Fatty Acyl Synthase and Pentose Phosphate Pathway

1
Lecture 12

• Fatty Acyl Synthase and Pentose Phosphate Pathway

2
Malonyl-CoA

• Activated acetyl-CoA
• Tagged and primed for lipogenesis
• But also a key regulator of fatty acid oxidation
• ACC is not only present in lipogenic tissues
• Also present in tissues that need to produce
  malonyl-CoA in regulatory amounts
• Malonyl-CoA inhibits carnitine palmitoyl
  transferase I (CPT-1)
• a.k.a carnitine acyl transferase I (CAT-1)
• CPT-1 is responsible for forming fatty acyl
  carnitine
• An essential step in fatty acid oxidation
• Only way of getting long chaing fatty acyl-CoAs
  into the mitrochondria
• So when ACC is active in, say, muscle
• Malonyl-CoA concentration rises
• CPT-1 is inhibited
• Fatty acid oxidation stops
• Cell must use carbohydrate instead
• Therefore insulin, by stimulating acetyl-CoA
  carboxylase, encourages carbohydrate oxidation
  and inhibits fatty acid oxidation

3
Fatty Acyl Sythase
4
FAS - simplified
5
Lipogenesis

• Fatty acyl synthase (FAS) is a multi-functional
  enzyme
• Lots of different enzyme activities in the
  complex
• Can you count them all?
• Bringing in acetyl and malonly groups, catalysing
  the reaction between the decarboxylated malonyl
  and the growing fatty acid chain, the
  reduction/dehydration/reduction steps, moving the
  fatty acid to the right site and finally
  releasing it as FA-CoA
• FAS has two free sulfhydry groups on an
  acyl-carring protein
• Keeps the intermediates in exaclty the right
  position for interaction with the right active
  sites
• Each new 2C unit is added onto the carboxy-end
• Each round of 2C addition requires
• 2 molecules of NADPH
• No ATP (!!)
• The release of the carbon dioxide that went on
  during the production of malonyl-CoA
• Thus the carboxylation of acetyl-CoA does not
  result in fixing CO2
• FAs start getting released as FA-CoA when chain
  length is C14
• Desaturation is done AFTER FAS

6
Pentose Phosphate Pathway

• Provides NADPH for lipogenesis
• NADPH - A form of NADH involved in anabolic
  reactions
• Rate of NADPH production by PPP is proportional
  to demand for NADPH
• Key regulatory enzyme is G6PDH
• Glucose 6-phosphate dehydrogenase
• G6P NADP ? 6-phosphogluconolactone NADPH
• The gluconolactone is further oxidised to give
  more NADPH
• But this step also causes decarboxylation to give
  a 5-carbon sugar phosphate (ribulose 5-phosphate)
• Need to put the 5-C sugar back into glycolysis
• Accomplished by rearranging and exchanging carbon
  atoms between 5C molecules
• Catalysed by enzymes called transaldolases and
  transketolases
• So, 5C 5C ? C7 C3 by a transketolase (2C unit
  transferred)
• Then C7 C3 ? C6 C4 by a transaldolase (3C
  unit transferred)
• Then C4 C5 ? C6 C3 by a transketolase (2C
  unit transferred)
• The C6 and C3 sugars can go back into glycolysis
• Alternatively, the PPP can be used to make ribose
  5-phosphate
• Important in nucleotide pathways
• Or the PPP can be used to generate NADPH as an
  anti-oxidant
• Particularly in red blood cells where a
  deficiency in G6PDH can cause anemia

7
Esterification

• Formation of Fat
• Glycerol plus three fatty acids
• Glycerol needs to be glycerol 3-phosphate
• Derived from the reduction of glyceraldehyde
  3-phosphate derived from glycolysis
• Glycolysis important not just for the production
  of acetyl-CoA but for the production of fat!
• Esterification enzyme uses FA-CoA
• Not just FAs
• FAs added one at a time
• Both esterification enzyme and FAS are
  upregulated by insulin
• Gene expression and protein synthesis
• FAS is downregulated when lots of fat around
• As in a Western diet!!

8
Regulatory Overview
Fat
glucose
ESTERIFICATION
GLUT-4
No GS
X
fatty acids
glucose
G6P
G6PDH
glycerol 3-P
FAS
LIPOGENESIS
GLYCOLYSIS
ACC
pyruvate
acetyl-CoA
Acetyl-CoA transport stimulated by increased
production of citrate
acetyl-CoA
pyruvate
PDH
citrate
G6PDH stimulated by demand for NADP
KREBS CYCLE
Insulin stimulates GLUT-4. PDH and ACC. Also
switches on the genes for FAS and esterification
enzyme.
CO2
Krebs cycle will be stimulated by demand for ATP