Fatty Acid Synthesis vs.

Beta oxidation
Michelle Jay G. Francisco
 Mitochondrial beta-oxidation

 Beta-oxidation is the process by which

long chain fatty acyl CoA is degraded.
The products of beta-oxidation are:
 acetyl CoA
 FADH2, NADH and H+
 The overall reaction, using palmitoyl
CoA (16:0) as a model substrate:
 7 FAD + 7 NAD+ + 7 CoASH + 7 H2O +

H(CH2CH2)7CH2CO-SCoA -->
8 CH3CO-SCoA + 7 FADH2 + 7 NADH +
7 H+
 Fate of acetyl CoA
 Oxidation by the citric acid cycle to CO2 and H2O.
 In liver only, acetyl CoA may be used for ketone body
synthesis.

Fate of the FADH2 and NADH + H+

 FADH2 and NADH + H+ are oxidized by the
mitochondrial electron transport system, yielding ATP.
 Four enzymes and reactions

There are four individual reactions of beta-oxidation,

each catalyzed by a separate enzyme:

 Dehydrogenation between the alpha and beta

carbons (C2 and C3) in a FAD-linked reaction.
 Hydration of the double bond by enoyl CoA
hydratase.
 A second dehydrogenation in a NAD-linked reaction.
 Thiolytic cleavage of the thioester by beta-ketoacyl
CoA thiolase.
This sequence of four steps is repeated until the fatty
acyl chain is completely degraded to acetyl CoA.
 Dehydrogenation occurs between the alpha
and beta carbons (C2 and C3) in a FAD-linked
reaction catalyzed by acyl CoA
dehydrogenase.
 The oxidation power of FAD is required to
oxidize the alkyl chain, much as it is in the
succinate dehydrogenase reaction of the
tricarboxylic acid cycle. The product contains
a trans- double bond. Involvement of the
beta-carbon in this and subsequent steps
gives the pathway its name.
 There are three fatty acyl CoA
dehydrogenases. Each is specific for a
different acyl chain length, so different
enzymes are involved in different stages of
beta-oxidation.
• Long chain fatty acyl CoA dehydrogenase (LCAD)
acts on chains greater than C12.
• Medium chain fatty acyl CoA dehydrogenase
(MCAD) acts on chains of C6 to C12.
• Short chain fatty acyl CoA dehydrogenase (SCAD)
acts on chains of C4 to C6.
 MCAD deficiency is thought to be one of the
most common inborn errors of metabolism.
 Hydration of the double bond is catalyzed by
enoyl CoA hydratase. The product is an L-3-
hydroxyacyl CoA.

 A second dehydrogenation, of the alcohol,

occurs in a NAD-linked reaction catalyzed by
beta-hydroxyacyl CoA dehydrogenase. The
product is a ketone.
 Thiolytic cleavage of the thioester is catalyzed
by beta-ketoacyl CoA thiolase.
• Reaction products: The products are acetyl
CoA and a long chain fatty acyl CoA that is
two carbons shorter than the original fatty
acyl CoA.
 The shortened fatty acyl group is now ready
for another round of beta-oxidation. After the
fatty acyl CoA has been reduced to acetyl or
propionyl CoA, beta-oxidation is complete.
• Regulation: This reaction is inhibited by
high concentrations of acetyl CoA.
 Beta-oxidation is regulated as a whole
primarily by fatty acid availability; once
fatty acids are in the mitochondria they
are oxidized as long as there is
adequate NAD+ and CoA.
 This diagram shows production of propionyl
CoA from an odd-chain fatty acid and the
subsequent conversion of propionyl CoA to
succinyl CoA, which can be metabolized
through the citric (tricarboxylic) acid cycle.
                                
 SUMMARY: Synthesis
 Substrate availability: availability of acetyl
groups in the cytoplasm is regulated by the
activity of the citrate-malate antiport. Its
activity is decreased by palmitoyl CoA. The
mitochondrial concentration of citrate also
affects transport.
 Acetyl CoA carboxylase is a key enzyme of
fatty acid synthesis.
 It is activated allosterically by citrate and
covalently by phosphorylation.
 It is inhibited allosterically by palmitoyl CoA
and covalently by dephosphorylation.
 SUMMARY: Oxidation
 Oxidation is regulated at several levels, but
primarily by substrate availability, which in
turn is controlled hormonally.
 Hormone sensitive lipase in adipose tissue is
activated by phosphorylation (glucagon). Its
activity is low when insulin levels are high.
 High levels of malonyl CoA allosterically
inhibit CAT-I. This prevents beta-oxidation
during fatty acid synthesis.
 CoA must be available for beta-oxidation to
proceed, since it is a substrate for the
thiolase reaction.
FATTY ACID Metabolism

   
3 Steps of Fatty Acid Oxidation Cycle   [beta
oxidation]  
  
 1.   oxidation of COOH end of free fatty acid   &  
linking  FFA  to  CoASH
 2.   transport of fatty acyl-coA into mitoplasm from
cytoplasm
 3.   oxidation of fatty acyl-coA into 2 carbon fragments
of Acetyl-CoA   
 Fatty Acid Synthesis Fatty Acid Oxidation

 occurs in cytosol occurs in Mitochondrial matrix

 precursors linked to acyl carrier protein linked to CoA

(ACP)

 enzymes are in one big complex series of separate enzymes

(fatty acid synthetase)

 add 2-carbon groups from activated remove 2-carbon groups to

acetyl CoA
acetyl CoA (which comes from
decarboxylation of malonyl-CoA)

 reductant is NADPH NAD and FAD are oxidants

 stops at 16 carbons not limited in length in theory

(further elongation and double bonds
put in by other enzymes)