Chapter 4 metabolism of tag 2015819

Fatty Acid Biosynthesis
• Fatty acid are synthesized and degraded by different
pathways
– from acetyl CoA
– in the cytosol
– intermediates are attached to the acyl carrier
protein (ACP)
– the activated donor is malonyl–ACP
– reduction uses NADPH + H+
– stops at C16 (palmitic acid)


Reactivity of Coenzyme A
(HSCoA)
Nucleophilic acyl substitution
O
CH3CSCoA

HY ••

O
CH3C

Y •• +

HSCoA

Acetyl coenzyme A is a source of an acetyl
group toward biological nucleophiles(it is an
acetyl transfer agent)

Formation of Malonyl Coenzyme A
Formation of malonyl–CoA is the committed
step in fatty acid synthesis


Formation of Acetyl ACP and Malonyl
ACP
• The intermediates(acetyl-ACP and malonyl-ACP) in
fatty acid synthesis are covalently linked to the acyl
carrier protein (ACP)


– To start an elongation cycle, Acetyl–CoA and
Malonyl–CoA are each transferred to an acyl
carrier protein

O
||
CH3—C—S—ACP ( Acetyl-ACP)
O
||
-O—C—CH2—C—S—ACP (Malonyl-ACP)


Condensation and Reduction
In reactions 1 and 2 of fatty
acid synthesis:
• Condensation by a synthase
combines acetyl-ACP with

malonyl-ACP to form
acetoacetyl-ACP (4C) and
CO2 (reaction 1)
• Reduction converts a ketone
to an alcohol using NADPH
(reaction 2)


Dehydration and Reduction
In reactions 3 and 4 of
fatty acid synthesis:
• Dehydration forms a
trans double bond
(reaction 3)
• Reduction converts the
double bond to a single
bond using NADPH
(Reaction 4)


Lipogenesis Cycle Repeats
Fatty acid synthesis continues:
• Malonyl-ACP combines with
the four-carbon butyrylACP to form a six-carbonACP.
• The carbon chain lengthens
by two carbons each cycle


Lipogenesis Cycle Completed
• Fatty acid synthesis

is completed when
palmitoyl ACP
reacts with water to
give palmitate (C16)
and free ACP.


Elongation and Unsaturation
• Endoplasmic reticulum systems introduce double
bonds into long chain acyl–CoA's
– Reaction combines both NADH and the acyl–
CoA's to reduce O2 to H2O
• convert palmitoyl–CoA to other fatty acids
– Reactions occur on the cytosolic face of the
endoplasmic reticulum.
– Malonyl–CoA is the donor in elongation reactions


Summary of Fatty Acid Biosynthesis


The synthesis of TAG
1. Mono-acylglycerol pathway (MAG pathway)
(for dietary fat digestion and absorption)

CH2OCOR
CHOCOR
CH2OCOR
TAG

pancreatic
lipase

FA

CH2OCOR
CHOCOR

pancreatic
lipase

CH2OH
DAG

FA

CH2OH
CHOCOR
CH2OH
MAG

intestinal lumen

FA

FA
ATP,CoA

acyl CoA

acyl CoA

CH2OH
CHOCOR

CH2OCOR
CHOCOR
CH2OCOR
TAG

Chylomicrons

CH2OH
MAG

intestinal epithelium

lymphatic vessels

adipose tissue


2. Diacylglycerol pathway (DAG pathway)
(for TAG synthesis of in adipose tissue, liver and kidney)

glucose

CH 2OH
liver
adipose tissue

CO

NADH+H+

liver
kidney
ATP
ADP

NAD+ CH 2OH

CH2OH

CHOH
CHOH
phosphoglycerol
glycerol kinase
dehydrogenase
CH 2O-PO 3H2
CH2OH
CH 2O-PO 3H2

dihydroxyacetone
phosphate

glycerol

3-phosphoglycerol

RCO¡« SCoA

acyl CoA transferase
HSCoA
CH 2OCOR

HSCoA

CHOCOR
CH 2OCOR

triacylglycerol

RCO¡« SCoA CH 2OCOR
CHOCOR

Pi

H2 O

CH 2OCOR

HSCoA RCO¡« SCoA

CHOH

CHOCOR

CH 2OH
phosphatase CH 2O-PO 3H2
acyl CoA

transferase diacylglycerol
phosphatidate

CH 2OCOR

acyl CoA
transferase

CH 2O-PO 3H2

lysophosphatidate


Catabolism of TAG


Ketosis
In normal metabolic pathway, acetoacetate and bhydroxybutyrate are the ketone bodies which are
converted to acetyl - CoA. However, during starvation
and in uncontrolled diabetes, conc. of acetoactate is very
high and supply of oxaloacetate (a TCA component) is
insufficient,
thus
acetoacetate
spontaneously
decarboxylated to acetone - KETOSIS


 A 4-carbon acid (oxaloacetate) is needed to react with excess
acetyl-CoA and form citrate

 When OAA is not available, excess acetyl - CoA in liver are
condensed to form ketone bodies
 OAA is limited during scarcity of glucose for glycolysis. In starvation
and diabetes, glycogen is broken down. Fatty acids of fat depots
are metabolized to supply ATP needs producing excess of the
ketone bodies


Ketone Bodies
Most of the acetyl-CoA product during fatty acid oxidation is utilized
by the citric acid cycle or in isoprenoid synthesis. In a process called
ketogenesis, acetyl–CoA molecules are used to synthesize
acetoacetate, b-hydroxy butyrate and acetone, a group of molecules
called the ketone bodies
Ketone body formation occurs within mitochondria
Ketone bodies are used to generate energy by several
Tissues, e.g., cardiac and skeletal muscle and brain


Ketone Body Formation


Oxidation of ketone bodies
in brain, muscle, kidney, and intestine
NAD+

NADH

-Hydroxybutyrate

Acetoacetate
-Hydroxybutyrate
dehydrogenase
CoA

2 Acetyl CoA

Succinyl CoA synthetase = loss of GTP

Thiolase

Succinyl CoA

CoA transferase

Acetoacetyl CoA

Succinate

Citric
Acid
Cycle


Conversion of Ketone Bodies to
Acetyl-CoA