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7 Cards in this Set
- Front
- Back
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Recognize the role of compartmentalization of fatty acid synthesis and degradation |
FA synthesis: - formed from acetyl-CoA - synthesis occurs mostly in cytosol of hepatocytes
FA degradation: - occurs in the mitochondrial matrix - produces acetyl-CoA, NADH, FADH₂ - localization to the matrix allows these products to be quickly incorporated into the TCA and ETC, respectively |
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Recognize how fatty acids are transported into the mitochondria, proteins involved, and the relevance of this step |
Short & Medium Chain Fatty Acids: - small enough to diffuse directly though the mitochondrial membranes into the matrix
Long Chain Fatty Acids: - activated in the cytosol - acyl-CoA synthtase uses ATP to add a CoA molecule to the FA creating fatty acyl-CoA - fatty acyl-CoA can diffuse across the outer mitochondrial membrane - carnitine: palmitoyl-transferase I (CPT1) removes CoA from fatty acyl-CoA and adds carnitine forming fatty acylcarnitine - Carnitine: acylcarnitine nitrine translocase shuttles fatty acylcarnitine across the inner mitochondrial membrane - CPT2 removes carnitine from the fatty acylcarnitine and adds CoA back, reforming the fatty acyl-CoA which is the substrate for β-oxidation
Very Long Chain Fatty Acids: - must be shortened into long chain fatty acids in the peroxisomes - the new long chain fatty acids can then enter the mitochondria as detailed above
By relegating β-oxidation to the mitochondrial matrix, the products formed (acetyl-CoA, NADH, FADH₂ can all quickly feed into their respective cycles |
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Outline the overall steps in β-oxidation |
1. Acyl-CoA dehydrogenase oxidizes fatty acyl-CoA to trans ∆² fatty enoyl-CoA - FAD is reduced to FADH₂
2. Enoyl-CoA Hydratase hydrolyzes trans ∆² fatty enoyl-CoA to L-β-hydroxy acyl-CoA
3. β-hydroxy acyl-CoA dehydrogenase oxidizes L-β-hydroxy acyl-CoA to β-keto acyl-CoA - NAD⁺ is reduced to NADH
4. β-keto thiloase cleaves β-keto acyl-CoA to form an acetyl-CoA molecule and a new fatty acyl-CoA that is two carbons shorter than the previous one that started the cycle - this new fatty acyl-CoA can now feed back into the start of the β-oxidation spiral |
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Recognize how, when, and where ketone bodies are synthesized and degraded |
3 ketone bodies are formed by humans - acetone - acetoacetate - β-hydroxybutyrate
Acetoacetate is formed from the condensation of 2 acetyl-CoA molecules via two intermediates
Acetone forms via a spontaneous decarboxylation - it evaporates and we exhale it
β-hydroxybutyrate forms when acetoacetate is oxidized by β-hydroxybutyrate dehydrogenase - NAD⁺ is
All three are formed mostly in the liver during times of high energy availability - oxaloacetate is convert to malate which leaves the mitochondria to form glucose via gluconeogenesis - the extra acetyl-CoA produced from β-oxidation has nothing to condense with to start the TCA cycle so it will condense with itself to form acetoacetate
Ketone bodies are metabolized almost as quickly as they are formed - used by skeletal and cardiac muscle during physiological conditions - used by all cells, including neurons, during starvation conditions - RBCs and hepatocytes cannot metabolize ketone bodies - Hepatocytes lack key transferase enzyme needed for metabolism
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Recognize how fatty acid oxidation is regulated |
Regulation prevents futile cycles - immediate degradation of newly synthesized FAs or vice versa
Increased ATP/ADP levels slow the ETC leading to an increase in the concentration of NADH/FADH₂ - β-oxidation requires NAD⁺ and FAD and so it will be inhibited by this
Increased insulin levels promote conversion of acetyl-CoA to malonyl-CoA by acetyl-CoA decarboxylase - malonyl-CoA inhibits CPTI which inhibits β-oxidation
Increased AMP concentrations (typically caused by high ATP usage) will activate AMP protein kinase which inhibits acetyl-CoA decarboxylase, leading to a decrease in malonyl-CoA levels which allows CPTI to function normally |
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Acyl-CoA Dehydrogenase Deficiency |
Most common inherited defect of β-oxidation
These enzymes are size specific, defect in the medium chain specific enzyme is most common
Autosomal recessive
Clinical presentation: - hypoglycemia (no glycogenolysis or gluconeogenesis) - hypoketonemia (no extra acetyl-CoA to initiate ketogenesis) - accumulation of dicarboxylic acid from omega oxidation
Urinalysis for elevated dicarboxylic acid levels can be a diagnostic marker of disease |
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Very Long Chain Fatty Acid Degradation |
VLC FAs must be degraded in the peroxisomes to LC FAs
VLC FAs are activated in the cytosol by very long chain acyl-CoA synthase (VLACS) which adds a CoA to the VLC FAs
During degradation H₂O₂ is produced and subsequently degraded by catalase
Defects in VLACS can lead to β-oxidation deficiency because VLC FAs cannot be oxidized
Defects in catalase can lead to the build up of H₂O₂ a reactive oxygen species |
