Beta-Oxidation Flashcards
Location of beta-oxidation
What are the exception?
Mitochondria
Exceptions = RBC and brain
Hormones that stimulate B-ox
Glucagon, Epi
Fasting state
What does each round produce?
1 NADH
1 FADH2
1 Acetyl-CoA (which can be further oxidized for energy production)
Fatty Acid Activation
Mobilized FAs (from adipocytes) enter the cytosol…
There they are activated by Coenzyme A (CoA) … before they are transferred into the mitochondria
- FA —> Fatty acyl-adenylate intermediate and PPi (Fatty acyl CoA synthetase)…enzyme still bound to substrate
- PPi is immediately hydrolyzed to 2Pi (neg. delta G)…and FA-adenylate is activated with CoA (Fatty Acyl-CoA)
AMP is also released
Three pathways that the FA-CoA synthetase is used in…
- TG formation
- Glycerophospholipid formation
- Prelude to transport of FA into mitochondria (Beta-Ox)
FA-carnitine shuttle
Transfer system to get FA-CoA from cytosol to matrix of mitochondria
- Carnitine acyl-transferase I (CAT1) —> transfers FA-CoA to carnitine in cytosol (CoA is recycled)
- FA-carnitine is transported through outer membrane than through a transporter in the inner mito membrane
- Once in the matrix…CATII converts FA-carnitine back to FA-CoA
- Carnitine is shuttled back to the cytosol to be reused
**once in the matrix…committed to the beta-ox reaction
Carnitine deficiency
Can be produced in liver and kidney…but most comes from diet
Cannot used long chain FAs for energy production
Primary = autosomal recessive…CAT1 (liver) or CAT2 (cardiac and skeletal muscle) is dysfunctional
Secondary = liver disease, malnutrition…
The four repeating reactions of beta-ox
General
- Oxidation
- Hydration
- Oxidation
- Cleavage
1st oxidation step of Beta-ox
Enzyme: acyl-CoA dehydrogenase
Energy production: FADH2
Fatty acyl-CoA is oxidized and a double bond is formed between the alpha and beta carbons (trans configuration)
Product: trans-delta2-enoyl-CoA
Hydration step if beta-ox
Enzyme: Enoyl-CoA hydratase
Adds H2O across the double bond that was formed between the alpha and beta carbons
Product = beta-hydroxylacyl-CoA
2nd oxidation reaction of beta-ox (3rd overall reaction)
Enzyme: beta-hydroxyacyl-CoA dehydrogenase
Energy production: NADH + H
Oxidizes at the beta carbon to make…
Beta-ketoacyl-CoA (ketone group on beta carbon now (C=O)
Cleavage reaction in beta-ox
Enzyme: acyl-CoA acetyltransferase (thiolase)
2C unit (carboxyl and alpha carbons) is cleaved away as Acetyl-CoA…
The second CoA is attached to the beta-carbon which now becomes the new carboxyl (C1) to subsequent reactions —> repeat step #1
How many times can palmitate undergo beta-ox?
C16:0?
6 repeated steps = 6(FADH2 + NADH + Acetyl-CoA) + 4C Fatty acyl-CoA
7th reaction = FADH2 + NADH + 2Acetyl-CoA
Final Yield: 7(FADH2 + NADH) + 8 Acetyl-CoA
Fate of NADH/FADH2 and Acetyl-CoA
NADH/FADH2 = e-transport chain
Acetyl-CoA = citric acid cycle
Acetyl-CoA = # ATP?
10
NADH = #ATP
2.5
FADH2 = #ATP?
1.5 ATP
Medium chain acyl-CoA dehydrogenase deficiency (MCADD)
One of the most common inborn metabolic errors
AR
Deficiency in the Acyl-CoA dehydrogenase (first step enzyme in B-ox)
Has a higher affinity for medium chain FAs…so reduced ability to oxidized 6-10 length
Symptoms: accumulation of 6-10 FAs, low blood glucose, muscle weakness, sleepiness, vomitting, coma
Diagnosis = by high 6-10 and dicarboxylic acids in the urine
Cause of sudden infant death syndrome (SIDS)
Part of core panel of disorders screened for
Treatment = low fat/high carb diets…important to avoid fasting
Omega-FA oxidation
Minor route for MCFA oxidation
Carboxylic acid is produced on omega end —> dicarboxylic acid produced
These can enter the mito and oxidized by normal beta-ox
Ultimately succinyl-CoA is produced which can feed into the CAC
Stimulated pathway when person has MCADD
Odd chain beta-ox
After final reaction…propionyl-CoA is produced (instead of A-CoA)
Propionyl-CoA —> succinyl-CoA —> CAC
Two cofactors needed to do this…
- Biotin: used to add CO2 to the molecule —> methylmalonyl-CoA
- Vitamin B12: needed for a mutase to convert above product to succinyl-CoA
Methylmalonic acidemia
Occurs when there is a problem with the mutase in the odd-chain ox reaction to make succinyl-CoA from propionyl-CoA
Oxidation of very long chain FAs (VLCFAs)
Occurs in the peroxisome
2 aspects that differ from normal ox…
- Transport of VLCFAs into the peroxisome does not require carnitine
- Initial oxidation reaction that produces FADH2 (side product)…will oxidize back to FAD…and O2 —> H2O2
***NADH and Acetyl-CoA still produced each round
VLCFAs —> medium and short chains…leave the peroxisome as carnitine derivatives —> enter mito to undergo normal FA
Zellweger syndrome
Elevated VLCFAs
Inability to target peroxisome matrix proteins to the peroxisome
X-linked adrenoleukodystrophy
Elevated VLCFAs
Inability to transport molecules such as VLCFAs across peroxisomal membrane
Alpha-oxidation
For branched chain FAs
Occurs in peroxisome
Enzyme: alpha-hydroxylase
—> introduces a -OH group on alpha carbon (branch on beta carbon)
—> COOH group is then removed
** alpha carbon is now the new carboxyl carbon
**now the branch is on the alpha carbon
—> normal beta-ox yields propionyl-CoA (instead of Acetyl-CoA)
2nd round = acetyl-CoA
3rd round = branch on alpha carbon again —> so propionyl-CoA
4th round = acetyl-CoA and sooooo on….
LAST round = 4C isobutyryl-CoA
**recall: propionyl-CoA is converted to succinyl-CoA then goes to CAC
Refsum disease
Genetic defect in phytanoyl-CoA hydroxylase
= alpha-hydroxylase involved in the alpha-ox of phytanic acid…
Therefore unable to oxidation the branched points on that FA
High levels of phytanic acid in blood and tissues —>
Severe neurological problems
Restrict foods rich in this acid
