Fatty acid / Fat Catabolism Flashcards
What sources are fatty acids for catabolism obtained from?
-diet
-stored fats - fatty acids as triglycerols in adipocytes
-newly synthesised fats - triglycerols - that body synthesises - triglycerols stored in adipocytes - rich siurce of energy
What are triglycerols? (TAGS)
3 long-chain fatty acid chains esterified to glycerol backbone
-store most amount of H and C so most energy to be released - provide >50% of energy in liver, heart and resting skeletal muscle
-FA chains can be saturated or unsaturated
-more reduced and much less hydrated than glycogen so can stockpile large quantities in adipocytes
Brief overview of 3 stages of fatty acid catabolism
- Long chain fatty acid catabolism - 8 acetyl units in form of acetyl CoA called ß-oxidation (occurs in mitochondrial matrix)
- Acetyl groups oxidised in citric acid cycle
- Electrons derived from oxidations of stages 1 and 2 pass to O2 via the mitochondrial respiratory chain ATP synthesis by oxidative phosphorylation
What are the 3 stages present in Stage 1 of fatty acid oxidation?
- Mobilisation of stored triacylglycerols from adipocytes
- Fatty acid activation and transport into mitochondrial matrix
- ß-oxidation pathway
Where are triacylglyerols stored?
-TAGs stored within lipid droplets core (TAGs and sterol esters) in adipocytes
-Surrounded by monolayer of phospholipids
-Surface of droplet coated with protein perilipin - a protein which restricts untimely access to TAGS
How does mobilisation of stored TAGs from adipocytes take place?
-Adrenaline and glucagon secreted in response to low blood glucose conc
-these bind to receptors on adipocytes which activates adenylyl cyclase which increases cAMP and thus activates PKA (protein kinase)
-PKA phosphorylates perilipins and other proteins (Hormone Sensitive Lipase) that open the lipid droplet
-This allows the activity of 3 cytosolic lipases including hormone sensitive lipase which degrade TAGs to liberate fatty acids
(CGI-58 protein dissociates from perilipin and CGI-58 recruits and stimulates adipose tricylglycerol lipase to diacylglycerols)
(Phosphorylated perilipin associates with phosphorylated HSL, allows it access lipid droplet and HSL converts diacylglycerols to monoacylglycerols - monoacylglycerol lipase MGL hydrolyses monoacylglycerols
What happens fatty acids when they enter the blood?
-Fatty acids bind to serum albumen to be carried to tissues which need energy (liver, skeletal muscle, renal cortex ) and enter via fatty acid transporter protein
How do fatty acids get into the cell?
-Fatty acids dissociate from serum albumen and go through fatty acid transporter protein into the cytosol of cells that need energy
-But fatty acids must enter mitochondria for fatty acid ß-oxidation to occur
-FA chains less than 14 C long can enter mitochondria
-FA chains> 14 Cs are helped into mitochondria by activation and use of enzymes and transporter protein in inner mitochondrial membrane
How does fatty acid activation take place?
Fatty acids activated/ energised by CoA adds on using fatty acyl-CoA Synthetase isoenzymes
Fatty acid acyl CoA-Synthetase formula?
FA + CoA + ATP -> fatty acyl-CoA + AMP + PPi
Particularly favourable bc large neg energy (-34KJ/mol)
What 2 reactions does this break into?
Fatty Acid + ATP -> Acyl-AMP + PPi
Acyl-AMP + CoASH -> Acyl-CoA + AMP
What does Fatty acyl-CoA synthetase do?
Catalyzes formation of thioester linkage between fatty acid carboxyl group and thiol group of coenzyme A to yield a fatty acyl-CoA - uses ATP in reaction
Why is Fatty acyl-CoA made?
High energy compound that is much more amenable to catabolism than FAs - bc FAs so stable
How does Fatty acyl transport into the mitochondrial matrix take place?
The carnitine shuttle
1. Fatty acyl-CoA bond hydrolysed and fatty acyl group attaches to -OH of carnitine in outer mitochondrial membrane catalysed by carnitine acyl-transferase-1
2. Fatty acyl-carnitine enters mitochondrial matrix through carnitine transporter on inner mitochondrial membrane
3. Fatty acyl group enzymatically transferred to intramitochondrial CoA by carnitine acyl-transferase-2
4. Carnitine re-enters intermembrane space and process starts again
What happens in Step 3 (ß-oxidation of fatty acyl CoA finally fats oxidised/catabolism for energy)
-In ß-oxidation each 2C of fatty acyl-CoA cleaved and converted to Acetyl-CoA
-4 enzymes needed for formation of each acetyl-CoA that is cleaved off during ß-oxidation (dehydrogenase, hydratase, dehydrogenase, thiolase
e.g 16C palmitoyl-CoA -> 8 Acetyl-CoA
What enzymes are needed in ß-oxidation and for what?
Enzyme 1- dehydrogenase
2- hydratase - brings in water to break bond
3- dehydrogenase - reducing power
4- Thiolase - cleavage enzyme to release final 2 Acetyl CoA
LOOK AT ENZYME FUNCTION on slide show
How many times in total are the 4 steps of ß-oxidation carried out for the complete conversion of 16C palmitoyl-CoA to 8 molecules of Acetyl CoA?
7 times
C16 palmitoyl-CoA goes through 4 enzyme steps of ß-oxidation -> 1 Acetyl CoA goes through 4 enzyme steps of ß-oxidation so 1Acetyl CoA made and C14 myristoyl fatty acyl-CoA left
ß-oxidation repeats 6 more times - 6 more acetyl CoAs made and one Acetyl CoA left at end
-If fatty acyl chain has an odd number left w 3C Propionyl CoA, this breaks down further in 3 enzymatic steps
How much energy is obtained via ß-oxidation of 16C palmitoyl-CoA
Loads
7FADH2 and 7NADH deliver electrons to respiratory chain and 8 acetyl CoA enter citric acid cycle
Triangle G’0 = -9800kJ/mol (compared with 2380kJ/mol for complete oxidation 1 glucose)
What are fatty acids with double bonds called and what configuration are these usually in?
-Unsaturated fatty acids
-Usually in cis configuration
What extra enzymes are needed to catabolise fatty acids with double bonds?
-Isomerase converts cis to trans
-In polyunsaturated FA - need extra reductase enzyme
Glucose vs fatty acid metabolism?
Glucose metabolism yields ATP but fatty acid metabolism yields higher levels of ATP whilst regenerating glucose
Which yields more energy glucose or palmitoyl-CoA?
Palmitoyl
What does acetyl-CoA dehydrogenase deficiency result in
-low energy
-fat accumulation
-vomiting
-sleeplessness
-coma
