Download Fatty acid synthesis

Fatty acid synthesis
Dr. Nalini Ganesan M.Sc., Ph.D
Associate Professor
Department of Biochemistry
SRMC & RI (DU)
Porur, Chennai - 116
Harper’s biochemistry 24th ed, Pg 218
Fatty acid Synthesis
• Known as lipogenesis
• Extramitochondrial
• Highly active process
• Elongation takes place in microsomes
•Takes place primarily in liver & lactating
mammary glands
• To lesser extent in adipose tissue &
kidney
Harper’s biochemistry 24th ed, Pg 218
Biomedical importance
• Reduced importance in humans
• Critical diseases of this pathway has not
been reported because of this.
• Variation in its activity between individuals
may have an effect on the nature and extent
of obesity.
• Inhibition of lipogenesis is the lesion in
Type I diabetes mellitus
Harper’s biochemistry 24th ed, Pg 218 -219
Rate controlling step in Fatty acid synthesis
Production of Malonyl CoA
CH3-CO~s-CoA
Enz-biotin -* COO-
-OO
*C-CH2-CO~S-CoA
Enz-biotin
ADP + Pi
ATP + HCO3- + Enz-biotin
Enz – Acetyl CoA Carboxylase
Biochemistry – Pamela - 2nded- Pg175
Allosteric regulation of acetyl CoA carboxylase
Citrate
+
Protomer
(inactive)
Polymer
(active)
Malonyl CoA, Palmitoyl CoA
Biochemistry – Pamela - 2nded- Pg174
Production of cytoplasmic Acetyl CoA
Mitochondrial acetyl CoA is produced from
• Oxidation of pyruvate
•Degradation of fatty acids
•Degradation of ketones bodies
•Degradation of amino acids
Coenzyme A portion of acetyl Co A cannot
cross mitochondrial membrane
Acetyl CoA combines with Oxaloacetate to form
Citrate
Citrate enters into the cytoplasm and gets cleaved by
citrate lyase.
Provision of acetyl CoA
Harper’s biochemistry 24th ed, Pg 216
Fatty acid synthase complex
• Multienzyme complex
• Dimer with head to tail arrangement
• Each monomer have seven enzymes
• Encoded by single gene
Harper’s biochemistry 24th
ed, Pg 216
Fatty acid synthase complex
• Contains acyl carrier protein (binds to acyl radical)
• ACP contains pantothenic acid
• Performs the role of CoA
• Performs with great efficiency
• Three domains
Condensing unit - Acetyl transferase
Malonyl transferase
α ketoacyl synthase
Reduction unit - ACP
β ketoacyl reductase
dehydrase
Releasing unit
- Thioesterase
www.rpi.edu/dept/bcbp/molbiochem/MBweb/
Fatty acid synthase complex
Harper’s biochemistry, 24th ed. Pg218
Biosynthesis of long chain fatty acids
CO2
Acetyl-CoA
Malonyl CoA
C2
Acetyl-CoA Carboxylase C3
Acetyl Transacylase
HS-Pan- 1 -Cys-SH
MalonylCoA
Transacylase
- 1 -Cys –S~CO-CH3
HS-Cys- 2 -Pan-SH
- 2 -Pan –S~CO-CH -COO2
Fatty Acid synthase
multienzyme complex
Acyl(acetyl)-malonylenzyme
Harper’s biochemistry, 24th ed. Pg218
Biosynthesis of long chain fatty acids
Acyl(acetyl)-malonylenzyme
- 1 -Cys –S~CO-CH3
- 2 -Pan –S~CO-CH2-COO-
3-ketoacyl synthase
CO2
1
- 1 -Cys –SH
3-ketoacyl enzyme
- 2 -Pan –S~CO-CH2-CO-CH3
3-ketoacyl reductase
D(-)3-hydroxyacyl enzyme
NADPH + H+
NADP+
2
- 1 -Cys –SH
- 2 -Pan –S~CO-CH2-CHOH-CH3
Harper’s biochemistry, 24th ed. Pg 218
Biosynthesis of long chain fatty acids
- 1 -Cys –SH
D(-)3-hydroxyacyl enzyme
- 2 -Pan –S~CO-CH2-CHOH-CH3
Hydratase
H2O
3
- 1 -Cys –SH
2,3 unsaturated acyl enzyme
- 2 -Pan –S~CO-CH=CH-CH3
Enoyl reductase
NADPH + H+
NADP+
4
- 1 -Cys –SH
Acylenzyme
- 2 -Pan –S~CO-CH2CH2-CH3
Harper’s biochemistry, 24th ed. Pg 218
Biosynthesis of long chain fatty acids
Acyl enzyme
Transferred from 2nd position of FAS complex to the 1st
Undergoes steps 1 –4 six more times to form palmitate
Thioesterase
Palmitate
+
FAS
Harper’s biochemistry, 24th ed. Pg 219
Overall equation for the synthesis of palmitate
from acetyl CoA and malonyl CoA
CH2CO.S.CoA+ 7HOOC.CH2.CO.S.CoA + 14NADPH + 14H+
CH3(CH2)14COOH + 7 CO2 + 6H2O + 8CoASH + 14NADP+
Harper’s biochemistry 24th ed, Pg 219
Sources of NADPH
• HMP pathway
• Malic enzyme
• Cytosolic isocitrate dehydrogenase
Harper’s biochemistry 24th ed, Pg 219
Fate of palmitate after biosynthesis
Acylglycerol
Cholesterol esters
Esterfication
ATP + CoA
Palmitate
AMP + PPi
Palmityl CoA
Acyl-CoA
Synthase
Chain elongation
desaturation
Acyl CoA
Harper’s biochemistry 24th ed, Pg 221
Fatty acid elongation
• Takes place in microsomes
• Malonyl CoA donates acetyl CoA
• Fatty acids having more than 10 carbon atoms
acts as a primer
• Fasting abolishes elongation
• Elongation process is very active during myelination
in brain
Harper’s biochemistry 24th ed, Pg 221 -222
Regulation of lipogenesis
• Nutritional state
Main factor
Depressed under conditions of restricted calorie
intake
High fat diet
Deficiency of insulin
Harper’s biochemistry 24th ed, Pg 221 -222
Regulation of lipogenesis
•Short term mechanism
Allosteric and covalent modification of enzymes
Acetyl CoA carboxylase & Pyruvate dehydrogenase
•Long term mechanism
Changes in gene expression governing rates of
synthesis of enzymes
Harper’s biochemistry 24th ed, Pg 221 -222
Regulation of lipogenesis
• Hormones
Insulin – Stimulates lipogenesis by increasing
the transport of glucose into cells
Activates pyruvate dehydrogenase &
acetyl CoA carboxylase
Depresses cAMP levels inhibits lipolysis
in adipose tissue
Glucagon & Epineprine antagonizes the action of insulin
• Fatty acid synthase Complex and
acetyl CoA carboxylase are adaptive enzymes
THANK YOU