Anda di halaman 1dari 24

Chapter 23

Fatty Acid Catabolism


Biochemistry
by
Reginald Garrett and Charles Grisham

Garrett and Grisham, Biochemistry, Third Edition

How are fatty acids catabolized, and how is their


inherent energy captured by organisms?
Why Fatty Acids?
The carbon in fatty acids (mostly CH2) is reduced (so its
oxidation yields the most energy possible).
Fatty acids are not hydrated (as mono- and polysaccharides
are), so they can pack more closely in storage tissues

Garrett and Grisham, Biochemistry, Third Edition

A duct at the junction of the


pancreas and duodenum
secretes pancreatic juice
into the duodenum, the
first portion of the small
intestine.

Hydrolysis of triacylglycerols
by pancreatic and
intestinal lipases.
Pancreatic lipases
cleave fatty acids at the
C-1 and C-3 positions.
Resulting
monoacylglycerols with
fatty acids at C-2 are
hydrolyzed by intestinal
lipases. Fatty acids and
monoacylglycerols are
absorbed through the
intestinal wall and
assembled into
lipoprotein aggregates
termed chylomicrons.

Carboxilic acid salt


with steroid backbone

Lipoprotein aggregates

Garrett and Grisham, Biochemistry, Third Edition

Fatty acids are


degraded by
repeated cycles of
oxidation at the bcarbon and
cleavage of the
CCb bond to
yield acetate units.

acetyl-CoA

CoA activates FAs for oxidation


Acyl-CoA synthetase condenses fatty acids with CoA, with simultaneous
hydrolysis of ATP to AMP and PPi

Formation of a CoA ester is expensive energetically


Reaction just barely breaks even with ATP hydrolysis
But subsequent hydrolysis of PPi drives the reaction strongly forward
Mitochondria/out of mitochondria

The acyl-CoA synthetase reaction activates fatty acids for b-oxidation. Formation
of a thiol ester bond between fatty acid and thiol group of CoA. The reaction is
driven by hydrolysis of ATP to AMP and pyrophosphate and by the subsequent
hydrolysis of pyrophosphate.

Carnitine as a Carrier
Carnitine carries fatty acyl groups
across the inner mitochondrial
membrane

fatty acyl CoA

Short chain fatty acids are


carried directly into the
mitochondrial matrix
Long-chain fatty acids cannot
be directly transported into the
matrix
Long-chain FAs are converted
to acyl carnitines and are then
transported in the cell
Acyl-CoA esters are formed
inside the inner membrane in
this way
The formation of acylcarnitines and their transport across the inner mitochondrial membrane.
The process involves the coordinated actions of carnitine acyltransferases on both sides of
the membrane and of a translocase that shuttles O-acylcarnitines across the membrane.

Garrett and Grisham, Biochemistry, Third Edition

The b-oxidation of
saturated fatty acids
involves a cycle of four
enzyme-catalyzed
reactions. Each cycle
produces single
molecules of FADH2,
NADH, and acetyl-CoA
and yields a fatty acid
shortened by two
carbons. (The delta [D]
symbol connotes a
double bond, and its
superscript indicates
the lower-numbered
carbon involved.)

Summary of b-Oxidation
Repetition of the cycle yields a succession of acetate units

Thus, palmitic acid yields eight acetyl-CoAs


Complete b-oxidation of one palmitic acid yields 106
molecules of ATP
Large energy yield is consequence of the highly reduced state
of the carbon in fatty acids

Garrett and Grisham, Biochemistry, Third Edition

How Are Odd-Carbon Fatty Acids


Oxidized?
b-Oxidation yields propionyl-CoA
Odd-carbon fatty acids are metabolized normally, until
the last three-C fragment - propionyl-CoA - is reached

Three reactions convert propionyl-CoA to succinylCoA

Succinyl-CoA: TCA cycle: oxalacetate/gluc or CO2


gluconeogenesis
malic enzyme, cytosol

Succinyl CoA

pyr dehydrogenase
Acetyl CoA

Garrett and Grisham, Biochemistry, Third Edition

How Are Unsaturated Fatty Acids Oxidized?


Consider monounsaturated fatty acids:

Oleic acid, palmitoleic acid

Normal b-oxidation for three cycles

cis-D3 acyl-CoA cannot be utilized by


acyl-CoA dehydrogenase

Enoyl-CoA isomerase converts this to


trans- D2 acyl CoA
b-oxidation continues from this point

Garrett and Grisham, Biochemistry, Third Edition

Polyunsaturated Fatty Acids


Slightly more complicated
Same as for oleic acid, but only up to a point:
3 cycles of b-oxidation
enoyl-CoA isomerase
1 more round of b-oxidation
trans-D2, cis-D4 structure is a problem!

2,4-Dienoyl-CoA reductase to the rescue!

Linoleic acid

Garrett and Grisham, Biochemistry, Third Edition

Peroxisomal b-Oxidation
Peroxisomes - organelles that carry out flavin-dependent oxidations,
regenerating oxidized flavins by reaction with O2 to produce H2O2

Similar to mitochondrial b-oxidation, but initial double bond


formation is by acyl-CoA oxidase (no acyl-CoA dehydrogenase)

Electrons go to O2 rather than e- transport

Fewer ATPs result


FAD-dependent acyl-CoA oxidase

Fatty acyl-CoA

Trans-D-Enoyl-CoA

Garrett and Grisham, Biochemistry, Third Edition

Phytanic acid

Branched-Chain Fatty Acids


An alternative to b-oxidation is
required

Branched chain FAs with


branches at odd-number carbons
are not good substrates for boxidation

-oxidation is an alternative

Phytanic acid -oxidase


decarboxylates with oxidation at
the alpha position

b-oxidation occurs past the


branch

oxidation

TCA cycle:
Succinyl-coA

Garrett and Grisham, Biochemistry, Third Edition

What Are Ketone Bodies, and What Role Do They Play


acetyl-CoA
in Metabolism?
-CoA
A special source of fuel and energy
for certain tissues
Some of the acetyl-CoA produced
by fatty acid oxidation in liver
mitochondria is converted to
acetone, acetoacetate and bhydroxybutyrate

These are called "ketone bodies

Synthesis in mitochondrial matrix

Synthesized in liver, Source of


fuel for brain, heart and muscle

Major energy source for brain


during starvation, they are
transportable forms of fatty
acids!

-CoA
-CoA
-CoA

Garrett and Grisham, Biochemistry, Third Edition

-CoA

-CoA

Ketone Bodies and Diabetes

Glucose is abundant in blood, but uptake by cells in muscle, liver, and


adipose cells is low. Insulin is not signaling high levels of glucose.

Cells, metabolically starved, turn to gluconeogenesis and fat/protein


catabolism

In type I diabetics, OAA is low, due to excess gluconeogenesis, so AcCoA from fat/protein catabolism does not go to TCA, but rather to ketone
body production

Acetone can be detected on breath of type I diabetics

Garrett and Grisham, Biochemistry, Third Edition

Garrett and Grisham, Biochemistry, Third Edition

Chapter 24
Lipid Biosynthesis
Biochemistry
by
Reginald Garrett and Charles Grisham

Garrett and Grisham, Biochemistry, Third Edition

How Are Fatty Acids Synthesized?

The Biosynthesis and Degradation Pathways are Different


As in cases of glycolysis/gluconeogenesis and glycogen
synthesis/breakdown, fatty acid synthesis and degradation go by
different routes

There are four major differences between fatty acid breakdown


and biosynthesis:

1-Intermediates in synthesis are linked to -SH groups of acyl


carrier proteins (as compared to -SH groups of CoA)

2- Synthesis in cytosol; breakdown in mitochondria

3- Enzymes of synthesis are one polypeptide

4- Biosynthesis uses NADPH/NADP+; breakdown uses


NADH/NAD+
Garrett and Grisham, Biochemistry, Third Edition

Activation by Malonyl-CoA
Acetate Units are Activated for Transfer in FA Synthesis by Malonyl-CoA

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

Acetate units are activated for transfer by conversion to malonyl-CoA (ATP)

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


growth

Chain grows to 16-carbons

Other enzymes add double bonds and more Cs

AcetylCoA + 7 malonyl-CoA + 14 NADPH + 13H+ + H2O

plamitate + 7HCO3- + 8CoASH + NADP+

Garrett and Grisham, Biochemistry, Third Edition

Ac-CoA in Cytosol

Amino acid degradation produces cytosolic acetyl-CoA

FA oxidation produces mitochondrial acetyl-CoA

Glycolysis yields cytosolic pyruvate which is converted to acetylCoA in mitochondria

Citrate-malate-pyruvate shuttle provides cytosolic acetate units


and reducing equivalents for fatty acid synthesis

Garrett and Grisham, Biochemistry, Third Edition

Citrate-malate-pyruvate shuttle: acetyl-CoA cannot cross the membrane!!

Pentose phosphate pathway

14 NADPH (needed for palmitate)


oxalacetate + NADH + H+
malate + NADP+

malate + NAD+

pyruvate + CO2 + NADPH + H+

Garrett and Grisham, Biochemistry, Third Edition

Acetyl-CoA Carboxylase
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

Malonyl-CoA
carbonylphosphate intermediate

ACC uses bicarbonate and ATP


(AND biotin!)
N-carboxybiotin

Animal enzyme is one polypeptide


with all three functions - biotin
carboxyl carrier, biotin carboxylase
and transcarboxylase

Malonyl-CoA

Garrett and Grisham, Biochemistry, Third Edition

Acetyl-CoA Carboxylase

As a committed step, ACC is


carefully regulated (biotin carboxyl
carrier moiety, biotin carboxylase,
carboxyltranferase)

Palmitoyl-CoA (product) favors


inactive monomers

Citrate favors the active polymeric


form

Phosphorylation decreases affinity


for citrate (and activation) and
palmitoyl-CoA inhibition

Dephosphorylated form favors citrate binding

Garrett and Grisham, Biochemistry, Third Edition

The Effect of Phosphorylation

Garrett and Grisham, Biochemistry, Third Edition