BIOCHEMISTRY

(BCM 2622: Metabolism)

Dr S.C Tshidino
New Life Sciences Building
2nd floor, Office SF012

UNIVERSITY OF VENDA
 CHAPTER 18
[Biochemistry by Campbell and Farrell, 6th up to latest
edition]

❖ GLUCONEOGENESIS.
❖ THE CORI CYCLE AND GLUCOSE-ALANINE
CYCLE.
❖ CONTROL IN CARBOHYDRATE METABOLISM
 Gluconeogenesis
• Conversion of pyruvate to glucose occurs
by a process called gluconeogenesis.
• This process is not an exact reversal of
glycolysis.
• Gluconeogenesis bypasses 3 reversible
reactions in the glycolytic pathway.
• Glycolysis involves three irreversible
steps and gluconeogenesis differs
from glycolysis at those 3 reactions.
NB! Pyruvate is a product of glycolysis, but it
can be formed from other sources (lactate,
glycerol, gluconeogenic amino acids alanine and
glutamine and odd chain fatty acids) as a starting
point of the gluconeogenesis.
 Substrates for gluconeogenesis
1. Glycerol
2. Lactate Form pyruvate, which is
3. Amino acids converted to glucose .
❑ Glycerol is released during breakdown of
triacylglycerols in adipose tissue.
❑ Lactate released into the blood by cells that
lack mitochondria and by exercising skeletal
muscle.
❑ α-Ketoacids derived from the metabolism of
glucogenic amino acids.
 The Cori cycle

• The glycogen in the muscle broken down to 2

lactate molecules via glycolysis.
• The Cori cycle describes the recycling of 2
lactate from muscle to liver, where they are
reconverted to 2 pyruvate that enter
gluconeogenesis to produce glucose.
• Glucose is released from the liver into the blood
circulation where it is taken up by the muscle
and other tissues.
Cori cycle
 The glucose-alanine cycle
• The glycogen in the muscle broken down to 2 pyruvate
molecules via glycolysis. Two pyruvates undergo
transamination to form 2 alanine.

• The glucose-alanine cycle describes the recycling of 2

alanine from muscle to liver, where they are reconverted
to 2 pyruvate that enter gluconeogenesis to produce
glucose.

• Glucose is released from the liver into the blood

circulation where it is taken up by the muscle and other
tissues.

• Alternatively, 2 alanine can undergo deamination to form

urea in the liver.
Glucose-alanine cycle
 Oxaloacetate an intermediate in
gluconeogenesis.
- Oxaloacetate from malate can directly enter the
gluconeogenesis.
• Conversion of pyruvate to phosphoenolpyruvate
(PEP), bypass 1) in gluconeogenesis takes place in
2 steps:
Step 1: Pyruvate reacts with CO2 to give
oxaloacetate. ATP is hydrolysed in the presence of
Mg2+ and biotin in this process.
- This reaction is catalysed by pyruvate
carboxylase, an allosteric enzyme found in the
mitochondria.
- Acetyl-CoA is an allosteric effector that
activates pyruvate carboxylase.

- Oxaloacetate from the TCA cycle can also be

a starting point for gluconeogenesis.
 2 fates of the oxaloacetate in mitochondria
with respect to gluconeogenesis

a) Oxaloacetate can continue to form PEP,

which is transported from mitochondria to enter
gluconeogenesis in the cytosol.
b) Oxaloacetate can be converted to malate by
mitochondrial malate dehydrogenase.

NB! gluconeogenesis occurs in the cytosol.

- Malate can leave mitochondria to cytosol.
- then converted back to oxaloacetate by cytosolic
malate dehydrogenase.
NB! Oxaloacetate cannot leave mitochondria.
✓ It has to be converted to either PEP, malate or
citrate first in the mitochondria, then
transported to the cytosol.
✓ The pathway via malate takes place in the
liver, where gluconeogenesis largely takes
place.
Transportation of oxaloacetate from
mitochondria to cytosol
❑ Gluconeogenesis also occurs in the kidney and
intestines, but OCCURS mostly in the LIVER.
• 1st reaction is the conversion of oxaloacetate to
PEP catalysed by PEP carboxykinase (PEPCK),
(bypass 1)
• 2nd reaction is the hydrolysis of F1,6bisP to F6P
and phosphate ion (Pi), (bypass 2).
- Catalysed by fructose1,6bisphosphatase, an
allosteric enzyme.
- Fructose1,6bisphosphatase also serves as
control point in the gluconeogenesis pathway.
• 3rd reaction, hydrolysis of G6P to glucose and
Pi by glucose-6-phosphatase (G6Pase)
(bypass 3).
- This reaction occurs in the endoplasmic
reticulum (ER).

- Thus gluconeogenesis requires 3 cellular

locations, mitochondria, cytosol and ER.
• Glucose-6-phosphate (G6P) produced from
gluconeogenesis can:
➢ Directly enters glycogenesis pathway to form
glycogen.
➢ Or enters the pentose phosphate pathway
(PPP).
➢ Or dephosphorylized by G6Pase to glucose and
Pi to complete the gluconeogenesis pathway.
• In the gluconeogenesis, ATP and GTP are
required as the source of energy.
 Control of carbohydrate metabolism
• Glucose has a central role in several
carbohydrates pathways, including glycolysis,
gluconeogenesis, synthesis and breakdown
of glycogen.
❑ Glucose is the starting point for glycolysis.
❑ Glucose is the product of gluconeogenesis.
❑ Glucose is also product of glycogenolysis
(breakdown of glycogen).
- Many glucose residues combine to form
glycogen (glucose storage form in the body).
Gluconeogenesis pathway
 Regulation of gluconeogenesis
1. Glucagon hormone stimulates gluconeogenesis
by three ways:
❑ Changes in allosteric effectors.
❑ Covalent modification.
❑ Induction of enzyme synthesis.
2. Substrate availability.
3. Allosteric activation by acetyl-CoA.
4. Allosteric inhibition by AMP.
Control points
Summary