LIPID METABOLISMSYNTHESIS OF FATTY ACIDS

Dr. Vijay Marakala, MBBS, MD.

Assistant professor BIOCHEMISTRY SIMS & RC

SYNTHESIS OF FATTY ACIDS

De Novo synthesis of fatty acids

• Saturated fatty acids are synthesized from acetyl CoA derived from glucose

• Occur in cytoplasm

Elongation of fatty acids

• Acetyl fragments are added to the existing fatty acids

• Occur in both cytoplasm and mitochondria

Desaturation of fatty acids

• Double bonds are introduced into the fatty acids

• Occur in microsomes

Acetyl CoA

Palmitic acid

Stearic acid

Oleic acid

C-2

C-16 fatty acid

C-18 fatty acid

C-18 fatty acid, Unsaturated ∆9

De novo synthesis

Elongation

Desaturation

DE NOVO SYNTHEISS OF FATTY ACIDS

Definition Differences

b/w synthesis and oxidation

Phases of FA synthesis

Reactions [Pathway]

Regulation

Definition

De novo synthesis of fatty acid is the synthesis of saturated fatty

acids from acetyl CoA that is primarily derived from glucose

DE NOVO SYNTHEISS OF FATTY ACIDS

DE NOVO SYNTHESIS OF FATTY ACIDS

» Occurs mainly in LIVER, ADIPOSE TISSUE and LACTATING MAMMARY GLAND

» DE NOVO synthesis means new synthesis from amphibolic compounds

» In FA biosynthesis acetyl-CoA used as PRIMER

» carbohydrate intake - acetyl CoA - fatty acids synthesis

» Occurred in cytosol» Need - acetyl CoA - NADPH ( from HMP shunt )

DE NOVO SYNTHESIS OF FATTY ACIDS

DE NOVO SYNTHESIS OF FATTY ACIDS

FATTY ACID SYNTHESIS VS DEGRADATION

SYNTHESIS DEGRADATION

Intermediates Linked to SH in Proteins (Acyl Carrier Proteins)

Linked to CoASH

Site Cytosol Mitochondria

Enzymes Components of single Peptide

Separate Polypeptides

RedoxCoenzymes

NADP+ / NADPH NAD+ / NADH

PHASES OF DE NOVO FA SYNTHESIS

Phase ITransport of substrates into cytosol

Carboxylation of acetyl-CoA to malonyl-CoA

Phase IIUtilization of substrate to form palmitate

By enzyme complex fatty acid synthase

Phase IIIElongation and desaturation of palmitate

To generate different fatty acids

Phase I

Transport of substrates into cytosolCarboxylation of acetyl-CoA to malonyl-CoA

PHASES OF DE NOVO FA SYNTHESIS

Citrate Citrate

Oxaloacetate

Malate

Pyruvate Pyruvate

Oxaloacetate

Mitochondria Cytosol

ACETYL-CoAACETYL-CoA

PHASE- I

Acetyl-CoA Malonyl-CoA

ATP ADP + Pi

BIOTIN

CO2

Acetyl-CoA carboxylase

Phase I

Transport of substrates into cytosolCarboxylation of acetyl-CoA to malonyl-CoA

Phase II

Utilization of substrate to form palmitateBy enzyme FATTY ACID SYNTHASE COMPLEX

PHASES OF DE NOVO FA SYNTHESIS

FATTY ACID SYNTHASE MULTIENZYME COMPLEX

» Is a polypeptide containing seven enzyme activities and acyl carrier protein (ACP) segment

Acetyl transacylase

Malonyl transacylase

3-ketoacyl synthase

3-ketoacyl reductase

3-hydroxyacyl hydratase

Enoyl reductase

Thioesterase

DE NOVO FA SYNTHESIS

DE NOVO FA SYNTHESIS

Condensation

DE NOVO FA SYNTHESIS

Reduction

DE NOVO FA SYNTHESIS

Dehydration

DE NOVO FA SYNTHESIS

5

Reduction

PALMITATE

THIOESTERASE

H2O

Acetyl CoA

Malonyl CoA

Acetyl S-enzyme

Acetyl malonyl S-enzyme

3-ketoacyl S-enzyme

3-Hydroxyacyl S-enzyme

2,3-Unsaturated acyl S-enzyme

Acyl S-enzyme

Fatt

y ac

id sy

ntha

se m

ultie

nzym

e co

mpl

ex

Acetyl CoA

Acetyl transacylase

Malonyl transacylase

3-ketoacyl synthase

3-ketoacyl reductase

Hydratase

Enoyl reductase

CoASH

Malonyl CoA

CoASH

CO2

NADPH+H+

NADPH

H2O

NADPH+H+

NADPH

Acetyl CoA carboxylase

CO2

ATP

ADP + Pi

Biotin

Palmitoyl S-enzyme

Palmitic acid

Fatt

y ac

id sy

ntha

se m

ultie

nzym

e co

mpl

ex

Thioesterase

Acyl S-enzyme

Fatty acid synthase

4 Carbon

16 Carbon

After cycling through steps - seven times2 5

H2O

REGULATION OF FATTY ACID SYNTHESIS

Enzymes Metabolites End products Hormones Diet

Fatty acid synthesis is regulated by

REGULATION OF FATTY ACID SYNTHESIS

Enzymes • Acetyl CoA carboxylase

Metabolites • Citrate

End products

• Palmitoyl CoA

Hormones• Insulin• Glucagon

Diet • High carbohydrate diet

REGULATION OF FATTY ACID SYNTHESIS

Glucagon

REGULATION OF FA SYNTHESIS

FATTY ACID SYNTHESIS

High carbohydrate diet

Acetyl-CoA carboxylase

Insulin

High fat diet Starvation Diabetes mellitus

+ + +

- --

ELONGATION OF

FATTY ACIDSElongation of fatty

acids

• Acetyl fragments (from malonyl CoA) are added to the existing fatty acids

• Occur in both ER and mitochondria

DESATURATION OF FA