Fatty acid oxidation

Features
   

Occur in mitochondria Sequential cleavage of two carbon atoms generates ATP Types: - oxidation - oxidation - oxidation

Differences between fatty acid oxidation and biosynthesis

Pathway Site Intermediates Oxidation Mitochondria CoA derivatives Biosynthesis Cytoplasm Linked to ACP Addition of 2 carbon units Multi-enzyme NADPH

Sequential units Removal of 2 carbon units Enzymes Co-enzymes Independent NAD+, FAD

Beta Oxidation: overview

Activation of fatty acids

  

Site: cytoplasm Requires energy (ATP) Acyl CoA synthetase (thiokinase) ER, Peroxisome, mitochondria. Inorganic pyrophosphatase hydrolyze PPi

drives the reaction towards completion

Carnitine
   

-hydroxy- -trimethyl ammonium butyrate Abundant in muscle, liver kidney Synthesis: lysine and methionine Function: transport of long chain fatty acids from cytoplasm to mitochondria

Transport of fatty acids

Carnitine deficiency
New born and pre-term infants inadequate biosynthesis renal leakage  Hemodialysis Clinical features: hypoglycemia


( fatty acid oxidation

ATP

gluconeogenesis)

glucose utilization

CPT I deficiency affects liver hypoglycemia, ketogenesis suphonylurea CPT I hyperglycemia fatty acid oxidation

Beta Oxidation: steps

   

Oxidation (FAD linked dehydrogenase) Hydration Oxidation (NAD linked dehydrogenase) Thiolytic cleavage

Energetics (ATP yield)

Palmitic acid (16 C)
7 Cycles

forms 8 acetyl CoA each acetyl CoA forms 12 ATP (TCA cycle) 8 X 12 ATP = 96 ATP

   

ATP from TCA cycle = 96 7 FADH2 X 2 = 14 7 NADH X 3 = 21 Total = 131 ATP ATP lost during fatty acid activation = 2 Net ATP yield: 131 2 = 129 ATP

Metabolism of odd chain fatty acids



End product: propionyl CoA succinyl CoA TCA cycle gluconeogenesis

Inborn errors of Propionate Metabolism

Propionate academia: defect: Propionyl CoA carboxylase deficiency Clinical features: ketoacidosis, developmental abnormalities  Methyl malonic aciduria defect in racemase / mutase / B12


Peroxisomal -oxidation
Uses: 1.Oxidation of very long chain fatty acids end product: acetyl CoA octanoyl CoA H2O2 not associated with ATP generation

enzymes are induced by high fat diet drugs (clofibrate)

2. Shorten the side chain of cholesterol in bile acid formation.

Zellwegers (cerebrohepatorenal) syndrome

absence of peroxisomes in all tissues.  accumulation of C26C38 polyenoic acids in brain tissue  also exhibit a generalized loss of Peroxisomal functions, eg, impaired bile acid and ether lipid synthesis.


Regulation of -oxidation


Carnitine palmitoyl transferase I rate limiting enzyme inhibited by malonyl CoA CPT I CPT I starvation well fed state glucagon insulin

-oxidation of unsaturated fatty acids

-oxidation of unsaturated fatty acids

Differs from saturated fatty acids cis-enoyl CoA is formed FAD dependent dehydrogenation doesn't occur less ATP production

Disorders of -oxidation
   

Carnitine deficiency Jamaican vomiting sickness Acute fatty liver of pregnancy Dicarboxylic aciduria

Jamaican vomiting sickness

cause: consumption of unripe fruit of akee tree contain hypoglycin (toxin) inactivates medium chain / short chain Acyl CoA DH inhibit -oxidation hypoglycemia

Acute fatty liver of pregnancy deficiency of long-chain 3-hydroxyacylCoA DH Dicarboxylic aciduria deficiency of medium chain chain Acyl CoA DH excretion of C6-C10 -di carboxylic acids

Alpha-oxidation
Fatty acids are oxidized by removing carbon atoms one at a time from the carboxyl end.  Occur in the brain  Site: peroxisomes Differ from -oxidation  Does not generate high-energy phosphates  Doesnt require CoA


Importance of -oxidation
fatty acids (eg: phytanic acid) with a methyl group on -carbon block -oxidation -oxidation removes the methyl group allows -oxidation

- hydroxylase (Fe, vit C)

phytanic acid

hydroxylation
dehydrogenase

keto acid
decarboxylase

(pristanic acid) fatty acid

Refsums Disease
 

Defect in -oxidation Genetic defect: -hydroxylase (phytanic acid oxidase) phytanic acid is not oxidized

Phytanic acid accumulates in the tissues

phytanic acid

blocks -oxidation

Clinical features: Polyneuropathy, retinitis pigmentosa, cerebellar ataxia

Omega-oxidation
  

Oxidation of fatty acids at -carbon Site: liver, kidney (ER) Enzyme: Hydroxylase cofactors: Cyt P-450 NADPH Importance Becomes significant when -oxidation becomes defective

CH3 group

CH2OH

COOH Dicarboxylic acid -oxidation

excretion of adipic (C6) and suberic (C8) acid in urine