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 acetyl-CoA units citric acid cycle 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 octanoyl-CoA

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 (β-

hydroxybutyrate), 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 FromProlonged 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