Anaerobic Glycolysis

This occurs in:‫تفتقر‬

a. Cells that lack mitochondria such as RBCs
b. Cells of avascular tissues such as eye lens/cornea and
kidney medulla where low oxygen level (Hypoxia)
c. Exercising muscle where more ATP is needed
What is the aim of this step?
We know that during glycolysis in step 6 we need NAD+ to be
reduced to NADH, this NADH must be reoxidized back to NAD+
in order to have a continuous supply of NAD+
(we must regenerate NAD+)
In Aerobic glycolysis NADH is reoxidized when it gives it’s
electron to Oxygen through ETC
But in RBCs where no ETC or when Oxygen is not available how
can we regenerate NAD+??
This is done by reducing Pyruvate to Lactate, this step
regenerate NAD+
Pyruvate
Q: the final electron acceptor in Anerobic Glycolysis is …………………………
This step is reversible and the direction depends on the relative concentration of reactants and
products (Pyruvate/lactate ratio and more important NADH/NAD+ ratio) high NADH/NAD+ ratio
stimulate reduction of pyruvate to lactate
Now what is the fate of Lactate??
Lactate is diffused out of the cells to blood to be transported to the liver cells, where lactate is
converted back to pyruvate which is used for glucose synthesis “Gluconeogenesis”

Lactic acid (Lactate) is an Acid which lowers the pH, during heavy exercise lactic acid is accumulate
in muscles and
‫تشنج‬
blood this leads to:
- Muscle cramp and pain
- Lactic acidosis (low blood pH due to high Lactic acid)
‫استهالك‬
 Any thing ↑ production of Lactic acid or ↓ Lactic acid utilization will cause Lactic acidosis
Causes: ‫السكتة القلبية‬
‫فشل‬
1. Impaired O2 transport as in Myocardial Infarction (MI)
‫انهيار‬
→ Collapsed Circulatory system → Hypoxia → increase Lactic acid production ‫او اي سبب منطقي يؤدي لتراكم‬
2. Respiratory Failure as in Pulmonary Embolism ‫جلطة رئوية‬ NADH ‫ او ال‬Pyruvate ‫ال‬
↓O2 → Hypoxia → increase Lactic acid production
3. Uncontrolled Hemorrhage ‫نزيف حاد‬
↓Blood Pressure → ↓ Circulation → ↓O2 → Hypoxia → increase Lactic acid production
4. Alcohol Intoxication leads to increase NADH/ NAD+ ratio
Overall Reaction of Anaerobic Glycolysis

NO NADH is produced
Alcoholic Fermentation in Yeast and some Bacteria

This occurs in 2 Steps:

Aim: Regenerate NAD+ to be used in
Step 6

Q: The final electron acceptor in

Acetaldehyde
alcoholic fermentation is ………………….

Overall Reaction of Alcoholic Fermentation

 your body during Fed state and during Starvation

Irreversible Step
In words
When glucose is available (Fed State)
Glucose is converted to pyruvate by glycolysis
Pyruvate is converted to lactate in RBCs and Hypoxic tissues ,
then lactate is converted back to pyruvate in the liver
In other tissues pyruvate is Oxidatively decarboxylated to
Acetyl-CoA by Pyruvate dehydrogenase complex
Acetyl-CoA:
a. Oxidized by TCA cycle if energy is required
b. Converted to Fatty acids (FAT) if energy is not required

When Glucose is NOT available (Starvation)

Fat is degraded to Acetyl-CoA ↑↑↑
- High level of acetyl-CoA indicate that you are starved and Fat is catabolized in large amounts
In the liver Pyruvate must not be converted to acetyl-CoA but to oxaloacetate by Pyruvate Carboxylase
which require Biotin (B7) as cofactor, then oxaloacetate is used to synthesize glucose “Gluconeogenesis”
; so High acetyl-CoA inhibit pyruvate Dehydrogenase and activate Pyruvate Carboxylase
-During Starvation Pyruvate come mainly from amino acids
Fates of pyruvate
‫عليك تمييز الخطوات عن‬
‫طريق ال ‪Structures‬‬
‫لكن خلينا نتأكد اكثر من‬
‫الدكتورة‬

‫‪+‬‬

‫ما في ارقام خطوات‬

‫باالمتحان‬
‫يعني ما في‬
‫‪Step1‬‬
‫‪Step2‬‬
‫‪Step3‬‬
‫هاد كان لتسهيل الشرح‬
Gluconeogenesis ‫صناعة جلوكوز‬
As you know some cells have an absolute requirement of glucose such as Brain
and RBCs ‫سواء اكلت او ما اكلت جسمك بدو جلوكوز الزم تدبر حالك‬
Glucose sources
‫متقطع‬
1. Diet (sporadic)
‫ينفذ‬
2. 6-8 hours after meal, Dietary glucose will be depleted (Fasting) you depends
on Liver glycogen for 16-18 hours
3. After liver glycogen is finished (Starvation or prolonged fasting);‫المستمر‬ ‫مصدرك‬
Gluconeogenesis in the liver and Kidney will be your sustained source of
Glucose
During 90% of glucose synthesized in the 10% of glucoses synthesized in
Overnight Fasting liver the kidneys

During 60% of glucose synthesized in the 40% of glucose synthesized in the

Prolonged Fasting liver kidneys

Small Intestine can also synthesize Glucose

Gluconeogenesis ‫صناعة جلوكوز‬
)‫من الصفر (من مواد اولية‬
- it’s a de novo synthesis of‫الصيام‬Glucose. Occurs mainly in Liver and Kidney some
in small intestine during Fasting
Glycolysis: Glucose → 2 Pyruvate ‫عكس‬

• Gluconeogenesis is the Reverse of Glycolysis but NOT Exactly

Because we have 3 Irreversible steps (1, 3, 10)

‫حتى ترجع فيها الزم ربنا يخلقلك انزيم‬

‫اخر او طريق اخر مختلف‬
‫اذا ما عندك هاد االنزيم االخر ما بتقدر‬
‫ترجع بهاي الخطوات‬
‫‪These 3 enzymes‬‬
‫‪work Only for‬‬
‫‪Glycolysis‬‬
‫حتى ترجع بهاي الخطوات الزم‬
‫يكون عندك انزيمات ثانية‬
‫باقي الخطوات ‪Reversible‬‬
‫بترجع فيها بنفس انزيمات ال‬
‫‪Glycolysis‬‬
 Glycolysis

Gluconeogenesis
 PEP ‫ الى‬Pyruvate ‫اعادة‬

‫يحفز‬
Glucagon induce the
gene of this Enzyme

Found in the Cytosol

In Words:
Pyruvate(3C) is first Carboxylated and converted to Oxaloacetate
(4C) this consume ATP by enzyme called Pyruvate carboxylase
which require Biotin (B7) as coenzyme, this enzyme found only
in the Mitochondria
Then Oxaloacetate is decarboxylated and phosphorylated from
GTP by enzyme called Phosphoenolpyruvate Carboxykinase
(PEPCK) ‫تتجاوز‬
Pyruvate carboxylase and PEPCK bypass Pyruvate kinase reaction
 1. Pyruvate is Carboxylated
to Oxaloacetate in the
Mitochondria
2. Oxaloacetate
is reduced to
malate Cannot get out (No carrier)

3. Malate get
out by specific
carrier
4. Malate is
oxidized back to
oxaloacetate
‫صار برا‬ Cytosol ‫باقي الخطوات بتصير بال‬
 ‫فقط رسمة الكتاب للموضوع اللي شرحته‬ ‫ال جديد‬

 Pyruvate carboxylase of liver and kidney cells to allow production of PEP for gluconeogenesis, and to provide
Oxaloacetate (OAA) that can replenish the TCA cycle intermediates
 Muscular PC use the OAA product only for the replenishment purpose but not for gluconeogenesis.
 ‫تحويلة‬
What is the aim of Malate Shunt?
You know that we need NADH in the Cytosol in step 6 for Gluconeogenesis, malate shunt
get NADH from mitochondria to the Cytosol
So if 𝑁𝐴𝐷𝐻Τ𝑁𝐴𝐷+ ratio in the Cytosol is low we go through malate shunt.
Now
Steps 9 → 3 all are reversible, Occur in the cytosol
Step 7: 2ATP → 2ADP
Step 6: 2NADH → 2NAD+

Step 2 is reversible and occurs in the cytosol (phosphoglucose Isomerase convert Fructose-6-P to Glucose-6-P)
 Glucose-6-P is transported from the Cytosol to ER by
Glucose-6-P Translocase which found in the ER membrane ‫الشبكة االندوبالزمية‬

General notes:
Gluconeogenesis take place in Mitochondria, Cytosol and Endoplasmic Reticulum
Overall reaction of Gluconeogenesis
gluconeogenesis from two pyruvate molecules
couples the cleavage of six high-energy phosphate
bonds and the oxidation of two NADH with the
formation of one glucose molecule

Q: what is the source of energy

and NADH required for
Gluconeogenesis??
Fatty acids Catabolism
6ATP
What are the molecules that we can use to synthesize Glucose (Precursors)??
‫المواد االولية لتصنيع الجلوكوز‬
* First you should know that all glycolysis and Krebs cycle intermediates can be converted to glucose
1. Lactate in liver oxidized to pyruvate
2. Glycerol from Fat degradation in the Adipocytes is converted to Dihydroxyacetone-P

‫تذكر انو االحماض االمينية في منها‬

Glucogenic → degraded to pyruvate
or TCA intermediates
Ketogenic → degraded to Acetyl-CoA
Mixed
‫االهم‬
3. Amino acids (all except Lysine and Leucine) converted to pyruvate or TCA cycle intermediate

• Note: you can NOT synthesize Glucose from Acetyl-CoA

 Cori Cycle
During Heavy Exercise Anaerobic Glycolysis

Cori Cycle ‫محصلة‬

2 ATP ‫تكسير‬ Gluconeogenesis
2 GTP ‫تكسير‬

In Words:
During heavy exercise the muscle generate ATP by anaerobic glycolysis producing lactate, the lactate is
transported to the liver by blood; then the liver synthesize Glucose from lactate by gluconeogenesis,
after that the glucose is returned to the muscle in order to continue exercising
 Control of Gluconeogenesis

• When Glucose is Low (Fasting)

 Fat is degraded to Acetyl-CoA ↑↑↑
‫حالة جوع‬
- High level of acetyl-CoA indicate that you are starved and Fat is catabolized in large amounts
 In the liver Pyruvate must be converted to glucose not to acetyl-CoA; so High acetyl-CoA inhibit pyruvate
Dehydrogenase and activate Pyruvate Carboxylase

Also Glucagon inhibit liver pyruvate

kinase (Step 10 in Glycolysis)
Step 3 in Glycolysis and Gluconeogenesis

Most potent
activator of PFK I

• If PFK II is active → ↑ Fructose 2,6 BP → PFK I is activated “Glycolysis”

• If Fructose Bisphosphatase II (FBP II) is active → ↓ Fructose 2,6 BP → Fructose 1,6 bisphosphatase
is activated “Gluconeogenesis
In the Liver
In Words:
When Glucose is low → high Glucagon/Insulin ratio, Glucagon bind to its receptor activating an enzyme called
adenylate kinase which convert ATP to cAMP; now cAMP activate Protein Kinase A (PKA) which add phosphate to
PFKII/FBPII complex
PFKII is inactivated
FBFII is activated
Now the level of Fructose 2,6 Bisphosphate is decreased
Fructose 1,6 Bisphosphatase is not inihibited (Activated)
Gluconeogenesis is active/Glycolysis is inactive

When Glucose is available → high Insulin/Glucagon ratio, Insulin bind to its receptor activating phosphatases which
Remove phosphate from PFKII/FBPII complex
PFKII is activated
FBFII is inactivated
Now the level of Fructose 2,6 Bisphosphate is increased which is the most potent activator for PFK I
PFKI is activated (Glycolysis is active)
Fructose 1,6 Bisphosphatase is inhibited (Gluconeogenesis is inactive)
Regulation summary )‫مؤثر ايجابي (منشط‬

1. Glucagon activate Gluconegenesis “Positive Regulator” in 3 mechanisms

a. Changes in the concentration of allosteric effectors
It decrease the level of Fructose 2,6 bisphosphate by activating FBPII this will activate
Gluconeogenesis and inhibit glycolysis
‫يحفز‬ ‫اضافة الفوسفات بالتسلسل المعتاد‬

b. Inhibit Liver Pyruvate kinase (Step 10) of Glycolysis by inducing phosphorylation of

this enzyme
‫يحفز‬ ‫نسخ‬
c. Induction of enzyme synthesis: Glucagon increases
‫بالتالي‬
the transcription‫توفر‬of
/ ‫كمية‬
Phosphoenolpyruvate carboxykinase gene, thereby increasing the availability of this
enzyme.

‫توفر المواد االولية لتصنيع الجلوكوز‬

2. Substrate Availability
‫تكسير‬

Low insulin, High Glucagon (low Insulin/Glucagon Ratio) leads to mobilization of

muscle proteins to amino acids (degradation of muscle proteins)
• Amino Acids activate gluconeogenesis because they are the main substrate
3. Allosteric activation by acetyl CoA “Positive Regulator”
‫ينشط‬
• High levels of Acetyl Co-A enhance the enzyme Pyruvate Carboxylase and inhibits the
Pyruvate Dehydrogenase Complex.
4. Allosteric inhibition by AMP “Negative Regulator”
‫يدل على‬ ‫نقص‬
High levels of AMP signal that shortage of energy in the liver, so it cannot synthesize
glucose since gluconeogenesis require 6ATP
Try at home
Determine whether glycolysis or gluconeogenesis is active in the liver in the following
conditions explain your answer?
High Insulin/Glucagon ratio Glycolysis
Low Glucagon/Insulin ratio Glycolysis
High Glucagon/Insulin ratio Gluconeogenesis
High ATP/AMP ratio Gluconeogenesis
Low ATP/AMP ratio Glycolysis
High cAMP level Gluconeogenesis