Fatty Acid Oxidation Flashcards
what are the key concepts of FA catabolism?
- FA are transported to tissues where they’re activated and enter the mitochondria
- FA are catabolized to 2-carbon units in mitochondria via B-oxidation pathway
- oxidation reactions occur in discreet steps coupled to FADH and NADH production and generation of ATP
- acetyl CoA units generated from fatty acids by B-oxidation ultimately enter TCA where they yield more ATP
- different enzymes catabolize short, medium and long chain FA
under what conditions would you need to rely upon FA to generate ATP?
- prolonged fast
- running a marathon
- uncontrolled diabetes
what does B-oxidation extract from FAs?
it extracts energy via ATP, CO2 and H2O from FAs
what’s the overview of the stages in converting FA to CO2 and H2O?
- activation by Coenzyme A
- transport into mitochondria by carnitine shuttle
- B-oxidation to Acetyl CoA (4 steps)
- oxidation of acetyl CoA via TCA
what is the first step in converting FA to CO2 and H2O?
to begin FA breakdown, FA enters the cell by crossing the cell membrane and entering the cytoplasm
FFA must be activated and be conjugated to Coenzyme A to begin the conversion process
what is the second step in converting FA to CO2 and H2O?
now we need to get the FA from the cytoplasm into the mitochondria via the carnitine shuttle
what is the third step in converting FA to CO2 and H2O?
once in the mitochondria, B-oxidation has 4 repeating steps that release a molecule of acetyl CoA and 2 carbons at a time until eventually we get all the way down to just acetyl CoA
what is the fourth step in converting FA to CO2 and H2O?
acetyl CoA is oxidized via TCA cycle which releases energy (ATP), CO2 and H2O
what’s the chemistry of the first step in converting FA to CO2 and H2O?
starts with FFA activation through conjugation to Coenzyme A - this enzyme reaction is a 2 step reaction
Step 1: FA + ATP –> Acyl AMP + PPi
Step 2: acyl AMP + HS-CoA –> acyl-CoA + AMP
Side rxn: pyrophosphatase: PPi + H2O –> 2Pi + 2H+
Overall: FA + ATP + HS-CoA –> Acyl-S-CoA + AMP + PPi
catalyst: acyl-CoA synthase = FA thiokinase
pyrophasphatase helps break the 2 phosphate bonds in ATP which drives the reaction forward
does acyl-CoA synthetase work on everything?
works on all long chain FA including palmitate, oleate, etc.
the exception is for medium and short chain FA in which this activation step is skipped
what’s the chemistry of the second step in converting FA to CO2 and H2O?
you want to move acyl-S-CoA from the cytosol to the mitochondrial matrix for B-oxidation
cytosolic acyl-S-CoA –> mitochondrial acyl-S-CoA
enzymes: carnitine acyltransferase I (CPTI), translocate, carnitine acyltransferase II (CPTII)
what does CPTI do?
long chain acyl-CoA can’t cross the mitochondrial membrane so we need a carrier (carnitine) and an enzyme (CPTI)
CPTI transfers the acyl group to carnitine and at the end of the reaction RCO-carnitine is in the inter membrane mitochondrial space
what does translocase do?
in the intermembrane space RCO-carnitine reacts with translocase enzyme to move the RCO-carnitine across the mitochondrial inner membrane into the mitochondrial matrix
what does CPTII do?
once it’s in the mitochondrial matrix, RCO-carnitine is conjugated back onto S-CoA via CPTII enzyme
this gives us the final product of RCO-S-CoA inside the mitochondrial matrix and it’s ready for B-oxidation!
do short and medium chain FA need the carnitine shuttle?
nope
short = 4-6 carbons
medium = 6-12 carbons
they don’t need the carnitine shuttle to move from the cytosol to the mitochondrial matrix, they can pass through via diffusion
what’s the chemistry of the third step in converting FA to CO2 and H2O?
you want to break down acyl-S-CoA 2 carbons at a time and extract energy through B-oxidation
acyl-S-CoA + 7FAD + 7NAD+ + 7H2O –> 8acetyl-CoA + 7FADH2 + 7NADH + 7H+
enzymes: acyl CoA dehydrogenase**, enoyl-CoA hydrates, B-hydroxy acyl CoA dehydrogenase, B-ketothiolase
what’s wrong with acyl CoA dehydrogenase?
it’s a genetic hot spot for mutation with clinical phenotype
what are the 4 reoccurring steps in B-oxidation of fatty acyl-CoA?
- oxidation by FAD
- hydration
- oxidation by NAD+
- cleavage by CoA
acyl chain is shortened by 2 carbons
FADH2, NADH, and acetyl-CoA are generated
ATP is generated via ETC and we use the acetyl-CoA and put it through TCA which will also generate ATP!
what is the first step in B-oxidation?
oxidation by FAD via acyl CoA dehydrogenase
dehydration that removes hydrogens and creates a double bond and also FADH2 is generated
FADH2 can generate energy in the ETC
enzyme is chain length specific!!!! aka there are long, medium and short chain acyl CoA dehydrogenase
what’s the second step in B-oxidation?
enoyl-CoA hydratase is basically going to add water in the hydration step = you add a hydroxyl group to the double bond in the trans-enoyl CoA
trans-enoyl CoA + H2O –> B-hydroxyacyl CoA
enzyme: enoyl-CoA hydratase
what’s the third step in B-oxidation?
oxidation by NAD
we remove two more hydrogens to yield NADH + H+ and convert the hydroxyl group to the keto group
what’s the 4th step in B-oxidation?
extract energy via TCA
acetyl CoA goes into the TCA cycle
NADH & FADH2 go into ETC
how do cells deal with odd chain FAs in B-oxidation?
they go through B-oxidation the same but once the chain has reached 3 carbons, it’s converted to succinylcholine CoA
succinylcholine CoA enters TCA cycle later so we lost out on 2 NADH!
odd numbered carbon chains are usually from plants and they’re very rare
how do cells deal with mono and polyunsaturated FA?
these are very abundant in the diet!
they are also oxidized to yield ATP but the enzymes in the 4 normal steps of B-oxidation can’t react with the double bonds from these types of fats
two accessory enzymes are needed: cis-enoyl-CoA isomerase and 2,4-dienoyl-CoA reductase
isomerase = “flips” double bonds around and repositions them so that the substrate is compatible fo r cleavage
reductase = important for polyunsaturated fats; will reduce some double bonds to change their positions
