Chapter 17 Lipid Biosynthesis Flashcards
Where does fatty acid catabolism take place?
in the mitochondrial matrix
Where does fatty acid catabolism take place?
in the mitochondrial matrix
Where are the electrons for fatty acid synthesis obtained from?
NADPH sourced from the pentose phosphate pathway and the malic enzyme.
Why do thioesters have high energy?
the sulfur atom is large and so there is no effective resonance taking place. Bond is weaker as a result and bond breakage is more spontaneous.
Under what conditions are fatty acids synthesized
when there is an excess of acetyl coA
What are the three stages of fatty acid synthesis?
- Preparatory: acetyl coA is transferred from mitochondria to the cytoplasm
- Activation: in cytoplasm acetyl-coA is activated, acetyl coA is converted to malonyl coA.
- Reaction: intermediates are attached to an acyl carrier protein.
In what form is acetyl-coA transported out of the mitochondria for lipid synthesis in the cytosol?
in the form of citrate, citrate is converted back into oxaloacetate and acetyl coA in the cytoplasm
What enzyme converts citrate into oxaloacetate and acetyl coA?
ATP-citrate lyase
What does citrate inhibit that affects the rate of glycolysis?
Citrate is an inhibitor of phosphofructokinase-1.
How is citrate lyase activated?
Citrate lyase is activated by phosphorylation through the insulin/PI3 Kinase/Akt Pathway.
How does the return of the carbon into the mitochondria enable the synthesis of NADPH used in lipid biosynthesis?
oxaloacetate is reduced to malate.
the malate is oxidized and decarboxylated to pyruvate generating NADPH.
What molecule is the direct precursor of fatty acid synthesis?
malonyl-coA
How many carbons are in added to the growing fatty acid chain in each round of biosynthesis?
2 carbons
What is the acetyl-coA carboxylase mechanism?
It is used to convert acetyl coA into malonyl coA in order to synthesize lipids.
What are the steps of the acetyl-coA carboxylase mechanism?
- formation of a phosphorylated bicarbonate intermediate- this reaction requires a molecule of ATP. ATP activates the bicarbonate for addition to biotin.
- The CO2 is transferred to the acetyl-coA to form malonyl coA.
Write the mechanism for the acetyl-coA carboxylase mechanism.
refer to slides
What is the first committed step of fatty acid synthesis?
synthesis of the malonyl coA
What are two sources of acetyl-coA for fatty acid biosynthesis?
mitochondrial acetyl-coA
- acetyl coA generated in the mitochondria through the breakdown of pyruvate in the pyruvate dehydrogenase complex
cytosolic acetyl coA
-citrate is transported from the mitochondria to the cytoplasm where it is converted back into acetyl coA and oxaloacetate by the enzyme citrate lyase.
What are the two fates of the oxaloacetate that is produced by the malic enzyme?
- oxaloacetate is reduced to the malate and returns to the mitochondria.
- oxaloacetate —> malate. Malate is oxidized and decarboxylated to pyruvate generating NADPH.
What three promoters make up the acetyl coA carboxylase complex? What is the cofactor for this complex?
biotin carrier protein, biotin carboxylase, and the transcarboxylase. The cofactor for this complex is biotin.
Describe the mechanism of regulation for the acetyl-coA carboxylase
AMPK phosphorylates carboxylase inactivating it.
Protein phosphatase dephosphorylates carboxylase activating it.
How is acetyl coA carboxylase regulated allosterically?
palmitoyl coA and citrate are allosteric regulators. The enzyme acetyl-coA carboxylase is active when it is polymerized into a filament.
polymerization is blocked by palmitoyl coA and stimulated by citrate.
How is acetyl coA carboxylase regulated allosterically?
palmitoyl coA and citrate are allosteric regulators. The enzyme acetyl-coA carboxylase is active when it is polymerized into a filament.
polymerization is blocked by palmitoyl coA and stimulated by citrate.
What is the name of the enzyme that catalyzes the biosynthesis of fatty acids?
The Fatty Acid Synthase
The acyl carrier protein forms covalent bonds with which two molecules?
the acetyl-coA and the malonyl-coA
What type of covalent bond is formed by the ACP with its substrate?
a thioester bond
How many substrates may bind with a single ACP?
1
Draw a cartoon representation of each step of fatty acid synthesis
refer to slides or problem set.
What happens in each stage of fatty acid synthesis?
- The acetyl coA binds to the ACP domain. Then it is transferred to KS domain.
- The malonyl coA binds to the ACP domain.
- The CH2 of malonyl coA carries out nucleophilic attack on carbonyl of acetyl coA. The KS domain is reset. CO2 leaves
- NADP+ reduces the carbonyl oxygen of acetyl coA.
- Water leaves, a double bond forms between two carbons
- NADPH reduces the double bond.
- The new fatty acyl chain is transferred from ACP domain to KS domain.
How are fatty acids longer than 16 carbons synthesized?
using elongation systems which are present in the ER.
What is a mixed function oxidase?
two substrates become oxidized but oxygen does not appear in final product.
What is the common biological intermediate to triacylglycerols and glycerolphospholipids?
phosphatidic acid
What is the activating group used in the synthesis of glycerol phospholipids?
CDP
What are the two strategies for attachment of head groups to glycerolphospholipids?
- involves a nucleophilic attack of a headgroup hydroxyl on the CDP phosphate. In this case diacylglycerol is activated with CDP.
- ONLY USED BY EUKARYOTES: involves the hydroxyl of 1,2-diacylglycerol displacing CMP. In this case headgroup is activated with CDP.
Show a serine headgroup being attached to diacylglycerol
refer to slides
Where does the biosynthesis of cholesterol take place?
cytosol
Where are all the carbon atoms in cholesterol obtained from?
acetyl coA
What are the four phases of cholesterol synthesis?
- 3 acetyl coA molecules combine to form the 6C mevalonate.
- mevalonate converted to isopentyl-pyrophosphate.
- six of these 5 carbon molecules polymerize to form 30 C squalene.
- squalene cyclizes to form lanosterol which forms cholesterol.
Steroid sensor mechanism
when cholesterol levels are high, the SCAP and Insig retain SERBP in the ER membrane.
These proteins form the cholesterol sensor
When steroid concentration drops, INSIG dissociates from SCAP. This allows SREBP to move to the Golgi where it is cleaved by a specific protease. Protease releases a protein that moves to the nucleus where it promotes the transcription of genes required for steroid synthesis.
What is the function of VLDL?
distributes excess fatty acids or cholesterol from the liver to the tissues.
Is there a cholesterol catabolism pathway?
No, there is no way to break down cholesterol.
How can we excrete cholesterol?
only way to excrete cholesterol is through bile salts.
What is statin drugs?
are a class of drugs that lower plasma cholesterol because they are inhibitors of HMG-coA reductase.
What is the importance of the HMG-reductase?
It catalyzes the critical conversion of HMG-coA to mevalonate.
Cholesterol Regulation
steroid sensor protein present in the ER (complex of proteins contains SREBP, SCAP, and Insig).
All proteins are physically touch each other.
Insig and SCAP bridged by cholesterol.
Cholesterol low: Insig no longer being held to SCAP
Insig anchored into ER, SCAP and SREBP drift on forward to golgi. They will meet protease. Protease will cut piece of SREBP and SREBP will activate gene to make cholesterol.
What is major regulator of cholesterol?
Steroid sensor
High density lipoproteins (HDL)
good cholesterol
scavenge things such as cholesterol and triacylglycerol and bring them to liver for catabolism and recycling
Low density lipoproteins (LDL)
bad cholesterol
distributing the fats to the tissues
How doe LDL and HDL enter?
Lipoprotein right shape to fit receptor, conformational change in receptor, receptor mediated endocytosis.
