Fatty Acid Oxidation Flashcards
1
Q
Metabolism of fats
A
- Store fat in the body as Tri Acyl Glycerides (TAGs)
- Triglycerides – triesters of fatty acids and glycerol.
- Fatty acids can be of any type.
- Phospholipids (PL)
2
Q
Phospholipids (PL)
A
- Glycerol esterifed with two FAs; the third hydroxyl group of glycerol is linked by phosphate group to other molecules – the polar part of phospholipids – different classes of PL
3
Q
Triacylglycerides (TAG) as a source of fatty acids
A
- digested in the small intestine
- pancreatic lipase
- releases fatty acids and monoacylglycerol
- these diffuse into enterocytes (facilitated by bile salts) where TAG are resynthesised
4
Q
Enterocytes
A
- export TAGs and cholesterol as chylomicrons (a type of lipoprotein) first into lymph vessels (lacteals in the intestinal villi), then they reach the blood – used by tissues
- Adipose tissue cells – store TAGs
- Muscle tissue, liver cells and other tissues – use the FAs from TAGs as sources of energy
5
Q
Liver cells export what?
A
- Excess of nutrients (glucose, FA) is exported as TAGs in lipoprotein particles – VLDLs from liver to the adipose tissue cells (for storage) and muscle cells; liver cells also produce HDLs
- As TAG from VLDLs are used -> IDLs -> LDLs
6
Q
TAG breakdown
A
- TAG from chylomicrons hydrolysed in blood capillaries by Lipoprotein lipases (LPL) – attached to the outside of cells lining the capillaries – glycerol and free FA are produced and can enter the cells supplied by those capillaries
- Enzymes are Lipoprotein lipases LPL (hormone-sensitive).
- Insulin - increase adipocyte LPL and placement capillary endothelium, decreased muscle LPL
- glucagon, adrenalin - increase Muscle and Myocardial LPL
- When FA are released from adipose tissue cells (low insulin, high glucagon) – hormone sensitive lipase enzyme – free fatty acids (FFA) - transported by serum albumin to the cells that need them as source of energy (muscle, liver, etc – not brain – where the uptake of FFA is very slow due to the blood brain barrier)
7
Q
Activation of fatty acid
A
- Formation of fatty acyl-CoA
- Requires ATP hydrolysis
- Acyl-CoA synthetase (Thiokinase)
- ATP convert to AMP.
- AMP is substrate for Adenylate kinase: ATP is needed to phosphorylate to ADP – overall 2ATP molecules are required per molecule of FA activated
- occurs on the outer mitochondrial membrane
8
Q
B-oxidation strategy
A
- sequence of four reactions (4 steps) that removes a 2-Carbon atom fragment from the long hydrocarbonate chain of a fatty acid (an activated fatty acid – fatty acyl~CoA)
- 2-Carbon atom fragment is removed as Acetyl~CoA
- (n-2) fatty acyl~CoA produced undergoes another round of beta-oxidation steps until two Acetyl~CoA are formed in the last round
9
Q
Step 1 of b-oxidation
A
- formation of an enoyl-CoA (incorporation of a trans double bond).
- Enzyme, Acyl-CoA dehydrogenase requires FAD cofactor.
- FAD cofactor regenerated via the Electron Transport Chain (1.5ATP)
- Electron Transport Flavoprotein – transfers electrons to ubiquinone pool inner mitochondrial membrane
- Deficiency in medium chain acyl-CoA dehydrogenase – linked to SIDS (sudden infant death syndrome)
10
Q
Step 2 of b-oxidation
A
- formation of 3-L-hydroxyacyl-CoA
- Enzyme - Enoyl-CoA hydratase (various isoforms depending on FA length).
- Involves the addition of water across the double bond
11
Q
Step 3 of b-oxidation
A
- formation of b-Ketoacyl-CoA
- Enzyme – 3-L-hydroxyacyl-CoA dehydrogenase.
- Requires NAD+ - formation of C=O
12
Q
Step 4 of b-oxidation
A
- Cleavage of Ca-Cb bond – release of acetyl-CoA
- Enzyme – b-Ketoacyl-CoA thiolase.
- Requires an additional molecule of CoA.
- Acetyl-CoA enters TCA cycle, Fatty acyl-CoA renters oxidation pathway.
13
Q
Yield from b-oxidation
A
- a new FA CoA: 2 carbons shorter than parent
- 1 acetyl CoA (citric acid cycle)
- 1 NADH + H+
- 1 FADH2
14
Q
B-oxidation of unsaturated fatty acids
A
- Unsaturated fatty acid contain one or more cis C=C bonds
- Monunsaturated – 1 double bond
- Polyunsaturated – several double bonds
- Most contain first double bond between C9-C10 (D9).
- Additional double bonds occur at 3 carbon intervals
- Problem occurs at first double bond.
- Not a substrate for enoyl-dehydratase
- Requires bond rearrangement
15
Q
Convert from cis-3 bond to a trans-2 bond in b-oxidation
A
- Enzyme is Enoyl-CoA isomerase – changes the location of the double bond from C 3 and 4 (beta and gamma) to C 2 and 3 (alpha and beta)
- Now a substrate for Enoyl-CoA hydratase – another round of beta-oxidation takes place – and another;
- Then the first reaction of the next round introduces a C 2=3 double bond – but there is also a C4=5 double bond (D4 bond)
16
Q
First stage of B-oxidation of odd length fatty acids
A
- Metabolism of odd length fatty acids – same pathways.
- Last cycle produce acetyl-CoA and propionyl -CoA
- Propionyl-CoA converted to succinyl-CoA.
- Enzyme require Biotin as a co-enzyme
17
Q
Second and final step of odd length fatty acids b-oxidation
A
- Second stage is conversion of S to R chiral isoform.
- Final step requires Cobalamine (Vit B12) as a co-enzyme: Succinyl-CoA enters
TCA cycle. Substrate for gluconeogenesis
18
Q
Methylmalonic Aciduria
A
- Deficiency in Methylmalonyl-CoA mutase – accumulation of methylmalonyl-CoA.
- Converted to methylmalonic acid – accumulation.
- Causes metabolic acidosis and methylmalonic acidaemia/methylmalonic aciduria
- Leads to branched fatty acids into membranes - results in neurological problems
seizures, encephalopathy - Treatment: given special diets low in branched chain amino acids on diagnosis
- Milder form of disease due to reduced affinity for coenzymes
19
Q
Ketone bodies
A
- Formed when there is high usage of fatty acids as fuels – high level of b-oxidation: Diabetes, Starvation, High fat diet, Endurance exercise
20
Q
KB synthesis in healthy people
A
- KB synthesis is activated by high glucagon & low insulin conditions eg during fasting or early starvation during low carbohydrate/ ketogenic diets
- takes place only in liver cells ->released into the blood for other tissues, including CNS (pass easily through the blood brain barrier)
21
Q
Relationship between b-oxidation and ketone bodies
A
- high level of b-oxidation
- high level of acetyl CoA
- citric acid cycle is saturated (unable to handle the high levels of acetyl CoA)
- Acetyl CoA is diverted into Ketone bodies
22
Q
First step in ketone bodies formation
A
- “fusion” of 2 molecules of acetyl-CoA
- Thiolase reaction as involves the regeneration of Co-enzyme A
23
Q
Second step in ketone bodies formation
A
- addition of 3rd molecule of acetyl-CoA
- Addition of water to reduce C=O bond and formation of O-–C–O- group
- Branch point between ketone bodies and cholesterol formation
24
Q
Final step in ketone bodies formation
A
- removal of a molecule of acetyl-CoA.
- Reformation of C=O bond on middle acetyl molecule.
- Acetyl-CoA can enter pathway again
25
Q
What can Acetoacetate be further metabolised to?
A
- D-b-hydroxybutyrate (reduction)
- Acetone (decarboxylation)
26
Q
Fate of ketone bodies
A
- Ketone bodies are released into the blood by the liver.
- easily transportable molecules.
- Can be reconverted to acetyl-CoA by mitochondria of many tissues (not the liver).
- The brain can use them as a fuel during starvation
- Acetone can be detected on the breath of diabetics – ketoacidosis.
27
Q
Energy generation pathway
A
- reverse of formation
- Step 1: conversion to acetoacetate.
- Step 2: conversion to acetoacetyl-CoA.
- Requires succinyl-CoA as donor of enzyme CoA
- Final step generates 2 molecules of acetyl-CoA.
- Acetyl-CoA enters TCA cycle – generation of ATP
28
Q
Alcohol
A
- Ethanol can also be used as an energy source
- 2 step reaction: Alcohol dehydrogenase, Aldehyde dehydrogenase
- Generates NADH + H+
- Alcohol is ketogenic – fatty acid synthesis
- Second minor pathway in liver
- Involves membrane bound enzyme CYP2E1 (Cytochrome P450 2E1)
- Also leads to generation of acetaldehyde
29
Q
CYP2E1 (Cytochrome P450 2E1)
A
- member of the cytochrome P450 mixed-function oxidase system – drug metabolism
