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 – FADH 2 – 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 H 2 O 2 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 Δ 3 -cis-acyl-CoA compound or a Δ 4 -cis-acyl-CoA compound is formed (Δ 3 cis Δ 2 -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 CO 2 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