 Biochemistry Report

 Regulation of gluconeogenesis
 Dr.Qutaiba Abdulkareem Qasim

o Muammil Jamel Hattab

o Third STAGE
o 2nd COARSE 2019/2020
 Introduction
o The need for energy is important to sustain life.
Organisms have evolved ways of producing substrates
required for the catabolic reactions that is necessary to
sustain life when desired substrates are unavailable.

o Gluconeogenesis is a metabolic event that results in

generation of glucose from non-carbohydrate carbon
sources [ fatty acid - amino acid - pyruvate - lactate ..etc ]

o Gluconeogenesis occurs beyond around 8 hours of

fasting when liver glycogen stores start to deplete and an
alternative source of glucose is required

o When the dietary carbohydrate is unavailable,

glucose required to support metabolism in vital tissues, is
synthesized by gluconeogenesis process

o This pathway is important to maintain the appropriate

amount of blood glucose when liver glucose gets
depleted. This pathway is essential because many cells
types and tissues such as neurons, red blood cells and
skeletal muscles depend on glucose for meeting
their ATP demand. Majority of the reactions in this
pathway occur in the cytosol and a fraction in
mitochondria and the step is achieved within the
endoplasmic reticulum cisternae

o In mammals this gluconeogenesis process occurs in the

liver 50-60% and kidneys 40% and minor in intestine

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 GLUCOSE
GLUCOSE 6
GLUCOKINASE
Phosphatase
GLUCOSE-6-PHOSPHATE

FRUCTOSE-6-PHOSPHATE
FRUCTOSE 1_6
PHOSPHOFRUCTOKINASE
BISPHOSPHATASE

FRUCTOSE-1-6-BISPHOPHATE

DHA-PHOSPHATE

PHOSPHOENOL GLYCEROL 3-PHOSPHATE

PYRUVATE
CARBOXYKINASE

PHOSPHOENOL PYRUVATE
GLYCEROL
PHOSPHOFRUCTOKINASE

2XPYRUVATE LACTATE

Oxaloacetate
CO2
Pyruvate carboxylase
ATP

Oxaloacetate

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 Regulation of gluconeogenesis
The regulation of gluconeogenesis involves the enzymes unique
to pathway, and not the common ones.
the major control points of gluconeogenesis are the reactions
catalyzed by
fructose 1,6-bisphosphatase and pyruvate carboxylase.
The other two enzymes unique to gluconeogenesis, glucose-6-
phosphatase and PEP carboxykinase, are regulated at
transcriptional level.

1. Pyruvate carboxylase enzyme

 In the mitochondrion, will converted pyruvate to oxaloacetate
 The metabolic fate of pyruvate depends on the availability of
acetyl-CoA, that is, by the availability of fatty acids in the
mitochondrion.
 When fatty acids are available, their β-oxidation leads to the
production of acetyl-CoA, that enters the Krebs cycle and
leads to the production of GTP and NADH.
 When the energy needs of the cell are met,, and acetyl-CoA
accumulates in the mitochondrial matrix. Acetyl-CoA is a
positive allosteric effector of pyruvate carboxylase, and a
negative allosteric effector of pyruvate kinase.
 This means that when the energy charge of the cell is high,
the formation of acetyl-CoA from pyruvate slows down, while
the conversion of pyruvate to glucose is stimulated.
 Summarizing, when the energy charge of the cell is high
pyruvate carboxylase is active, and that the first control point
of gluconeogenesis determines what will be the fate of
pyruvate in the mitochondria.

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2. Phosphoenolpyruvate carboxykinase

 It will converted oxaloacetate to phosphoenol pyruvate

 It regulated at transcriptional level. As levels of oxaloacetate

increase, Phosphoenolpyruvate carboxykinase increases
activity and more phosphoenol pyruvate is produced

3. Fructose 1,6-bisphosphatase Enzyme

 It will converted fructose1-6 bio phosphate to fructose -6
phosphate

 It is the second major control point in gluconeogenesis is the

reaction catalyzed by fructose 1,6-bisphosphatase. The
enzyme is allosterically inhibited by AMP.

 when AMP levels are high, gluconeogenesis slows down,

and glycolysis accelerates;

 when ATP levels are high or when acetyl-CoA or citrate are

present in adequate concentrations, gluconeogenesis is
promoted, while glycolysis slows down.

 The increase in citrate levels indicates that the activity of the

citric acid cycle can slow down; in this way, pyruvate can be
used in glucose synthesis.

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 4. glucose-6-phosphatase Enzyme
 The conversion of glucose-6-P to glucose with use of
glucose-6-phosphatase

 is controlled by substrate level regulation. The metabolite

responsible for this type of regulation is glucose-6-P. As
levels of glucose-6-P increase, glucose-6-phosphatase
increases activity and more glucose is produced.

References
1. Garrett, H., Reginald and Charles Grisham. Biochemistry.
Boston: Twayne Publishers, 2008

2. Raven, Peter. Biology. Boston: Twayne Publishers, 2005.

3. CARBOHYDRATES, METABOLISM
GLUCONEOGENESIS