight enzymes that completely oxidize acetate (a two carbon
molecule), in the form of acetyl-CoA, into two molecules each of carbon
dioxide and water. Through catabolism of sugars, fats, and proteins, the
two-carbon organic product acetyl-CoA (a form of acetate) is produced
which enters the citric acid cycle. The reactions of the cycle also convert
three equivalents of nicotinamide adenine dinucleotide (NAD+) into three
equivalents of reduced NAD+ (NADH), one equivalent of flavin adenine
dinucleotide (FAD) into one equivalent of FADH2, and one equivalent each
of guanosine diphosphate (GDP) and inorganic phosphate (Pi) into one
equivalent of guanosine triphosphate (GTP). The NADH and
FADH2 generated by the citric acid cycle are, in turn, used by the oxidative
phosphorylation pathway to generate energy-rich ATP.
One of the primary sources of acetyl-CoA is from the breakdown of sugars
by glycolysis which yield pyruvate that in turn is decarboxylated by
the pyruvate dehydrogenase complex generating acetyl-CoA
Steps of citric acid cycle
The citric acid (Krebs) cycle. All the intermediates of the cycle are potentially glucogenic,
since they can give rise to oxaloacetate, and hence net production of glucose (in the liver and
kidney, the organs that carry out gluconeogenesis; see Chapter 19). The key enzyme that
catalyzes net transfer out of the cycle into gluconeogenesis is phosphoenolpyruvate
carboxykinase, which catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate,
with GTP acting as the phosphate donor. The GTP required for this reaction is provided by
the GDPdependent isoenzyme of succinate thiokinase. This ensures that oxaloacetate will not
be withdrawn from the cycle for gluconeogenesis if this would lead to depletion of citric acid
cycle intermediates, and hence reduced generation of ATP.
 Gluconeogenesis

Overview

Gluconeogenesis is the reversal of glycolysis, with several workarounds

for the irreversible reactions in that pathway. In this scheme, the reactions
that are shared between glycolysis and gluconeogenesis are shown in
blue, whereas reactions that are specific for gluconeogenesis are shown
in red. Both pyruvate and oxaloacetate are starting points for red arrows;
therefore, any pathway that yields either of these, or indeed any other
intermediate of glycolysis, can supply substrate carbon for
gluconeogenesis. These pathways are indicated here by green arrows.

The major substrate supply for gluconeogenesis is protein, both dietary

and endogenous. Protein is first broken down into its constituent amino
acids. Those amino acids that can be converted to pyruvate or any of the
TCA cycle intermediates can serve as substrates for gluconeogenesis, and
are therefore called glucogenic.
Precursors
In humans the main gluconeogenic precursors are lactate, glycerol (which
is a part of the triacylglycerol molecule), alanine and glutamine.
Altogether, they account for over 90% of the overall
gluconeogenesis.[7] Other glucogenic amino acids as well as all citric acid
cycle intermediates, the latter through conversion to oxaloacetate, can also
function as substrates for gluconeogenesis.[8] In ruminants, propionate is
the principal gluconeogenic substrate.[5][9] In nonruminants, including
human beings, propionate arises from the β-oxidation of odd-chain and
branched-chain fatty acids is a (relatively minor) substrate for
gluconeogenesis.[10][11] Generally, consumption of gluconeogenic
substrates in food does not result in increased gluconeogenesis.[12].
Lactate is transported back to the liver where it is converted into
pyruvate by the Cori cycle using the enzyme lactate dehydrogenase.
Pyruvate, the first designated substrate of the gluconeogenic pathway, can
then be used to generate glucose.[8] Transamination or deamination of
amino acids facilitates entering of their carbon skeleton into the cycle
directly (as pyruvate or oxaloacetate), or indirectly via the citric acid cycle.
The contribution of Cori cycle lactate to overall glucose production
increases with fasting duration.[13] Specifically, after 12, 20, and 40 hours
of fasting by human volunteers, the contribution of Cori cycle lactate to
gluconeogenesis was 41%, 71%, and 92%, respectively.[13]
Whether even-chain fatty acids can be converted into glucose in animals
has been a longstanding question in biochemistry.[14] It is known that odd-
chain fatty acids can be oxidized to yield propionyl-CoA, a precursor
for succinyl-CoA, which can be converted to pyruvate and enter into
gluconeogenesis. In plants, specifically seedlings, the glyoxylate cycle can
be used to convert fatty acids (acetate) into the primary carbon source of
the organism. The glyoxylate cycle produces four-carbon dicarboxylic
acids that can enter gluconeogenesis.[8]
The existence of glyoxylate cycles in humans has not been established, and
it is widely held that fatty acids cannot be converted to glucose in humans
directly. However, carbon-14 has been shown to end up in glucose when it
is supplied in fatty acids.[17] Despite these findings, it is considered unlikely
that the 2-carbon acetyl-CoA derived from the oxidation of fatty acids
would produce a net yield of glucose via the citric acid cycle – however,
 acetyl-CoA can be converted into pyruvate and lactate through
the ketogenic pathway.[14][18] Put simply, acetic acid (in the form of acetyl-
CoA) is used to partially produce glucose; acetyl groups can only form part
of the glucose molecules (not the 5th carbon atom) and require extra
substrates (such as pyruvate) in order to form the rest of the glucose
molecule. But a roundabout pathway does lead from acetyl-coA to
pyruvate, via acetoacetate, acetone, hydroxyacetone (acetol) and then
either propylene glycol or methylglyoxal.[18][19][20]

Catabolism of proteinogenic amino acids. Amino acids are classified

according to the abilities of their products to enter gluconeogenesis:[6]

 Glucogenic amino acids have this ability

 Ketogenic amino acids do not. These products may still be used
for ketogenesis or lipid synthesis.
 Some amino acids are catabolized into both glucogenic and ketogenic
products.
 Steps of Gluconeogenesis

Reversal of the reaction catalyzed by pyruvate kinase in glycolysis

involves two endothermic reactions.
Step 1: Conversion of pyruvate to phosphoenolpyruvate
1) Mitochondrial pyruvate carboxylase catalyzes the carboxylation of
pyruvate to oxaloacetate, an ATP-requiring reaction in which the vitamin
biotin is the coenzyme. Biotin binds CO2 from bicarbonate as
carboxybiotin prior to the addition of the CO2 to pyruvate The resultant
oxaloacetate.

2) Oxaloacetate cannot directly cross the inner mitochondrial membrane.

Therefore, it is converted to malate or to aspartate, which can cross the
mitochondrial membrane exported from the mitochondrion into the
cytosol and there oxidized back to oxaloacetate.
3) A second enzyme, phosphoenolpyruvate carboxykinase, catalyzes
the decarboxylation and phosphorylation of oxaloacetate to
phosphoenolpyruvate using GTP as the phosphate donor in liver and
kidney, the reaction of succinate thiokinase in the citric acid cycle
produces GTP (rather than ATP as in other tissues), and this GTP is used
for the reaction of phosphoenolpyruvate carboxykinase, thus providing a
link between citric acid cycle activity and gluconeogenesis, to prevent
excessive removal of oxaloacetate for gluconeogenesis, which would
impair citric acid cycle activity

Step 2 Fructose 1,6-Bisphosphate & Fructose-6-Phosphate

The same as reversed glycolysis. However, fructose 1,6-

bisphosphatase converts fructose 1,6-bisphosphate to fructose 6-
phosphate, using one water molecule and releasing one phosphate (in
glycolysis, phosphofructokinase 1 converts F6P and ATP to F1,6BP
and ADP). This is also the rate-limiting step of gluconeogenesis. Its
presence determines whether a tissueis capable of synthesizing glucose
(or glycogen) not only frompyruvate, but also from triose phosphates. It
is present in liver,kidney, and skeletal muscle, but is probably absent
from heart and smooth muscle.
Step 3 Glucose-6-Phosphate & Glucose

Glucose-6-phosphate is formed from fructose 6

phosphate by phosphoglucoisomerase (the reverse of step 2 in
glycolysis). Glucose-6-phosphate can be used in other metabolic
pathways or dephosphorylated to free glucose. Whereas free glucose can
easily diffuse in and out of the cell, the phosphorylated form (glucose-6-
phosphate) is locked in the cell, a mechanism by which intracellular
glucose levels are controlled by cells.

The final gluconeogenesis, the formation of glucose, occurs in

the lumen of the endoplasmic reticulum, where glucose-6-phosphate is
hydrolyzed by glucose-6-phosphatase to produce glucose and release an
inorganic phosphate. Like two steps prior, this step is not a simple
reversal of glycolysis, in which hexokinase catalyzes the conversion of
glucose and ATP into G6P and ADP. Glucose is shuttled into the
cytoplasm by glucose transporters located in the endoplasmic reticulum's
membrane.

Thus, the net requirements to make one glucose molecule are:

 Two pyruvate.
 Four ATP and two GTP.
 Two NADH.
 Six H2O
Significance of Gluconeogenesis Pathway
1. Gluconeogenesis meets the needs of the body for glucose when
sufficient carbohydrate is not available from the diet or glycogen
reserves.
2. Glycogen stored in adipose tissue and in skeletal muscle is
converted to glucose by glycogenolysis. However the stored
glycogen may not be sufficient during heavy exercise, diabetic
conditions,or during fasting etc. so during shortage, glucose is
synthesized by gluconeogenesis process.
3. A continual supply of glucose is necessary as a source of energy
especially for the nervous system and erythrocytes.
4. Gluconeogenesis mechanism is used to clear the products of the
metabolism of other tissues from the blood, eg: Lactate, produced
by muscle and erythrocytes and glycerol, which is continuously
produced by adipose tissue.

Associated Disease
Deficiency in any of the gluconeogenic enzymes leads to hypoglycemia.
Failure of gluconeogenesis may be fatal.
Discussion
Glycolysis is a cytoplasmic pathway which breaks down glucose into two
three-carbon compounds and generates energy. Glucose is trapped
by phosphorylation, with the help of the enzyme hexokinase. Adenosine
triphosphate (ATP) is used in this reaction and the product, glucose-6-P,
inhibits hexokinase. Glycolysis takes place in 10 steps, five of which are
in the preparatory phase and five are in the pay-off
phase. Phosphofructokinase is the rate-limiting enzyme. ATP is generated
by substrate-level phosphorylation by high-energy compounds, such as
1,3-bisphosphoglycerate and phosphoenolpyruvate.
Glycolysis is used by all cells in the body for energy generation. The final
product of glycolysis is pyruvate in aerobic settings and lactate in
anaerobic conditions. Pyruvate enters the Krebs cycle for further energy
production.

Gluconeogenesis is the process of synthesizing glucose from non-

carbohydrate sources. The starting point of gluconeogenesis is pyruvic
acid, although oxaloacetic acid and dihydroxyacetone phosphate also
provide entry points. Lactic acid, some amino acids from protein and
glycerol from fat can be converted into glucose. Gluconeogenesis is
similar but not the exact reverse of glycolysis, some of the steps are the
identical in reverse direction and three of them are new ones. Without
going into detail, the general gluconeogenesis sequence is given in the
graphic on the left.

Notice that oxaloacetic acid is synthesized from pyruvic acid in the first
step. Oxaloacetic acid is also the first compound to react with acetyl CoA
in the citric acid cycle. The concentration of acetyl CoA and ATP
determines the fate of oxaloacetic acid. If the concentration of acetyl CoA
is low and concentration of ATP is high then gluconeogenesis proceeds.
Also notice that ATP is required for a biosynthesis sequence of
gluconeogenesis.

Gluconeogenesis occurs mainly in the liver with a small amount also

occurring in the cortex of the kidney. Very little gluconeogenesis occurs
in the brain, skeletal muscles, heart muscles or other body tissue. In fact,
these organs have a high demand for glucose. Therefore, gluconeogenesis
is constantly occurring in the liver to maintain the glucose level in the
blood to meet these demands.
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