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Chapter 16 (Part 3). Fatty acid Synthesis. Fatty Acid Synthesis. In mammals fatty acid synthesis occurs primarily in the liver and adipose tissues Also occurs in mammary glands during lactation. Fatty acid synthesis and degradation go by different routes

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Chapter 16 part 3

Chapter 16 (Part 3)

Fatty acid Synthesis


Fatty Acid Synthesis

  • In mammals fatty acid synthesis occurs primarily in the liver and adipose tissues

  • Also occurs in mammary glands during lactation.

  • Fatty acid synthesis and degradation go by different routes

  • There are four major differences between fatty acid breakdown and biosynthesis


The differences between fatty acid biosynthesis and breakdown

  • Intermediates in synthesis are linked to -SH groups of acyl carrier proteins (as compared to -SH groups of CoA)

  • Synthesis in cytosol; breakdown in mitochondria

  • Enzymes of synthesis are one polypeptide

  • Biosynthesis uses NADPH/NADP+; breakdown uses NADH/NAD+


Acp vs coenzyme a
ACP vs. Coenzyme A breakdown

  • Intermediates in synthesis are linked to -SH groups of acyl carrier proteins (as compared to -SH groups of CoA)


Citrate Lyase breakdown

Citrate synthase

Malate

dehydrogenase

Pyruvate

carboxylase

Malate Enzyme

Fatty Acid Synthesis Occurs in the Cytosol

  • Must have source of acetyl-CoA

  • Most acetyl-CoA in mitochondria

  • Citrate-malate-pyruvate shuttle provides cytosolic acetate units and reducing equivalents for fatty acid synthesis


Fatty acid synthesis
Fatty Acid Synthesis breakdown

  • Fatty acids are built from 2-C units derived from acetyl-CoA

  • Acetate units are activated for transfer to growing FA chain by conversion to malonyl-CoA

  • Decarboxylation of malonyl-CoA and reducing power of NADPH drive chain growth

  • Chain grows to 16-carbons (eight acetyl-CoAs)

  • Other enzymes add double bonds and more Cs


Acetyl coa carboxylase
Acetyl-CoA Carboxylase breakdown

Acetyl-CoA + HCO3- + ATP  malonyl-CoA + ADP

  • The "ACC enzyme" commits acetate to fatty acid synthesis

  • Carboxylation of acetyl-CoA to form malonyl-CoA is the irreversible, committed step in fatty acid biosynthesis


Acetyl coa carboxylase1
Acetyl-CoA breakdown Carboxylase


Regulation of Acetyl-CoA Carboxylase (ACCase) breakdown

  • ACCase forms long, active filamentous polymers from inactive protomers

  • Accumulation of palmitoyl-CoA (product) leads to the formation of inactive polymers

  • Accumulation of citrate leads to the formation of the active polymeric form

  • Phosphorylation modulates citrate activation and palmitoyl-CoA inhibition


Regulation of Acetyl-CoA Carboxylase (ACCase) breakdown

  • Unphosphorylated ACCase has low Km for citrate and is active at low citrate

  • Unphosphorylated ACCase has high Ki for palmitoyl-CoA and needs high palmitoyl-CoA to inhibit

  • Phosphorylated E has high Km for citrate and needs high citrate to activate

  • Phosphorylated E has low Ki for palmitoyl-CoA and is inhibited at low palmitoyl-CoA


Fatty acid synthesis1
Fatty Acid Synthesis breakdown

  • Step 1: Loading – transferring acetyl- and malonyl- groups from CoA to ACP

  • Step 2: Condensation – transferring 2 carbon unit from malonyl-ACP to acetyl-ACP to form 2 carbon keto-acyl-ACP

  • Step 3: Reduction – conversion of keto-acyl-ACP to hydroxyacyl-ACP (uses NADPH)

  • Step 4: Dehydration – Elimination of H2O to form Enoyl-ACP

  • Step 5: Reduction – Reduce double bond to form 4 carbon fully saturated acyl-ACP








Termination of fatty acid synthesis
Termination of Fatty Acid Synthesis breakdown

Acyl-CoA

synthetase


Organization of fatty acid synthesis enzymes
Organization of Fatty Acid Synthesis Enzymes breakdown

  • In bacteria and plants, the fatty acid synthesis reactions are catalyzed individual soluble enzymes.

  • In animals, the fatty acid synthesis reactions are all present on multifunctional polypeptide.

  • The animal fatty acid synthase is a homodimer of two identical 250 kD polypeptides.




Regulation of FA Synthesis Elongation

  • Allosteric modifiers, phosphorylation and hormones

  • Malonyl-CoA blocks the carnitine acyltransferase and thus inhibits beta-oxidation

  • Citrate activates acetyl-CoA carboxylase

  • Fatty acyl-CoAs inhibit acetyl-CoA carboxylase

  • Hormones regulate ACC

  • Glucagon activates lipases/inhibits ACC

  • Insulin inhibits lipases/activates ACC


Allosteric regulation of fatty acid synthesis occurs at ACCase and the carnitine acyltransferase


Glucagon inhibits fatty acid synthesis while increasing lipid breakdown and fatty acid b-oxidation

Insulin prevents action of glucagon


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