Fatty Acid Synthesis. Ketone Body Synthesis and Utilization
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- Where does fatty acid synthesis occur?
- in the liver
- When does fatty acid synthesis occur?
- in fed state
- What is required in fatty acid synthesis that is formed from cytoplasmic citrate?
- glucose or gluconeoginic precursors
- what forms acyl CoA?
- cytosolic citrate
- What reduced equivalents are required in fatty acid synthesis? What pathway provides these particular moieties⬦ and thus what tissues?
- NADPH in two steps⬦ pentose pathway⬦ liver
- What provides CoA with 2-carbon units?
- Malonyl CoA
- What is needed to transport citrase into the cytosol and convert it to acetyl CoA and OAA?
- Citrate lyase
- CoA is used in fatty acid synthesis, what happens to the OAA?
- it is converted back into pyruvate and enter the mitochondria
- What is the pathway for OAA being converted back to pyruvate? (include requirements and start from citrate entering the cytosol)
- a) citrate --> OAA + acetyl CoA, used for fatty acid synthesis. Required: citrate lyase +ATP⬦ b) OAA --> Malate, requirements: cytosolic malate dehydroggenase + NADH⬦ c) Malate --> pyruvate, requirements: malic enzyme + NADP+ Note CO2 leaves.
- Besides this pyruvate recycling, where else does NADPH get generated?
- Pentose cycle
- malic enzyme and citrate lyase are inducible⬦ what does this mean?
- the amount of enzyme is increased via transcription
- When is fatty acid synthesis occuring?
- Fed state⬦ insulin up
- Which enzyme is necessary to activate acetyl CoA by converting it to malonyl CoA in fatty acid synthesis? What else is required in this highly regulated rxn?
- a) Acetyl CoA Carboxylase⬦ b) ATP + Biotin + CO2
- What is the first of 5 key points to remember for synthesis of palmitate by fatty acid synthase?
- 1) FA Synthase has 7 catalytic activities and an acyl carrier protein (ACP)
- What is the second of 5 key points to remember for synthesis of palmitate by fatty acid synthase?
- ACP has phosphopantetheinyl redidue with the -SH that forms thioesters
- What is the third of 5 key points to remember for synthesis of palmitate by fatty acid synthase?
- FA synthesis starts with acetyl CoA, adds 2 carbons from malonyl CoA at the carboxyl end, and uses 2 NADPH for reductions
- What is the fourth of 5 key points to remember for synthesis of palmitate by fatty acid synthase?
- Palmitate, C16:0, the product, is released after 7 rounds of malonyl CoA condensation to acetyl CoA
- What is the last of 5 key points to remember for synthesis of palmitate by fatty acid synthase?
- Elongation of palmitate and desaturation of palmitate occur in the ER (no double bonds in cytosol⬦ only ER)
- Which enzymes desaturate (add double bonds) in fatty acid synthesis? And which configuration will they orient, cis or trans?
- Desaturase⬦ Cis
- Why are some fatty acids essential? Which are they?
- a) Because humans (animals) lack the appropriate desaturase, they cannot make them⬦ b) These essential FAs contain a double bonds between the 10 carbon and the carbonyl end (w), (or in other words, double bonds cannot be added after carbon after 9)
- In FA synthesis, what are the intermediates from glucose to Palmitoyl CoA?
- glucose --> citrate --> acetyl CoA --> Malonyl --> palmitrate --> palmitoyl CoA
- How is acetyl CoA carboxylase regulated? (part I of question⬦ Hint: phosphorylation/dephosphorylation)
- a) due to a high insulin/glucagon ratio, a phosphatase dephosphorylates acetyl CoA carboxylase and thus activates it⬦ b) due to a low insulin/glucagon ratio an AMP-activated protein kinase phosphorylates acetyl CoA carboxylase and thus deactivates it...
- How is acetyl CoA carboxylase regulated? (part II of question⬦ hint:allosteric)
- ALSO c) It is allosterically activated by citrate (feed-forward activation)⬦ d) it is allosterically inhibited by palmitoyl CoA (feedback inhibition)
- Why does it make sense that acetyl CoA will be inhibited by high levels of AMP?
- it means your energy levels are low, and thus you don't want to store energy as fat (FA synthesis), you want to break down FA in gluconeogenesis.
- What is the key player in the balance between FA synthesis and ß-oxidation?
- Malonyl: a) Malonyl CoA is the activated acetyl CoA and the first commited step in FA synthesis… b) Malonyl CoA also inhibits ß-oxidation by inhibiting CPT-I (CPT-I removes the CoA from FAs entering the mitochondria, adds carnitine, so that the fatty acyl can enter the matrix, where ß-oxidation occurs.)
- What tissues does fatty acid degradation mainly occur?
- liver and muscles
- What tissues does FA synthesis occur?
- Liver
- What cellular compartment does FA synthesis occur?
- cytosol
- What cellular compartment does FA degradation occur?
- Mitochondrial matrix
- What is the carrier for FA synthesis?
- acyl carrier protein
- What is the carrier for FA degradation?
- Coenzyme A
- What are the cofactors for FA synthesis?
- NADPH
- What are the cofactors for FA degradation?
- NADH, FAD
- What is the donor for FA synthesis?
- malonyl CoA
- What is the donor for FA degradation?
- acetyl CoA
- What is the actviator for FA synthesis?
- citrate
- What is the inhibitor of FA synthesis?
- Fatty acyl CoA
- What is the inhibitor of FA degradation?
- malonyl CoA
- What is the product of FA synthesis?
- (e.g., palmitate)
- What is the product of FA degradation?
- acetyl CoA
- Besides glucose, what else can the brain use as a fuel source?
- ketone bodies, to a lesser degree
- What is the starting substrate for ketone synthesis? What is this substrates metabolic origin?
- a) acetyl CoA⬦ b) which mostly comes from FA oxidation⬦ also glycolysis and TCA cycle
- Which organs produce ketone bodies? Why can't other organ produce KB?
- a) Mainly liver, some in kidney⬦ b) they don't have HMG CoA synthase in their Mitochondrial matrices
- what are the steps of ketone synthesis from acetyl CoA to the ketone (e.g., acetoacetate)
- acetyl CoA --> acetoacetyl CoA (enzyme: thiolase)⬦ acetoacetyl CoA --> HMG CoA (enzyme:HMA CoA synthase)⬦ HMG CoA --> ketone body, e.g., acetoacetate (enzyme: HMG CoA lyase)
- The ketone body (acetoacetate) can convert to D-ß-hydroxybutyrate, what determines this? What is the normal ratio for these two moieties?
- Low NADH/NAD ratio goes to acetoacetate… b) D-ß-hydroxybutyrate:acetoacetate is 3:1
- How are ketone bodies harvested for energy? (give steps with enzymes)
- In tissues other than the liver: D-ß-hydroxybutyrate --> acetoacetate (D-ß-hydroxybutyrate dehydrogenase)… b) acetoacetate --> acetoacetyl CoA (succinyl CoA-acetoacetate CoA transferase... succinyl CoA is also needed)… c) acetoacetyl CoA --> acetyl CoA (thiolase)
- Where is the enzyme that converts acetoacetate to acetoacetyl CoA (Acetoacetate CoA transferase) not present? (thus this is the key enzyme in the oxidation of ketone bodies)
- Liver
- What is the key enzyme in ketone body oxidation?
- Succinyl CoA-acetoacetate CoA transferase
- Where do ketone bodies get the CoA needed for their oxidation?
- Succinyl CoA
- In ß-oxidation acetyl CoA is produced, where does it go for energy utilization?
- TCA cycle and the production of ketone bodies
- Can cells that lack mitochondria use ketone bodies? Why?
- No, because KB are converted to acetyl CoA and used in the TCA cycle, and TCA cycle is MM.
- So, why have ketone bodies?
- So that tissues (cells) that can use them don't use the glucose. This is important because RBCs and the brain can only use glucose as a fuel.
- What causes ketoacidosis?
- long term production of ketone bodies
- What is hypoketonic?
- people with MCAD have hypoglycemia due to low number of ketones
- What is hypoketonic a symptom of?
- MCAD
- Ketone bodies come from acetyl CoA, so can you make ketone bodies from glucose->pyruvate->acetyl CoA?
- No, the acetyl CoA must come from the ß-oxidation of fatty acids… thus MCAD results in hypoketonic
- Why does ketoacidosis occur with people that consume alcohol?
- alcohol metabolism cause a rise in NADH, which shuts down the TCA cycle, which means that pyruvate will form acetyl CoA to be shunted to ketone synthesis⬦ thus ketoacidosis (occurs in MM)
- Why are NADH levels in the cytosol increased in people that consume too much alcohol?
- Alcohol metabolism in the cytosol reduces NAD to NADH
- What would you give an alcoholic that came in with ketoacidosis?
- Glucose⬦ because they are in a starved state due to an inability carry out gluconeogenesis⬦ instead they are making ketone bodies and getting sick
- What is another cause of the lower of blood pH is seen in alcoholics?
- lactic acidosis
- Besides glucose, what would you want to give a person that came in with alcohol induced ketoacidosis?
- thiamine
- Would you give glucose to diabetics that are suffering from ketoacidosis?
- No
- What would you prescribe to diabetics suffering from ketoacidosis?
- deal with dehydration⬦ then insulin