Oxidation of Fatty Acids BIOMEDICAL IMPORTANCE Oxidation in
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-Co. A 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-Co. A synthetase (thiokinase) • Long-chain fatty acids penetrate the inner mitochondrial membrane as carnitine derivatives • Carnitine – β-hydroxy-γ-trimethylammonium butyrate
• palmitoyl- Co. A forms eight acetyl-Co. A 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- Co. A plus a molecule of propionyl-Co. A • Oxidation of Fatty Acids Produces a Large Quantity of ATP – 7*5 mol ATP – 8*12=96 mol ATP – 129 × 51. 6* = 6656 k. J.
• Peroxisomes Oxidize Very Long Chain Fatty Acids • A modified form of β-oxidation • formation of acetyl-Co. A and H 2 O 2 • the β-oxidation sequence ends at octanoyl. Co. A
Oxidation of unsaturated fatty acids • by a modified -oxidation pathway • Formation of Co. A esters • β-oxidation until either a Δ 3 -cis-acyl-Co. A compound or a Δ 4 -cis-acyl-Co. A compound is formed • (Δ 3 cis Δ 2 -trans-enoyl-Co. A 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-Co. A – 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-Co. A
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-Co. A 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-Co. A – 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-Co. A dehydrogenase – Inhibiting β-oxidation • Dicarboxylic aciduria – Medium-chain acyl-Co. A 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
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