Fatty Acid Synthesis

Question 1

Acetyl CoA carboxylase

Answer 1

• A biotin containing enzyme
• The regulated step in fatty acid synthesis
• converts acetyl CoA to malonyl CoA
• induced by citrate and insulin
  
  • activated when phosphate group removed by insulin induced phosphatase
• inhibited by palmitoyl CoA
  
  • low energy levels (AMP-activated protein kinase, including cAMP dependent PKA) induce phosphorylation of acetyl CoA carboxylase inactivating it

Question 2

Fatty acid synthase

Answer 2

• dimer with 2 identical subunits
  
  • phosphopantetheine (vit. B5) and a cysteine amino acid; both attach to FA’s via SH groups
• each subunit contains 7 enzyme activities and an acyl carrier group (often called “acyl carrier protein”)
  
  • The acyl carrier group contains a phosphopantetheine (vit. B5) prosthetic group

Question 3

Steps in fatty acid synthesis

Answer 3

• 1st time only: acetyl CoA binds to P-site of FA synthase
• moves to SH-site and malonyl CoA binds to P-site
• coupling condensation b/w the 2 on FA synthase
• reduction of chain; loss of H2O; reduction of chain
• moves to SH-site and malonyl CoA binds to P-site
• coupling condensation
• reduction; loss of H2O; reduction
• moves to SH-site and malonyl CoA binds to P-site
• continues until 16-carbon chain is formed

Question 4

Elongation of Palmitate to longer chain FA

Answer 4

• fatty acyl-CoA synthetase
  
  • attaches acetyl CoA to palmitate
• FA elongase
  
  • multienzyme complex
• occurs in the smooth ER

The brain especially needs the very-long-chain FA (C22-C24)

Question 5

Desaturation of fatty acids to create double bonds

Answer 5

• occurs in the ER
• uses molecular oxygen
• both FA and NADH are oxidized
• the desaturase enzyme cannot introduce double bonds b/w carbons beyond carbon-10 and the terminal methyl carbon
  
  • CAN introduce double bonds b/w the carboxyl end and C-10
• typically the first double bond is inserted b/w carbons 9 and 10
• humans have carbon 9, 6, 5, and 4 desaturases, but cannot introduce double bonds from carbon 10 to the omega end of the chain

Example: palmitate (C16)===> palmitoleic acid (C16:1) w/ double bond b/w 9-10

Question 6

Essential fatty acids are needed

b/c

Answer 6

• we cannot form double bonds beyond C-10

Question 7

Long-term regulation of fatty acid synthesis

Answer 7

• induction of 5 key enzymes all contribute to increased FA synthesis
  
  • Citrate lyase
  • Acetyl CoA carboxylase
  • G6PD
  • Malic enzyme
  • FA synthase
• enzymes are increased:
  
  • good diet over time
  • high carbohydrate or fat free diet
• enzymes are decreased:
  
  • fasting or on a high fat diet

Question 8

Preventing “futile cycles” b/w FA synthesis and FA oxidation

Answer 8

• malonyl CoA prevents newly formed FA-CoA from being transferred by carnitine back into the mitochindria to be metabolized by beta-oxidation
  
  • malonyl CoA blocks carnitine palmitoyl transferase 1 (CPT-1) on the outer mitochondrial membrane

Question 9

Triglyceride synthesis

Answer 9

• start w/ backbone glycerol-3-phosphate
  
  • liver has choice of 2 paths
  • adipose has only 1 path
• add 3 acyl-CoA chains, one at a time by acyltransferase

Question 10

Sources of glycerol phosphate in triacylglycerol synthesis

Answer 10

• liver can get glycerol phosphate from either glycolysis or from glycerol via glycerol kinase
  
  • glycerol kinase only exists in the liver
• adipose can only get glycerol from glycolysis (adipose lacks glycerol kinase)

Question 11

Preventing “futile cycles” b/w TG synthesis and TG breakdown in adipose

Answer 11

• prevented by the fact that adipose does not contain glycerol kinase
  
  • therefore when HSL (on action of glucagon) breaks down TG to glycerol + 3FA, they cannot be reformed to TG (a futile cycle) unless insulin is around to bring glucose into the adipose to make glycerol-3-phosphate. These are 2 diff. sets of conditions-fed and fasted

Question 12

ApoB100

Answer 12

• made on RER
• attached to VLDL
• derived from the same gene as apoB48
• allow VLDL to enter cells through lipoprotein lipase

Question 13

ApoB48

Answer 13

• attached to chylomicrons
• derived from same gene as apoB100
• allow chylomicrons to enter cells through lipoprotein lipase

Question 14

Lipoprotein lipase

Answer 14

• secreted in response to insulin

- activated in response to apoprotein C-11

Question 15

Obtaining NADPH for lipogenesis

Answer 15

• Provided by (1) the pentose pathway and (2) the malic enzyme

Question 16

OAA to Malate enzyme

Answer 16

• cytosolic malate dehydrogenase

* consumes an NADH forming NAD+

Question 17

Conditions for FA synthesis

Answer 17

when there are lots of reactants:

- ↑ ATP, ↑ Acetyl CoA, ↑ NADPH (lots of citrate in TCA cycle)