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Fatty Acid Oxidation, Total yield, Carnitine palmitoyl transferase I,…
Fatty Acid Oxidation
Ketone bodies
Formed when there is high usage of fatty acids as fuel
Lots of \(\beta\)-oxidation
Lots of acetyl-CoA produced
CAC saturated
Acetyl-CoA converted to KBs
Under certain conditions
Diabetes
Starvation
High fat diet
Endurance exercise
In healthy persons
KB synthesis activated by high glucagon + low insulin conditions
Fasting/early starvation
Low carbohydrate/ketogenic diets
Only takes place in liver cells
Formation of ketone bodies
Step 1
Step 2
Addition of 3rd Acetyl-CoA
Addition of H\(_2\)O
Reduce C=O bond + form O\(^-\)--C--O\(^-\) group
Branch point between ketone bodies + cholesterol formation
Step 3
Removal of acetyl-CoA molecule
Reformation of C=O bond on middle acetyl molecule
Acetyl-CoA can enter pathway again
Fusion of 2 acetyl-CoA molecules
Thiolase
Regeneration of CoA
Fate of ketone bodies
Released into blood by liver
Easily transportable molecules
Reconverted to acetyl-CoA by mitochondria of many tissues
Not liver
Used by brain as fuel in starvation states
Ketoacidosis - acetone on breath of diabetics
Energy generation pathway
Almost reverse of formation
Step 1
Conversion to acetoacetate
Step 2
Step 3
Generation of 2 x acetyl-CoA
Conversion to acetyl-CoA
Requires succinyl-CoA as donor of CoA
Alcohol
Ethanol as energy source
2 step reaction
Alcohol dehydrogenase
Aldehyde dehydrogenase
Generates NADH + H\(^+\)
Ketogenic - fatty acid synthesis
Second minor pathway in liver
Membrane bound enzyme CYP2E1
Member of cytochrome P450 mixed-function oxidase system
Drug metabolism
Generation of acetaldehyde
\(\beta\)-oxidation of fatty acids
Step 1 - activation of FA
Formation of fatty acyl-CoA
Requires ATP hydrolysis (ATP --> AMP)
AMP is substrate for
adenylate kinase
ATP is needed to phosphorylate ADP - overall 2ATP needed per molecule of FA activated
Enzyme is
Acyl-CoA synthetase (thiokinase)
On outer mitochondrial membrane
Problem - enzymes for \(\beta\)-oxidation + TCA cycle are in mitochondrial matrix
Carnitine used for transport of fatty acyl-CoA
Carnitine in cytosol of mitochondria binds to fatty acyl-CoA, removing H-SCoA
Acyl-carnitine is transported by a carrier protein into the matrix
Carnitine is removed from acyl group which binds to H-SCoA in the matrix, reforming fatty acyl-CoA
Occurs in 4 steps
First 3 are similar to conversion of succinate to oxaloacetate in the CAC
Strategy of reactions in CAC to regenerate oxaloacetate (reactive molecule)
Introduction of double bond
Addition of water to the double bond
Oxidation of -OH group to a =O group forming a keto-acid
Step1 - formation of an enoyl-CoA
Step2 - formation of 3-L-hydroxyl-CoA
Step3 - formation of \(\beta\)-ketoacyl-CoA
Step4 - cleavage of C\(\alpha\)-C\(\beta\) bond - release of acetyl CoA
\(\beta\)-ketoacyl-CoA thiolase
Requires additional molecule of CoA
Acetyl-CoA enters CAC
Fatty acyl-CoA renters oxidation pathway
3-L-hydroxyacyl-CoA dehydrogenase
Required NAD\(^+\) - formation of C=C
Enoyl-CoA hydratase
Various isoforms depending on FA length
Involves the addition of water across the double bond
Acyl-CoA dehydrogenase
requires FAD cofactor
FAD regenerated via ETC
Deficiency in medium chain
acyl-CoA dehydrogenase
linked to SIDS (sudden infant death syndrome)
Strategy of \(\beta\) oxidation
Sequence of 4 reactions removing a 2C fragment from long carbohydrate chain of FA
2C atom fragment removed as acetyl-CoA
n-2 fatty acyl-CoA produced undergoes another round of \(\beta\)-oxidation until 2 acetyl-CoA are formed in the last round
Yield from \(\beta\) oxidation
Each pass of oxidation spiral
New FA-CoA - 2 carbons shorter than present
1 acetyl CoA
CAC
1 NADH + H\(^+\)
1 FADH\(_2\)
Energy yield from fat metabolism
\(\Delta\)H = 37kJg\(^{-1}\) dry weight
Highly exergonic
Palmitoyl CoA (16C)
8 acetyl CoA
80ATP
7FADH\(_2\)
10.5ATP
7NADH + H\(^+\)
17.5ATP
How is fat stored?
Triacylglyceride's (TAGs)
Trisesters of fat + glycerol
Fatty acids can be of any type
Phospholipids (PL)
Glycerol esterified with 2 x FAs
3rd hydroxyl group of glycerol is linked by phosphate group to other molecules
Polar region of phospholipids - different classes of phospholipids
Sources of fatty acids
Dietary
Mostly TAGs
Digested in small intestine by pancreatic lipase
Fatty acids + monoacylglycerol released
Diffuse into enterocytes (facilitated by bile salts)
TAG resynthesises
Enterocytes export TAGs + cholesterol as chylomicrons (lipoprotein) into lymph vessels
Lacteals in intestinal villi
From lymph vessels into the blood where they are transported for use in tissues
Adipose tissue cells
1 more item...
Muscle, liver + other tissues
1 more item...
Excess nutrients
e.g. glucose, FAs
Exported by liver cells as TAGs in lipoprotein particles
VLDLs from liver to adipose tissue (storage) + muscle cells
HDLs
At tissue level
First step of TAG breakdown
Removal of FA chains
TAG from chylomicrons hydrolysed in blood capillaries by
lipoprotein lipases (LPL)
(attached to outside of cells lining capillaries)
LPL
enzymes are hormone-sensitive
High insulin
Adipocyte LPL + placement capillary endothelium high
Muscle LPL low
High glucagon, adrenalin
Muscle + myocardial LPL high
FA released from adipose tissue cells
Hormone sensitive
lipase
+ free fatty acids (FFA) transported by serum albumin to cells that need them as source of energy
Muscle, liver etc
NOT brain - uptake of FFA very slow due to blood brain barrier
Glycerol + free FA produced + can enter cells supplied by those capillaries
Free acids taken up by cells as energy substrates with enter \(\beta\)-oxidation pathway
Removal of all 3 FA chains from triacylglycerol generates glycerol
Exported as a potential substrate for gluconeogenesis
Can be phosphorylated in liver cels
Adipose tissues do not have
glycerol kinase
+ cannot use free glycerol for TAG synthesis - glucose + intermediates of glycolysis required
Odd length FA oxidation
Same pathways as even length FA oxidation
Last cycle produces acetyl-CoA and propionyl-CoA
Propionyl-CoA converted so succinyl-CoA
Enzyme required biotin as co-enzyme
Clinical presentations
Deficiency in
methylmalonyl-CoA mutase
Accumulation of methylmalonyl-CoA which is converted to methylmalonic acid
Metabolic acidosis + methylmalonic acidaemia/aciduria
Branched chain FA into membranes
Neurological symptoms e.g. seizures, encephalopathy
Treatment
Diet low in branched chain amino acids
Supplementation with B12 - cobalamin
\(\beta\)-oxidation of unsaturated fatty acids
Unsaturated FA's have one or more C=C bond
Most contain the first double bond between C9-C10 (\(\Delta\)9)
Additional double bonds occur at 3 carbon intervals
Problem occurs at first double bond
No substrate for
enoyl-dehydratase
Solution
Convert cis-3 bond to trans-2 bond
Enoyl-CoA isomerase
changes location of the double bond from C3 + 4 (\(\beta +\gamma\)) to C2 + 3 (\(\alpha+\beta\))
Problem 2
Presence of \(\Delta\)4 cis bond
Converted to trans-2 bond in 2-step process
NADPH needed as reducing equivalent source
2,4-dienoyl-CoA reductase
adds hydrogen atoms to the chain, removing a double bond
3,2-enoyl-CoA isomerase
moves the double bond to the \(\alpha + \beta\) position + \(\beta\) oxidation can continue
Carnitine shuttle
Regulation of fatty acid oxidation
Total yield
108ATP
Less 2 due to activation = 106ATP
Carnitine palmitoyl transferase I
Carnitine palmitoyl transferase I
1.5 ATP