1. BIOSYNTHESIS OF
FATTY ACIDS
Hendra Wijaya
Esa unggul University

2. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL

3. TRANSPORT OF ACETYL-COA INTO THE CYTOSOL
Acetyl-CoA generated in the mitochondrion
Mitochondrial membrane is impermeable to acetyl-CoA
Acetyl-CoA enters the cytosol in the form of citrate
Processing of malate to pyruvate generates NADPH for fatty acid biosynthesis

4. OVERVIEW OF FATTY ACID SYNTHESIS

5. SYNTHESIS OF FATTY ACID
MOVIE

6. Acetyl-CoA Carboxylase reaction

8. Acetyl-CoA Carboxylase reaction
Irreversible reaction that is the committed step in fatty acid synthesis
Biotin-dependent
Mechanism similar to that of pyruvate carboxylase
Subject to allosteric and hormonal control
Stimulated by citrate, inhibited by long-chain fatty acids
Phosphorylation, which inhibits enzyme activity, is promoted by glucagon and reversed by insulin

9. Intermediates in Fatty Acid Synthesis are Linked to Acyl Carrier Protein (ACP)

10. REACTION SEQUENCE FOR FATTY ACID BIOSYNTHESIS
Intermediates attached to the sulfhydryl terminus of a phosphopantetheine group
Phosphopantetheine linked to Ser hydroxyl of ACP, while attached to AMP in CoA
ACP can be considered a big CoA molecule
Individual enzymes in bacteria, enzyme complex in eukaryotes
Condensation of malonyl-CoA and acetyl-CoA driven by decarboxylation
Stereochemistry and reducing agent are different between synthesis and degradation
In subsequent round of elongation, butyryl thioester condenses with malonyl-ACP after transfer to condensing enzyme
Elongation cycles continue until palmitoyl(C16)-ACP is formed, which is hydrolyzed to give palmitate and ACP

11. STOICHIOMETRY OF FATTY ACID BIOSYNTHESIS
Stoichiometry of palmitate synthesis:
Acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14H palmitate + 7CO2 + 14NADP+ + 8CoA + 6H2O
Malonyl-CoA synthesis:
7 Acetyl-CoA + 7CO2 + 7ATP
7 malonyl-CoA + 7ADP + 7Pi + 7H+
Overall stoichiometry of palmitate synthesis:
8 Acetyl-CoA + 14 NADPH + 7ATP + 7H+
palmitate + 14NADP+ + 8CoA + 6H2O + 7ADP + 7Pi

13. FATTY ACID ELONGATION
In eukaryotes, elongation occurs in both mitochondria and the endoplasmic reticulum (ER), but the ER system has much higher activity
Reactions occur on separate enzymes rather than in a complex
Fatty acid is elongated as its CoA derivative
Two carbon units are added sequentially the carboxyl end of both saturated and unsaturated fatty acids
Malonyl-CoA is again the two-carbon donor

14. FATTY ACID DESATURATION
Double bonds are introduced into long-chain acyl-CoAs through an electron-transfer process coupled to the reduction of molecular oxygen
Reaction catalyzed by a complex of membrane-bound enzymes
Double bonds inserted such that the new double bond is three carbons closer to the CoA group, and never beyond the C9 position

15. ESSENTIAL FATTY ACID
The formation of D12 and D15 double bonds is not possible in animals
Animals cannot synthesize linoleic acid (18:2D9,12), linolenic acid (18:3D9,12,15), or arachidonic acid (20:4 D5,8,11,14), which are used in the synthesis of eicosanoid hormones
Prostaglandins
Leukotrienes
These are called essential fatty acids because they are essential lipid components that must be provided in the diet

19. BIOSYNTHESIS OF
TRIACYLGLYCEROL

21. TRIACYLGLYCEROL (TG) SYNTHESIS
Generally synthesized from glycerol 3-phosphate, which is produced by the reduction of dihydroxyacetone phosphate (DHAP)
Acylations performed with acyl-CoA and acyltransferases
Fatty acyl chain at C1 is usually saturated, fatty acyl chain at C2 is usually unsaturated
TG and phospholipid pathways generally diverge at phosphatidic acid and diacylglycerol
Diacylglycerol formed by phosphatase
Acyltransferase forms TG

23. CONFORMATIONAL MODEL OF (A) PHOSPHOLIPID PHOSPHATIDYLCHOLINE AND (B) TRIACYLGLYCEROL

25. GLYCEROPHOSPHOLIPID

26. GLYCEROPHOSPHOLIPIDS: Membrane
Lesitin
C1 substituents mostly saturated fatty acids, C2 substituents mostly unsaturated fatty acids
PE, PG, and CL found in bacteria, eukaryotes contain all six
Phospholipases serve as digestive enzymes and as generators of signal molecules

28. CTP: Citidene Tryphosphate

30. Biosynthesis Of PhospatidylserineI: CDP-Diacylglycerol Pathway
Sytosin
CTP: Citidene Tryphosphate

31. Biosynthesis Of Phospatidylcholine: CDP-Choline & CDP-ethanolamine

32. PHOSPHOLIPID SYNTHESIS

35. KETON BODIES

36. 4/21/2017
Metabolisme Lipida

37. KETONE BODIES
Acetyl-CoA from fatty acid oxidation enters the citric acid cycle when fat and carbohydrate breakdown are balanced
Entry depends on oxaloacetate
Oxaloacetate consumed to form glucose by gluconeogenesis in fasting, diabetes, and starvation
In the absence of oxaloacetate, acetyl-CoA is converted to acetoacetate or D-b-hydroxybutyrate through ketogenesis
Acetone is formed by the non-enzymatic decarboxylation of acetoacetate
Ketone bodies are important fuel molecules
OVERVIEW

38. Formation of keton bodies from acytil-CoA
Initial condensation
Ester condensation to form HMG-CoA (also precursor in cholesterol biosynthesis)
Acetoacetate and acetyl-CoA formed in a mechanism similar to the reverse of the citrate synthase reaction

39. Metabolic Conversion of Ketone Bodies to Acetyl-CoA S
Acetoacetate reduced to hydroxybutyrate in an NADH-dependent reaction
Acetoacetyl-CoA can be cleaved by thiolase to give 2 acyl-CoA
The liver can supply acetoacetate to other tissues

44. Cholesterol

50. SPHINGOLIPIDS

51. SPHINGOLIPIDS

52. SPHINGOLIPIDS

53. SPHINGOLIPIDS Backbone is ceramide rather than glycerol
Most sphingolipids contain carbohydrates as their head group
Sphingolipids play important roles in nervous tissue
Sphingomyelin is an important component of the myelin sheath
Gangliosides constitute 6% of the lipids in gray matter

54. SYNTHESIS OF CERAMIDA

55. Toy-Sachs Disease: A Disorder of Ganglioside Breakdown
Gangliosides are degraded inside lysosomes by the sequential removal of terminal sugars
In Tay-Sachs disease, ganglioside GM2 accumulates because hexosaminidase activity is absent
This ganglioside interferes with neuronal function
Genetic recessive disease

56. MEMBRANE LIPIDS Have a hydrophilic and hydrophobic component
1,2-diacylglycerol or N-acetylsphingosine (ceramide) linked to a polar head group
Hydrophobic acyl chains
Form bilayered membranes in aqueous media
Membranes are noncovalent, fluid assemblies
Membrane lipids synthesized predominantly on the cytoplasmic face of the ER, then transported in vesicles to their destinations

57. β
-OXIDATION vs
BIOSYNTHESIS

58. FATTY ACID BIOSYNTHESIS VS β-OXIDATION

60. TERIMA KASIH