1. OXIDATION OF FATTY ACIDS
BETA OXIDATION

2. Metabolism of Triacylglycerols in Tissues
FAs released in the capillaries by lipoprotein lipase are
taken up by tissues and either metabolized to CO2 (muscle)
or resynthesized into triglycerides (adipocytes).

3. Mobilization of Stored Fat
Hormone-sensitive lipase initiates the hydrolysis of TGs to
yield FAs (from either C-1 or C-3) and glycerol. Additional
lipases then take over.
The FAs can either be exported to other tissues or can be
metabolized to CO2.
3) In adipose tissue, the lipase is activated by epinephrine,
nor-epinephrine, and glucagon as follows.

4. Hormones bind to receptors on the plasma membrane and cause:
adenylate cylase activity, cAMP, protein kinase A
activity, thereby phosphorylating and activating the lipase
(Note: analagous to glycogen phosphorylase activation by
phosphorylation).
Insulin inhibits lipolysis by promoting dephosphorylation
of the lipase.
Fatty

5. Note: acetyl CoA carboxylase, the rate limiting enzyme in FA synthesis, is inhibited by hormone mediated
phosphorylation.
Therefore, if the cAMP-mediated cascade is activated, FA synthesis is turned off and TG degradation is turned on.

6. Mobilization of Triacylglycerols Stored in Adipose Tissue
Liver
≡ hormone-sensitive
lipase
Modified from Nelson & Cox, Lehninger Principles of Biochemistry, 3rd Edition, Fig

7. Metabolism of Fatty Acids
Activation: A FA must be “activated” before it can either be
broken down to CO2 or it can be used for TG synthesis.
FA “activation” is catalyzed by by acyl CoA synthetase (also
called fatty acid thiokinase).
(High energy compound.)
Activation reaction occurs in the outer mitochondrial membrane.
Reproduced from Stryer, Biochemistry, 4th Edition, p. 607.

8. Transport of Acyl-CoAs into Mitochondria:
< 12 carbon fatty acyl CoAs passively diffuse through the
mitochondrial inner membrane;
> 12 carbon fatty acyl CoAs are specifically transported
across the inner membrane.
Basic Strategy: Convert acyl CoA to an acyl carnitine
derivative, which is then transported.
Then regenerate the acyl CoA within the mitochondrial matrix.
Reproduced from Stryer, Biochemistry, 4th Edition, p. 608.

9. Note: The enzymes carnitine palmitoyl transferase I and II are
also called carnitine acyltransferase I and II.
Carnitine acyltransferase I is located on the outer
mitochondrial membrane (correction page 36).
Carnitine acyltransferase II is located on the inner surface of
the inner mitochondrial membrane.
Outer Membrane
Outer Membrane
Malonyl CoA is an intermediate
in the FA biosynthetic pathway.
(Regenerate fatty
acyl CoA)
Modified from Champe & Harvey, Biochemistry, 2nd Edition, Fig

10. Regulation: The principal point of regulation of FA
Inner
Membrane I II
Modified from Nelson & Cox, Lehninger Principles of Biochemistry, 3rd Edition, Fig
Regulation: The principal point of regulation of FA
oxidation is via inhibition of carnitine acyltransferase I
by malonyl CoA.
Two Important Points:
Inhibition occurs at the first committed step in the FA
oxidation pathway.
ii) Reciprocol regulation of degradative and synthetic pathway.
Thus, when FA synthesis occurs (producing malonyl CoA),
FA oxidation is inhibited.

11. Catabolism of Fatty Acyl CoAs in the Mitochondrial Matrix
Degradation of FAs proceeds 2 carbons at a time, starting
from the carboxyl end.
- The reactions occur in the mitochondrial matrix.
Oxidation reactions directly feed reducing equivalents to
the respiratory chain to make ATP.
The released acetyl CoA enters the citric acid cycle which
will yield additional ATP.

12. β-Oxidation of FA Per Cycle: 1 NADH, 1 FADH2, and 1 Acetyl
Hydration
Thiolysis
Split off the carboxy terminal 2-carbon
fragment as acetyl CoA.
Fatty Acyl CoA
shortened by 2
carbon atoms
β α
β α
The action will be at
the β carbon.
Per Cycle: 1 NADH,
1 FADH2, and 1 Acetyl
CoA are generated.
Modified from Nelson & Cox, Lehninger Principles
of Biochemistry, 4th Edition, Fig

13. First 3 cycles of degradation of palmitoyl-CoA:
NADH
FADH2
Reproduced from Stryer, Biochemistry, 4th Edition, Fig24-6.

14. Energy Yield of FA Oxidation
One Cycle
NADH 2.5 ATP
FADH2 1.5 ATP
Acetyl CoA 10 ATP (generated via citric acid cycle; i.e.,
3 NADH + 1 FADH2 +1 substrate
level phosphorylation)
TOTAL = 14 ATP generated per cycle
Example: Palmitate (16 carbons)
7 cycles of oxidation 28 ATP
8 acetyl CoAs produced 80 ATP
Fatty acid activation ATP
TOTAL = 106 ATP
Initial activation step involves breaking both
phosphoanhydride bonds in ATP; This is
energetically equivalent to 2 ATP.

15. 6. Oxidation of Unsaturated Fatty Acids For Mono Unsaturated FA
Enoyl CoA
Cis is the natural
configuration.
However, only the trans isomer
is oxidized via β-oxidation.
Importantly, the trans configuration
is generated by this step.
Trans
Reproduced from Stryer, Biochemistry, 4th Edition, Fig24-7.
This isomerase converts a cis double bonded carbon to
a trans double bonded carbon. The pathway then
proceeds as it does for saturated FAs.

16. Acetyl CoA produced via FA oxidation can enter the TCA cycle only if sufficient OAA exists.
When there is insufficient carbohydrate (fasting or diabetes) OAA is consumed to form glucose (via gluconeogenesis).
Note: OAA PEP is catalyzed by PEP-carboxykinase, an enzyme which is present in liver, but absent in muscle & heart.
Thus, there is no depletion of OAA in muscle & heart and therefore they can handle incoming acetyl CoA.
Depletion of TCA cycle OAA in liver causes acetyl CoA to be diverted to ketone body production.
Thus, it allows continued FA oxidation even when acetyl
CoA is not being oxidized by the cycle.

17. HMG CoA Synthase is the rate- limiting step and is present in
TCA Cycle OR
***
β-hydroxy-β-methyl-glutaryl CoA
HMG CoA Synthase is the rate-
limiting step and is present in
significant quantities only in
the liver.
Reproduced from Champe & Harvey, Biochemistry, 2nd Edition, Fig

18. high malonyl CoA inhibits
high palmitoyl CoA inhibits
citrate stimulates
TCA Cycle