Lipid metabolism 2

#16

made by Nour omar

corrected by laith sorour

date 17/11

Keton Bodies

Ketone bodies: acetone, -hydroxybutyrate, and acetoacetate

– formed principally in the liver mitochondria.

– can be used as a fuel in most tissues and organs.

• Formation occurs when the amount of acetyl-CoA produced is

excessive compared to the amount of oxaloacetate available to react

with it, because it is being used in gluconeogenesis

– during high intake of lipids and low intake of carbohydrates

– diabetes not suitably controlled

– strenuous exercise

– starvation

*Ketone bodies are formed in the liver. However, the liver does not use keton bodies

for itself. They are transported into other organs.

case of muscle in and brainbodies are important source of energy in Ketone*

).there is no glucose (because exercise )(strenuous severe and starvation

Fats are burned in the flame of carbohydrate: *

تحرق الدهون في نار الكربوهيدرات

*When there is increased fat intake and less carbohydrate intake this lead to

formation of large amount of Acetyl-coA because fatty acids degradation occur and

oxaloacetate is not available (because there is no glucose so it’s used in

gluconeogenesis).

When there is an accumulation of Acetyl-coA: some of which enter the citric acid

cycle and the other form ketone bodies there for keton bodies are formed in the

mitochondrial matrix beside citric acid cycle.

Also beta oxidation of fatty acids occur in mitochondrial matrix (thus these three

beta oxidation of fatty acids& citric acid cycle& keton body formationprocesses:

).matrix mitochondrialin the occur beside each other

The presence of carbohydrate help in consumption of Acetyl-coA:

لذلك ينصح بتناول الحلوى بعد الطعام)الكنافة بعد Acetyl-coAوجود الكربوهيدرات يساعد في استهالك ال

المنسف.(

CH3 -C- CH3

O

CH3 -C- CH2 -COO-

O

CH3 -CH-CH2 - COO-

OH

2 CH3 C-SCoA

O

CH3 CCH2 C- SCoA

OHS-CoA

O

Acetyl-CoA Acetoacetyl-CoA

Acetoacetate -Hydroxybutyrate

NADH

NAD+ + H+

CO2

Acetone

The presence of high level of Acetyl-coA and the absence of oxaloacetate lead to

another pathway which is keton bodies formation.

In case of starvation there is a degradation of fats, so accumulation of Acetyl-coA,

thus diabetes is not suitably controlled.

Brain and muscles prefer ketone bodies in starvation because there is no glucose.

*ketone bodies enter the brain directly unlike the glucose which needs insulin,

because of that we give Alzheimer patients coconut which have a lot of ketone

bodies.

Ketone bodies

include:

1-Acetoacetate.

2-Acetone.

3-Beta-

Hydroxybutyrat

e.

#Acetone is smelled in the breathe of uncontrolled diabetes patients. (Acetone smell

is rotten apple smell). رائحة التفاح المتعفن

# Acetoacetate & beta-Hydroxybutyrate are liked source of energy.

Q: Which tissues can use Keton bodies?

A: Brain, skeletal muscles & Heart.

Q: Why cannot RBCs and Liver use keton bodies for Energy production?

A: RBCs does not contain mitochondria at all & liver lacks some enzymes used for

ketone body formation.

Heart muscle and the renal cortex use acetoacetate in preference to

glucose. Glucose is the major fuel for the brain and red blood cells in

well-nourished people on a balanced diet. However, the brain adapts

to the utilization of acetoacetate during starvation and diabetes. In

prolonged starvation, 75% of the fuel needs of the brain are met by

ketone bodies.

The Heart usually uses fatty acids, but when there is no fatty acids the heart uses

keton bodies because the heart does not use Glucose.

على نفس brain\heartتنافس الحتى ال ي glucoseلال يستخدم ا قلبال من هاد الموضوع ان اكيد في حكمة

. يحتاج تزويد مستمر بالطاقة heartالمصدر و ايضا ال

*last source of energy finished is F.A

*hypoglycemia leads to coma

-CoA Transferase is absent in the liver.

-Acetoacetate contain two Acetyl-CoA molecules so it is a good source of energy.

-As we said before liver transport keton bodies to other organs (Heart, brain

&muscles).

Fatty Acid Biosynthesis

• Biosynthesis is not the exact reversal of oxidation

• Biosynthetic reactions occur in the cytosol

Fatty acid biosynthesis; (reversal of oxidation)

Occur in the cytosol.

All biosynthesis reactions occurred in cytosol.

The starting point of fatty acid synthesis is citrate (with acetyl COA and oxaloacetate)

The end product of fatty acid oxidation is the starting substrate of fatty acid

synthesis.

*Anabolic reactions take place in the cytosol

First reaction is carboxylation reaction … acetyl COA converted to malonyl COA... this

step needs biotin, Mn+2 and ATP .

-Carboxylation of acetyl-CoA in the cytosol

-catalyzed by acetyl-CoA carboxylase

-biotin is the carrier of the carboxyl group

-Malonyl-CoA is key intermediate that is produced

• Step 1: priming of the system by acetyl-CoA

*In fatty acid degradation there is no carrier, , NADH, FADH2 and acetyl coA were

released directly

*Here we need carrier protein called Acyl Carrier Protein (ACP), we build(synthesize)

on it fatty acid then we release it

As in the glycogen we need primer called glycogenin.

*Acyl carrier protein contain pantothenic acid.

.)donor electron( NADPHIn fatty acid synthesis we need *

# The main function of pentose phosphate pathway is to produce NADPH for

reductive biosynthesis (cholesterol biosynthesis, fatty acid biosynthesis, hormone

biosynthesis, bile…. ).

NOTE: NADPH is an electron donor WHILE NADP is an electron carrier.

CH3 C-SCoA

Acetyl-CoA

+ HCO3-

ATP ADP + Pi

CH2 C-SCoA

O

Biotin, Mn 2+COO-

Malonyl-CoA

O

CH3 C-SCoA + HS-ACP CH3 C-S-ACP + HS-CoA

O

Acetyl-CoA Acetyl-ACP

CH3 C-S-ACP

O

Acetyl-ACP

+ HS-Synthase CH3 C-S-Synthase

O

Acetyl-Synthase

+ HS-ACP

+ HS-Synthase CH3 C-S-Synthase

O

Acetyl-Synthase

+ HS-CoA

O

CH3 C-SCoA

Acetyl-CoA

O

*Fats are stored in reduced and dehydrated form so when oxidized it gives large

energy and fats become light.

-Phosphopantetheine group of ACP is similar to phosphopantetheine group of COA

IN STRUCTURE.

• The cycle now repeats on butyryl-ACP

--hydrolysis to remove palmitate (16 carbon atoms ) ---تستمر العملية و يحدث

مرات . 8تتكر العمليه

+ CH2 C-S-ACP

CO2-

Malonyl-ACP

CH3 CH2 CH2 C-S- ACP

O

CH3 CH2 CH2 CH2 CH2 C- S- ACP

Butyryl-ACP

Hexanoyl-ACP

3. condensation

4. reduction

6. reduction

5. dehydration

O

O

Sources of NADPH for Fatty Acid Synthesis

First, oxaloacetate is reduced to malate by NADH. This reaction is catalyzed by a

malate dehydrogenase in the cytosol.

Second, malate is oxidatively decarboxylated by an NADP + -linked malate enzyme

(also called malic enzyme).

CoA that is ne molecule of NADPH is generated for each molecule of acetyl O

Hence, eight molecules of NADPH are transferred from mitochondria to the cytosol.

formed when eight molecules of acetyl CoA are transferred to the cytosol for the

synthesis of palmitate (doesn’t come from TCA this is a new reaction)

The additional six molecules of NADPH required for this process come from the

yathwapentose phosphate p

Synthesis of Fatty Acids

• Repeated turns of this series of reactions occurs to lengthen the growing

fatty acid chain.

• Hexanoyl ACP returns to condense with malonyl ACP during the third turn

of this cycle.

• Longer products also return to condense with malonyl CoA until the chain

has grown to its appropriate length (most often C16).

The difference between synthesis and degradation of lipids is:

Synthesis uses Acetyl-CoA WHILE degradation release Acetyl-CoA.

*Precursor means the beginning

*in synthesis we need malonyl CoA (an intermediate) and in degradation we don’t

need it

*in degradation we don’t need biotin\in carboxylation of synthesis we need it

*degradation is oxidative process we need NAD+\FAD+ and release ATP but

reductive biosynthesis we need ATP and NADPH

*Degradation Begins at carboxyl end and synthesis Begins at methyl end ( CH

3CH2) end

*Degradation: In mitochondria, no ordered aggregate enzymes\Synthesis: In cytosol,

catalyzed by ordered multienzyme complex

degredation intermediate: L- - --- Hydroxyacyl intermediates

synthesis intermediate: D--Hydroxyacyl-ACP intermediates

Fatty Acid Synthase Inhibitors May Be Useful Drugs

• Mice treated with inhibitors of the condensing enzyme showed

remarkable weight loss due to inhibition of feeding.

• The results of additional studies revealed that this inhibition is

due, at least in part, to the accumulation of malonyl CoA.

• Thus, fatty acid synthase inhibitors are exciting candidates both

as antitumor and as antiobesity drugs.

Mammals lack the enzymes to introduce double bonds at carbon

atoms beyond C-9 in the fatty acid chain. Hence, mammals cannot

synthesize linoleate (18:2) and linolenate (18:3). Linoleate and

linolenate are the two essential fatty acids

Since the human body can synthesis only one double bond, Fatty acid Oleate

(omega-9) is not essential because it can be synthesized in the human body (contain

only one double bond).

Arachidonic fatty acid is not essential because it can be produced from Linoleate.