oxidation of fatty acids. biomedical importance oxidation in – mitochondria biosynthesis in –...
TRANSCRIPT
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