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Fatty Acid Synthesis. Fatty Acid Synthase Acetyl-CoA serves as a primer Addition of two-carbon units from malonyl-CoA Each two-carbon unit added must be reduced by 2 NADPH + 2 H + Reaction for the synthesis of Palmitic acid (C:16): Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14H +

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fatty acid synthesis
Fatty Acid Synthesis
  • Fatty Acid Synthase
    • Acetyl-CoA serves as a primer
    • Addition of two-carbon units from malonyl-CoA
    • Each two-carbon unit added must be reduced by

2 NADPH + 2 H+

    • Reaction for the synthesis of Palmitic acid (C:16):

Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14H+

Palmitic acid + 7 CO2 + 14 NADP+ + 8 CoA + 6 H2O

slide2

Cytosolic Acetyl-CoA & NADPH Generation (presented as in most text books, this scheme ignores the specificities of mitochondrial transporters; a more accurate description is in the handout)

Glycolysis

Mitochondrion

Acetyl-CoA

Pyruvate

Citrate

Pyruvate

Oxaloacetate

TCA cycle

Malate

Citrate

Cytosol

ATP + CoA

Citrate lyase

Malate dehydrogenase

ADP + Pi

Malic enzyme

Pyruvate

Malate

Oxaloacetate + Acetyl-CoA

NADPH

+ H+ + CO2

NADP+

NAD+

NADH+H+

ATP + CO2

Acetyl-CoA

carboxylase

ADP + Pi

Malonyl-CoA

Fatty acid

synthesis

fatty acid synthesis1
Fatty Acid Synthesis
  • Malonyl-CoA is produced by Acetyl-CoA carboxylase

Acetyl-CoA (cytoplasmic) + HCO3-Malonyl-CoA

O

||

CH3-C-S-CoA

O O

|| ||

- O-C-CH2-C-S-CoA

ATP

ADP + Pi

Acetyl-CoA Carboxylase

Requires Biotin

fatty acid synthesis2
Fatty Acid Synthesis
  • Acetyl-CoA Carboxylase
    • Rate limiting reaction for fatty acid synthesis
    • ACC1 is a liver isozyme
    • Small amounts of ACC2 are present in muscle where malonyl-CoA has a regulatory function (Fatty acid oxidation)
fatty acid synthesis3
Fatty Acid Synthesis
  • Acetyl-CoA Carboxylase 1
    • Highly regulated
      • Allosteric activation by citrate; inhibition by palmitoyl-CoA.
      • Inhibited by phosphorylation in the fasting state.
        • (low blood glucose inhibits; phosphorylation state is determined by both glucagon activation of a kinase and insulin activation of a phosphatase).
      • Transcriptional up regulation by ChREBP (high carbohydrate diet increases amount of ACC1 and most other enzymes of fatty acid synthetic pathway)
fatty acid synthesis4

P

P

Transcriptional control

Fatty Acid Synthesis

Acetyl-CoA Carboxylase 1

Xylulose-5-phosphate

Acetyl-CoA

+

Insulin

Transcription

Citrate

Palmitoyl-CoA

H2O Pi

+

+

CO2

ATP

ADP + Pi

Protein phosphatase

Phosphorylated

Acetyl CoA carboxylase

PKA

AMPK

Acetyl CoA carboxylase

Acetyl CoA carboxylase

+

+

(Inactive)

(Active)

ADP + Pi ATP

(Inactive)

Glucagon AMP

Malonyl-CoA

Allosteric regulation

Covalent modification

triacylglycerol synthesis
Triacylglycerol Synthesis
  • Long-term transcriptional regulation by ChREBP (Carbohydrate Regulatory Element Binding Protein).
    • In addition to short term regulation of Acetyl-CoA carboxylase
    • Many enzymes of fatty acid & triacylglycerol synthetic pathway are coordinately regulated by ChREBP.
    • ChREBP is inhibited by Protein Kinase A dependent phosphorylation.
    • ChREBP is activated by Protein Phosphatase 2A dependent dephophorylation (PP2A is stimulated by Xyulose-5-P).

Low Glucose:

Glucagon

cAMP

Protein kinase A

Inactive ChREPB-P

Fatty acid synthesis

High Glucose:

Xyulose-5-P

Protein Phosphatase A2

Active ChREPB-OH

Fatty acid synthesis

fatty acid synthesis5
Fatty Acid Synthesis
  • The main product of fatty acid synthase is palmitic acid (16:0).
  • Fatty acids can be elongated by other enzymes that add two carbon units from malonyl-CoA. Elongation is particularly important in brain.
  • Still other enzymes can add double bonds (usually at 9 ). Omega-3 and omega-6 fatty acids can not be synthesized by humans.
triacylglycerol synthesis1
Triacylglycerol Synthesis
  • Fatty acids must be activated to Acyl-CoA

Fatty acid + CoA + ATP Acyl-CoA + AMP + PPi

PPi + H2O 2 Pi

Acyl-CoA synthetase

Pyrophosphatase

triacylglycerol synthesis2
Triacylglycerol Synthesis
  • Glycerol-3-phosphate is required for triacylglycerol synthesis.

H2C-OH

|

HOCH O

| |

H2C-O-P-O -

||

O -

H2C-OH

|

O=C O

| |

H2C-O-P-O -

||

O -

Glycerol-3-phosphate

dehydrogenase

Dihydroxyacetone Phosphate Glycerol-3-phosphate

NADH + H+ NAD+

Glycerol-3-phosphate dehydrogenase

triacylglycerol synthesis3
Triacylglycerol Synthesis
  • Addition of 3 Acyl groups from Acyl-CoA to Glycerol-3-phosphate

Glycerol-3-phosphate Phosphatidate Triacylglycerol

2 Acyl-CoA CoA Acyl-CoA CoA + Pi

vldl formation
VLDL formation

Apolipoprotien B-100 has a repeating -helix/-sheet structure:

Lipids are packaged as apolipoprotein B-100 is being synthesized:

From Shelness & Sellers (2001) Curr Opin Lipidology 12:151-157

vldl formation1
VLDL formation
  • VLDL stands for Very Low Density Lipoprotein
  • As it is synthesized, VLDL contains:
      • One molecule of apoliprotein B-100
      • Triacylglycerol
      • Phospholipid
      • Cholesterol ester
  • Microsomal Triacylglycerol Transfer Protein(MTP) assists in the formation of the VLDL
  • Other components are added to the VLDL in the blood.
vldl formation2
VLDL formation
  • Apolipoprotein B-100 synthesis is required for the transport of lipid out of the liver
    • If protein synthesis is reduced (e.g. by malnutrition) fat droplets accumulate in the liver.
    • If the rate of lipid synthesis is greatly elevated with respect to protein synthesis (e.g. in type I diabetes or glucose 6-phosphatase deficiency) fat droplets accumulate in the liver.