Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the...

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Synthesis of Fatty Acids and Triacylglycerol Lippincott’s Chapter 16

Transcript of Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the...

Page 1: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Synthesis of Fatty Acids

and Triacylglycerol

Lippincott’s Chapter 16

Page 2: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

β Oxidation of Fatty Acids (overview)CH3 (CH2)n-CH2-CH2- COO-

CH3 (CH2)n -CH2-CH2-CO ~CoA

O

CH3 (CH2)n -C-CH2-CO ~CoA

CH3 (CH2)n -CO ~CoA + CH3-CO ~CoA

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?

?

?

Page 4: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Palmitic Acid

8Acetyl CoA

7FADH2

+7NADH

8CoA

Oxaloacetate

8CoA

GlucoseKetone bodies

CO2

CO2

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Fatty Acid Synthesis

• Mainly in the Liver

• Requires

– Carbon Source: Acetyl CoA

– Reducing Power: NADPH

8 CH3COO ➔ C15H33COO

– Energy Input: ATP

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Why Energy ?

Fatty Acid

Acetyl CoA

ΔGo

: -ve

Acetyl CoA

Fatty Acid

ΔGo

: +ve

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Why Energy ?

Fatty Acid

Acetyl CoA

ΔGo

: -ve

Acetyl CoA + n(ATP)

Fatty Acid + n(ADP)

ΔGo

: -ve

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FA Degradation and Synthesis

Acyl CoA (n)

↓ Oxidation

↓ Hydration

↓ Oxidation

↓ Thyolysis

Acyl CoA (n-2)

+

Acetyl CoA

Acyl CoA (n+2)

↑ reduction

↑ dehydration

↑ reduction

↑ condensation

Acyl CoA(n) + Malonyl CoA

AcetylCoA

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Carboxylation of Acetyl CoA

Produces Malonyl CoA

O O Oװ װ װ

CH3-C-CoA -OC-CH2-C-CoA

Acetyl CoA Carboxylase

Biotin-Containing Enzyme

CO2

ATP ADP + Pi

Page 10: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Fatty Acid Synthase Catalyzes the

remaining steps

• Multifunctional Enzyme Complex

• Dimer of two Identical Chains

• Each has Seven Catalytic Activities

– One activity is Condensing Enzyme with –SH

• One Domain is known as Acyl Carrier Protein

– Carries Intermediates during Catalysis

– (Acyl, Acetyl and Malonyl Groups)

– A protein joined to Phosphopantheine group

– Reactive SH group

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Adenine

Ribose

Pantothenic acid

β-Mercapto

ethylamine

phosphate

Phosphopantetheine group is part of ACP

and ?

Protein

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Fatty Acid Synthesis (Overview)

Acetyl-CE (Acyl-CE) + Malonyl ACP(n) (3)

CO2

Ketoacyl ACP(n+2)

Acyl ACP

Page 13: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

CH3CO~S-CE + OOC-CH2-CO~ACP

Acetyl Malonyl-ACP

(Acyl)

CO2

HS-CE

O║

CH3C-CH2-CO~ACP

Ketoacyl- ACP

Page 14: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Reduction of the Ketoacyl GroupO

CH3C-CH2-CO~ACP Ketoacyl- ACP

OHl

CH3CH-CH2-

H2O

CH3CH=CH-

CH3CH2-CH2-CO~ACP

NADPH

NADPH

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Synthesis of Palmitate by Fatty Acid Synthase

Page 16: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Synthesis of Palmitate by Fatty Acid Synthase (Cont.)

Page 17: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Synthesis of Palmitate (net reaction)

How many cycles of synthesis (Condensation)?

* 7

How many Malonyl CoA?

* 7

How many Acetyl CoA?

* 1

How Many NADPH?

* 14

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Production of

Cytosolic Acetyl CoA

for FA Synthesis

Inner mitochondrial

membrane is

immpermiable to

Acetyl CoA

Page 19: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

NADH

NAD+

Production of NADPHo Pentose Phosphate

Pathway

o NADP- dependent

malate

Dehydrogenase

NADPHThe Fate of

Oxaloacetate

Page 20: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Pyruvate + CO2

NADPH

NADP+

Malate

Return of Oxaloacetate

NAD+

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Regulation of FA Oxidation & Synthesis

OXIDATION

• Supply of Fatty Acids

-Hormonal Control

• Entry into Mitochondria

• Availability of NAD+

SYNTHESIS

• Regulation of AcCoA Carboxylase

-Allosteric Mechanism

- Phosphorylation

• Amounts of Enzymes

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Allosteric Regulation of

Acetyl CoA Carboxylase

Page 23: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Hormone-Mediated,

Covalent Regulation of

Acetyl CoA

Carboxylase ACC

Page 24: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Regulation of FA Oxidation & Synthesis

OXIDATION

• Supply of Fatty Acids

-Hormonal Control

• Entry into Miochondria

• Availability of NAD+

SYNTHESIS

• Regulation of AcCoA Carboxylase

-Allosteric Mechanism

- Phosphorylation

• Amounts of Enzymes

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↑Fatty Acids

Fatty Acyl CoA

Fatty Acyl Carnitine

Acetyl CoA

-

-

Malonyl CoA

↑NADH

Regulation of FA Oxidation

Acetyl CoA

ACC

Page 26: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains
Page 27: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Elongation of Fatty Acids

-in Endoplasmic Reticulum

- Similar Sequence of Reactions

- Different Enzymes

Malonyl CoA + Acyl CoA(n)

↓ 2NADPH + H+

↓ 2NADP+

Acyl CoA (n+2)

n = 16 or more carbons

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Elongation of Fatty Acids

in Mitochondria

Acetyl CoA + Acyl CoA (n)

↓↑

↓↑ NADH + H+

↓↑ NAD+

NADPH

NADP+

Acyl CoA (n+2)

n = less than16 carbons

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Introduction of Double Bonds

• Synthesis of Monounsaturated FA

- Oleic Acid 18:Δ9

- Palmitoleic 16:Δ9

• In endoplasmic reticulum

• No double bond can be introduced beyond

carbon 9 in human

Page 30: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Introduction of Double Bonds (Cont.)

Stearoyl CoA

NADPH + O2

NADP++2H2O

Oleoyl CoA

Δ9 Desaturase; Cytochrome b5

Palmitoyl CoA

Palmitoleoyl CoA

Page 31: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Introduction of Double Bonds (Cont.)

Formation and Modification of Polyunsaturated FA

-Elongation

- Desaturation

Additional double bonds can be introduced by:

Δ4 Desaturase

Δ5 Desaturase

Δ6 Desaturase

Page 32: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Modification of Polyunsaturated FALinoleic 18:2Δ9,12

Desaturation

18:3Δ6,9,12 ω ?

Elongation

20:3Δ8,11,14 ω ?

Desaturation

20:4Δ5,8,11,14 ω ? Arachidonic

Page 33: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Biosynthesis of Triacylglycerol &

Phosphoacylglycerol

G

L

Y

C

E

R

O

L

FATTY ACID

FATTY ACID

FATTY ACID

TRIACYLGLYCEROL

G

L

Y

C

E

R

O

L

FATTY ACID

FATTY ACID

PHOSPHOACYLGLYCEROL

PHOSPHATE

ALCOHOL

Page 34: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Phosphotadic Acid is Common Intermediate

G

L

Y

C

E

R

O

L

FATTY ACID

FATTY ACID

PHOSPHOACYLGLYCEROL

PHOSPHATE

Page 35: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Biosynthesis of TriacylglycerolRequires

• Acyl~CoA (Active form of FA)

• Glycerol Phosphate

Why Active form?

TAG + H2O DAG + FA ΔG –ve

DAG + FA TAG + H2O ΔG +ve

DAG + Acyl~CoA TAG + CoA ΔG –ve

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Page 37: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains
Page 38: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Production of Glycerol Phosphate- Glycerol + ATP ---→ Glycerol 3 Phosphate

Enz: Glycerol Kinase

Not in Adipose tissue

CH2OH CH2OHI IC = O C HOHI ICH2OPO3 CH2OPO3

NADH NAD+

Page 39: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

Production of Glycerol Phosphate

Page 40: Synthesis of Fatty Acids and Triacylglycerol · 2020. 11. 30. · Fatty Acid Synthase Catalyzes the remaining steps • Multifunctional Enzyme Complex • Dimer of two Identical Chains

DHAP

Glycerol- FA~CoA

TAG

Glycerol + Fatty Acids

P

Glucose