Oxidation of Fatty Acids
• BIOMEDICAL IMPORTANCE
• Oxidation in
– Mitochondria
• Biosynthesis in
– Cytosol
• Utilizes NAD+ and FAD as coenzymes
• generates ATP
• an aerobic process
• fatty acyl chains
citric acid cycle
acetyl-CoA units
generating ATP
• Increased fatty acid oxidation
– Starvation and of diabetes mellitus
• Ketone body production (ketosis)
– Ketoacidosis
• Impairment in fatty acid oxidation
– Hypoglycemia
• Gluconeogenesis is dependent upon fatty acid oxidation
– Carnitine deficiency
– Carnitine palmitoyltransferase
– inhibition of fatty acid oxidationby poisons
• Hypoglycin
• Fatty Acids Are Activated Before Being
Catabolized
– acyl-CoA synthetase (thiokinase)
• Long-chain fatty acids penetrate the inner
mitochondrial membrane as carnitine
derivatives
• Carnitine
– β-hydroxy-γ-trimethylammonium butyrate
• palmitoyl- CoA forms eight acetyl-CoA
molecules
Overview of β-oxidation of fatty acids
• The Cyclic Reaction Sequence Generates
– FADH2
– NADH
• Oxidation of a fatty acid with an odd number
of carbon atoms yields acetyl- CoA plus a
molecule of propionyl-CoA
• Oxidation of Fatty Acids Produces a Large
Quantity of ATP
– 7*5 mol ATP
– 8*12=96 mol ATP
– 129 × 51.6* = 6656 kJ.
• Peroxisomes Oxidize Very Long Chain Fatty
Acids
• A modified form of β-oxidation
• formation of acetyl-CoA and H2O2
• the β-oxidation sequence ends at octanoylCoA
Oxidation of unsaturated fatty acids
• by a modified -oxidation pathway
• Formation of CoA esters
• β-oxidation until either a Δ3-cis-acyl-CoA
compound or a Δ4-cis-acyl-CoA compound is
formed
• (Δ3cis Δ2-trans-enoyl-CoA isomerase)
• Hydration
• Oxidation
KETOGENESIS
• Ketone bodies
– acetoacetate and D(-)-3-hydroxybutyrate (βhydroxybutyrate), acetone
• In the Liver
Interrelationships of the ketone bodies
Ketogenesis
• In Mitochondria
• Acetoacetyl-CoA
– Starting material for ketogenesis
Pathways of ketogenesis in the liver
• Ketone bodies serve as a fuel for extrahepatic
tissues
• In extrahepatic tissues, acetoacetate is
activated to acetoacetyl-CoA
Formation, utilization, and excretion of ketone bodies
Transport and pathways of utilization and oxidation of ketone bodies in extrahepatic
tissues.
Regulation of Ketogenesis
• AT THREE CRUCIAL STEPS
– Control of free fatty acid mobilization from
adipose tissue
– the activity of carnitine palmitoyltransferase-I in
liver
– Partition of acetyl-CoA between the pathway of
ketogenesis and the citric acid cycle
Regulation of Ketogenesis
• Increase in the level of circulating free fatty
acids
– Uptake by the liver
• β-oxidized to CO2 or ketone bodies or esterified
• CPT-I , fed state
– Malonyl-CoA
– β-oxidation from free fatty acids is controlled by the CPT-I
gateway
– [insulin]/[glucagon] ratio
Regulation of ketogenesis
Regulation of long-chain
fatty acid oxidation in
the liver
CLINICAL ASPECTS
• Impaired Oxidation of Fatty Acids
– Hypoglycemia
• Carnitine deficiency
• Inadequate biosynthesis
• Renal leakage
• Losses hemodialysis
– Symptoms
• Hypoglycemia
• Muscular weakness
• Inherited CPT-I deficiency
CLINICAL ASPECTS
• CPT-II deficiency
– Affect primarily skeletal muscle
• Inherited defects in the enzymes of β-oxidation
and ketogenesis
• Jamaican vomiting sickness
– Hypoglycin
• Inactivates acyl-CoA dehydrogenase
– Inhibiting β-oxidation
• Dicarboxylic aciduria
– Medium-chain acyl-CoA dehydrogenase
CLINICAL ASPECTS
• Refsum’s disease
– accumulation of phytanic acid
• Blocks β-oxidation
• Zellweger’s (cerebrohepatorenal) syndrome
– absence of peroxisomes
Ketoacidosis Results From
Prolonged Ketosis
• Higher than normal quantities of ketone bodies
– Ketonemia
– Ketonuria
• Diabetes mellitus
• Starvation
– Depletion of available carbohydrate coupled
• Mobilization of free fatty acids
• Nonpathologic forms of ketosis
– High-fat feeding
– after severe exercise