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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?
What cellular compartment does FA synthesis occur?
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?
What are the cofactors for FA degradation?
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?
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)
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?
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?
Would you give glucose to diabetics that are suffering from ketoacidosis?
What would you prescribe to diabetics suffering from ketoacidosis?
deal with dehydration⬦ then insulin

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