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L11 Fatty Acid Oxidation (Fatty acids (TGs
E in TG not directly…
L11 Fatty Acid Oxidation
Fatty acids
Structure
- FA= alkyl (CH2 grps) chain w/ terminal carboxyl grp ( -COO or -COOH)
- Saturated (no C=C bonds) or unsaturated(some db bonds)
- Basic formula CH3-(CH2)n-COOH (completely saturated)
- Unsaturated- up to 6 db bonds per chain (almost always in cis config)
~ diff between cis and trans: orientation of the H's around tht bond
- Transported in circulation by albumin
Common FAs
- Most common Fa in bio syst have even #C atoms... C16, C18, C20
- Numerical symbol 16:1 (9) = 16 carbons, one db bond in ninth pos
- We are only going to consider oxidation of an even #C, saturated, long chain FA
TGs
- E in TG not directly available
- Must be hydrolysed by Lipases (ezm) to release FA & glycerol
~ Lipase: dreaking down a lipid, release FA to diglyceride, ... to monoglyceride to... glycerol
Efficient storage of E
- Fats & TGs are good eff E storage
- On a per weight basis
- TG stores yield 2+ times as much ATP as glycogen stores
- Store w/o association w/ H2O
- Glycogen ih hphilic binds ±x itw weight in H2O. ∴need 2+ times tissue weight of glycogen for E from same weight in fat
- Norm CH2O (carbs) store lasts ~24h of fasting
~ fat supply lasts several weeks (or more)
Clinical perspective
- Excess storage of FAs = Obesity
- IBW = ideal body weight (actuarial tables)
- BMI = body mass index = wt/ht^2 (kg/m^2)
- Overweight = 25-30kg/m^2
- Obese = >30kg/m^2
- If obese: dietary restriction, ⇈exercise, behaviour mod [eg. snacking all the time]
- Surgery if 100% above IBW
Catabolism of FAs
- Occurs in 3 phases
1) Activation of FA: in cytosol
2) Transport activated FA into mitochondria
3) 𝛽-Oxidation: successive removal of 2C units at a time → Ace CoA [18÷2 =9]
Phase 1 - FA activation
- In cytosol initial ATP " investment"
- FA + CoASH + ATP → Fatty acyl-CoA + AMP + PPi
- ezm: acyl-CoA synthase
- Note: Fatty acyl-CoA can't cross mitochondrial memb ... complicated transport
Phase 2 - Transport of Activated FA into mitochondria
- Fatty acyl-CoA can't cross memb & oxidising machinery is within the mitochondria
- Carnitine= prot, methinine & lysine (can get in red meat)
Process
- Fatty acyl CoA binds w/ carnitine [1] & CoASH released
- Fatty acyl carnitine goes thru outer mitochondrial memb by a carnitine carrier (carnitine acyltransferase 1)
- Passing thru intermemb space thru transporter into mtx
- Fatty acyl carnitine combines w/ CoASH again producing carnitine and fatty acyl CoA
- Carnitine goes back thru transporter and to OMM
Phase 3 - 𝛽-Oxidation of FAs
- Spiral pathway, multi-ezm complex, gt quick processing
- 2C units removed from COOH end [ and release Acetyl CoA in each round
- Series of rxns, rearrangement of bonds
- Final cleavage releases:
~ Acetyl CoA, 2C shorter FA-CoA (reenters spiral...) [pathway]
- E rich intermediates produced:
~ NADH & FADH2 (same as glucose) [will enter e- transport chain ETC]
- Final stage of FA oxidation = TCA cycle & ETC #
𝛽-Oxidation
- Accounts for the bulk of E production from FAs in humans
- Control of this pathway exerted by availability of substrates (FA-CoA) & co-factors e.g. carnitine shuttle of FA into mitochondria (vital part in dictating if 𝛽-ox can occur)
- Must be supplemented by other mechanisms to deal w/off chain & unsaturated FA
~ Req additional ezms
- Minor Pathways (NOT examinable)
~ α-Ox - methylated FA
~ 𝟂-Ox - methyl end of FA → dicarboxylic FA
E yield
- Each round of 𝛽-Ox
⇒ 1 Acetyl CoA
⇒ 1 FADH2
⇒ 1 NADH
- Stearate (C18 ) - 8 cleavages (2 Acetyl CoA in last round
- CH3(CH2)16-COOH
- E yield per gram lipid (±38 kJ/g), more than twice carb (±17 kJ/g)
Clinical Perspective
- Genetic deficiencies in Carnitine Transport
~ Carnitine essential to oxidise FA
- Mild recurrent muscle cramping: severe weakness - death
Degrees
1o = low carnitine in muscle, kidney & heart (not liver)
- Comprises long chain FA oxidation
- Overcome by dietary carnitine therapy
2o = genetic defect in 𝛽-ox ⇒ ⇈acylcarnitines ( & they cant actually process)
- Excreted in urine ⇒ ⇊lvls of carnitine
- Type I ⇒ muscle weakness, myoglobinuria (Uria: in your urine, myoglobin in you urine, muscle protein)
- Type II ⇒ (infants) precipated by fasting ⇒ hypoketotic, cardiac malfunction & death
~ Treat by avoiding starvation & diet low in long chain FA
Ketone Bodies
- Lipid based E source
- Water soluble (can be move thru the bld & ∴ supply to the brain
- Main 2 ketone bodies are:
~ 𝛽-hydroxybutyrate & acetoacetate [travel thru bld, can be converted into acetyl CoA
- 1o site of formation = Liver (mitochondrial mtx)
- Used by sk & cardiac muscle (conserve glucose for CNS) [brain & once glucose is used up, it can use the ketone bodies as well]
- Used by CNS in starvation as can't use FA (don't have al 𝛽-oxidation ezms) ∴gradually switch from glucose to ketone bodies
- Neonates: precursors for cerebral lipid synth
Ketone Body Formation in Liver
- NB: Ketone bodies are acidic [a problem]
~ too much ketone in bld= bld pH ⇊
- Ketone bodies can be converted back to Ac-CoA, yields 2 per ketone body...
- Acetone = metabolic dead end product, gives fruity breath
- Ketone bodies is a bad name
- 2 molecs of Acetyl CoA to make acetoacetate to make ketone body (𝛽-Hydroxybutyrate)
Ketone body Reconversion
- Ketone bodies reconverted to 2x acetyl CoA
- Acetyl CoA enters TCA Cycle
- Provides alternate fuel source e.g for CNS in starvation
~ w/o FA, bc don't have all the ezms in mitochondria to process
Clinical Perspective
- Diabetic ketoacidosis:
- Common illness in insulin dependent diabetes
- insulin deficiency + glucagon excess
- Hyperglycaemia
- Insulin deficiency ⇒ ⇈ FFA in bld drives ketone prod
- Ketonemia (↑ketone bodies in bld)
- Ketonuria (↑ketone bods in urine)
- Excess bld conc of acetoacetate & 𝛽-hydroxybutyrate (acidic)
- Life threatening ⇒ metabolic acidosis
Learning Outcomes
- Understand the nomenclature of common FA
- Describe the rxns in regulation of & cellular loc of 𝛽-oxidation
- Appreciate that TGs are an efficient E store
- Know the E yield of FA oxidation
- Explain why ketone bodies are important & how they are formed