Ketogenesis and Ketolysis

Dr Howaida Nounou
College of science
Biochemistry Department
When fatty acid oxidation produces more acetyl-CoA than
the capacity of TCA cycle to oxidize it ( more than that can be
combined with oxaloacetate to form citrate), then the "extra"
acetyl-CoA is converted to acetoacetyl-CoA
and ketone bodies, including acetone.
Ketogenesis (synthesis of ketone

bodies) in the liver mitochondria as
the enzyme responsible for
ketogenesis are present in the liver
mitochondria .
It takes place when the rate of fatty
acids oxidation in the liver is high.
Ketone bodies replace glucose as the major source of
energy for many tissues especially the brain, heart
and muscles during times of prolonged starvation.
Normal physiological responses to carbohydrate

shortages cause the liver to increase the production
of ketone bodies from the acetyl-CoA generated
from fatty acid oxidation.
Are distributed to peripheral tissues
(muscle, brain) to be used for ATP
production.
The Brain oxidizes KB but not Fat

Other Tissues oxidize KB and Fat
Ketogensis:
In Step 1, two acetyl-CoA molecules combine in a reversible
reaction catalyzed by thiolase to produce acetoacetyl-CoA.
In Step 2, a third acetyl-CoA and a water molecule react with

acetoacetyl-CoA to give 3-hydroxy-3-methylglutaryl-CoA
(HMGCoA) in a reaction catalyzed by HMGCoA synthase.
HMGCoA synthase is the regulatory enzyme of ketone bodies
synthesis, it is induced by high fats in blood and inhibited by
CoASH.
thiolase HMGCoA synthase

In Step 3: 3-hydroxy-3-methylglutaryl-CoA lyase catalyzes the
cleavage of HMGCoA removal of acetyl-CoA produces the first
of the ketone bodies, acetoacetate, the precursor of the other two
ketone bodies produced by ketogenesis, 3-hydroxybutyrate and
acetone.
HMGCoA lyase
In Step 4, the acetoacetate produced in Step 3 is reduced to
3-hydroxybutyrate by β-hydroxy butyrate dehydrogenase.
Note that 3-hydroxybutyrate and acetoacetate are connected by
a reversible and NADH-dependant reaction.
Both 3-hydroxybutyrate and acetoacetate can be transported
across the mitochondrial membrane of liver cells blood
stream used as fuel by other body cells.
β-hydroxy butyrate
dehydrogenase
Acetone is a spontaneous breakdown product of (a small amount)
acetoacetate (decarboxylation) in the bloodstream, and is excreted
primarily by exhalation, or it is formed by enzymatic cleavage of
acetoacetate by the enzyme acetoacetate decarboxylase
acetone formation is minimal under normal conditions, while in
severe diabetes acetone odor may be detected in breath or urine
thiolase HMGCoA synthase
HMGCoA lyase
β-hydroxy butyrate
dehydrogenase
Utilization of ketone bodies at extrahepatic tissues
( Ketolysis):
Under well-fed, healthy conditions, skeletal muscles derive a small
portion of their daily energy needs from acetoacetate, and heart
muscles use it in preference to glucose.
During the early stages of starvation, heart and muscle tissues burn
larger quantities of acetoacetate, thereby preserving glucose for use
in the brain. In prolonged starvation, even the brain can switch to
ketone bodies to meet up to 75% of its energy needs.
Ketolysis (utilization of ketone bodies) does not occur in liver

because liver does not contain the enzymes responsible for this
process
β-hydroxybutyrate is reconverted to
acetoacetate by β-hydroxybutyrate
dehyrogenase
Reactivation of acetoacetate by
mitochondrial enzyme β-ketoacyl-
CoA transferase(thiophorase),
present in non hepatic tissues, that uses
succinylCoA as source of CoA
Then, acetoacetylCoA is cleaved into

2 acetyl-CoA molecules by thiolase
what happens to these
two acetyl-CoA?
How many total ATP
from 2 acetyl-CoA?
6 NADH
2 FADH2
2 GTP
18 ATP
4 ATP
2 ATP
24 ATP
Enter Kreb’s cycle with

production of energy
ketosis
The condition in which ketone bodies are produced faster than

they are utilized (ketosis) occurs in diabetes. It is indicated by
the odor of acetone (a highly volatile ketone) in the patient’s
breath and the presence of ketone bodies in the urine
(ketonuria) and the blood (ketonemia).
Ketoacidosis
Two of the ketone bodies are carboxylic acids.
Ketoacidosis results from increased concentrations of ketone bodies in
the blood. The blood’s buffers mainly bicarbonate are depleted and blood
pH drops.
Ketoacidosis if untreated may lead to coma and death as in sever
uncontrolled diabetes.
CH3-CO-CH2-COOH + NaHCO3 CH3-CO-CH2-COONa +
H2CO3
H2CO3 H2O + CO2
Causes of ketosis: When there is high rate of fatty acid oxidation & lipolysis.
I-Non-pathologic:
a-Starvation b-carbohydrate poor diet
c-High fat diet d-sever exercise
II-pathological:
Diabetes mellitus
Increase glucagon & decrease insulin levels in blood will increase lipolysis &
release of FFAs in blood that undergo β-oxidation in the liver.
When the amount of acetyl CoA increases above the capacity of TCA cycle
to oxidize it, the excess amount will be directed to the formation of ketone
bodies.

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Dr Howaida Nounou

Ketogenesis (synthesis of ketone

Normal physiological responses to carbohydrate

The Brain oxidizes KB but not Fat

In Step 2, a third acetyl-CoA and a water molecule react with

thiolase HMGCoA synthase

Ketolysis (utilization of ketone bodies) does not occur in liver

Then, acetoacetylCoA is cleaved into

Enter Kreb’s cycle with

The condition in which ketone bodies are produced faster than

H2CO3 H2O + CO2

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