Biochemistry 432/832
September 12
Chapter 24 G&G
Fatty acid catabolism
Announcements:
- Exam #1 next Thursday (Sept 19)
- Chapters 23, 24
- Chapter 19 (glycolysis)
- Chapter 25, section 25.1, up to biosynthesis
of complex lipids (page 819)
Glucose
Glycogen
Glucose-6-P
Ribose-5-P + NADPH
Fructose-6-P
Glyceraldehyde-3-P
Nucleic acid
synthesis
Reducing
power
Pyruvate
1. Biosynthesis of ribose-5-P
and NADPH
ATP
Glucose
Glycogen
Glucose-6-P
Ribose-5-P + NADPH
Fructose-6-P
Glyceraldehyde-3-P
Pyruvate
2. Biosynthesis of
ribose-5-P
ATP
Glucose
Glycogen
Glucose-6-P
Ribose-5-P + NADPH
Fructose-6-P
Glyceraldehyde-3-P
Pyruvate
3. Biosynthesis of NADPH
ATP
Glucose
Glycogen
Glucose-6-P
Ribose-5-P + NADPH
Fructose-6-P
Glyceraldehyde-3-P
Pyruvate
4. Biosynthesis of
NADPH and ATP
ATP
Triacylglycerols
O
||
CH2 - O - C - (CH2)n - CH3
O
||
CH - O - C - (CH2)n - CH3
O
||
CH2 - O - C - (CH2)n - CH3
Glycerol
Fatty acid
Saturated versus
unsaturated
Why Fatty Acids are used for
storage of energy?
Two reasons:
– The carbon in fatty acids (mostly CH2) is
almost completely 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
Result: fatty acids have ~6 more energy of the
corresponding amount of proteins or glycogen
Activation of fatty acids for b-oxidation by acyl-CoA
synthetase
Role of
carnitine in
transferring
fatty acids
across the
mitochondrial
membrane
b-Oxidation of Fatty Acids
A Repeated Sequence of 4 Reactions
• Strategy: create a carbonyl group on the b-C
• First 3 reactions do that; fourth cleaves the "b-keto
ester"
• Products: an acetyl-CoA and a fatty acid two carbons
shorter, FADH2, NADH
The boxidation of
saturated
fatty acids
Acyl-CoA Dehydrogenase
•
•
•
•
Oxidation of the C-Cb bond
A family of three soluble matrix enzymes
Mechanism involves proton abstraction,
followed by double bond formation and hydride
removal by FAD
Electrons are passed to an electron transfer
flavoprotein, and then to the electron transport
chain
Enzyme is inhibited by a metabolite of
hypoglycin (from akee fruit)
The acyl-CoA dehydrogenase reaction
The mechanism of acyl-CoA dehydrogenase
Hydride
transfer
Proton
abstraction
Acyl-CoA dehydrogenase
structure
Inhibition of acylCoA dehyrogenase
by hypoglycin
Enoyl-CoA Hydratase
Adds water across the double bond
• at least three forms of the enzyme are
known
• Normal reaction converts trans-enoyl-CoA
to L-b-hydroxyacyl-CoA
Hydroxyacyl-CoA
Dehydrogenase
Oxidizes the b-Hydroxyl Group
• This enzyme is completely specific for Lhydroxyacyl-CoA
• D-hydroxylacyl-isomers are handled
differently
The L-b-hydroxylacyl-CoA dehydrogenase reaction
Fourth reaction: thiolase
b-ketothiolase
• Cysteine thiolate on enzyme attacks the b-carbonyl
group
• Thiol group of a new CoA attacks the shortened chain,
forming a new, shorter acyl-CoA
• The reaction is favorable and drives other three
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 the consequence of the highly
reduced state of the carbon and compact storage (no
hydration) of fatty acids
Odd-Carbon Fatty Acids
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
• The involvement of biotin and B12
Oxidation of fatty
acids containing
odd numbers of
carbons
Unsaturated Fatty Acids
•
•
•
•
•
Consider monounsaturated fatty acids:
Oleic acid, palmitoleic acid
Normal b-oxidation for three cycles
cis-3 acyl-CoA cannot be utilized by acylCoA dehydrogenase
Enoyl-CoA isomerase converts this to trans2 acyl CoA
b-oxidation continues from this point
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- 2, cis- 4 structure is a problem!
• 2,4-Dienoyl-CoA reductase to the rescue!
Peroxisomal b-Oxidation
Peroxisomes - organelles that carry out flavindependent 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
• Electrons go to O2 rather than e- transport
• Fewer ATPs result
The acyl-CoA oxidase reaction in peroxisomes
Ketone Bodies
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 b-hydroxybutyrate
• These are called "ketone bodies"
• Source of fuel for brain, heart and muscle
• Major energy source for brain during starvation
• They are transportable forms of fatty acids!
Ketone Bodies - II
Interesting Aspect of Their Synthesis
• Occurs only in the mitochondrial matrix
Ketone Bodies and Diabetes
•
•
•
•
•
•
"Starvation of cells in the midst of plenty"
Glucose is abundant in blood, but uptake by cells in muscle,
liver, and adipose cells is low
Type I diabetes - 10% - insufficient secretion of insulin
Type II diabetes - 90% - deficiency in insulin receptors
Cells, metabolically starved, turn to gluconeogenesis and
fat/protein catabolism
Oxaloacetate 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 in breath of diabetics