Lipid Biosynthesis Ch21.1, 21.2 et 21.4 Flashcards
What are biological functions of lipids?
- E Storage (TG)
- Constituents of membranes
- Anchors for membrane prots (prenyl gr, IP2,/PIP3)
- Cofactors for enzymes (vit K)
- Signaling molecules (eicosanoids, IP3)
- Pigments (retinal)
- Detergents (bile salts– help abs. Of more lipids and fats from diet)
- Transporters of other lipids.
- Act as antioxidants (vit. A)
What are the 2 phases of synthesizing FA?
1-Acetyl CoA activation as Malonyl-CoA
2-Add 2 carbons of FA using Fatty acyl synthase
PHASE 1-Make MALONYL-CoA using this big enz. (ACETYLCoA CARBOXYLASE)made out of TRANSCARBOXYLASE and BIOTIN CARBOXYLASE;
- Acetyl-CoA has a COO- that adds it to biotin carbolyxase, which causes a conformational change from cis to trans– activates the transcarboxylase.
- When Acetyl CoA goes to that transcarboxylase, then malonyl-CoA is formed.
PHASE 2- Addition of 2 carbons of FA chain using FATTY ACYL SYNTHASE– This enzyme does 4 processes (condensation, reduction, dehydration, reduction).
- CONDENSATION: activated acyl group (an acetyl group from acetyl-CoA) and two carbons derived from malonyl-CoA, with elimination of CO2 from the malonyl group, extends the acyl chain by two carbons. Decarboxylation facilitates condensation.
REDUCTION: the a-keto group is reduced to an alcohol (taking away a double bond by adding 2H+ with NADH)
DEHYDRATION: elimination of H2O creates a double bond between the acetyl group and the 2 C derived from malonyl coA
REDUCTION: the double bond is reduced to form the saturated fatty acyl group, thus extension of FA is done.
Why is malonyl-CoA essential to synthesize?
In mammalian cells, we can synthesize 16C FA called Palmitate (16:0)
It is used to elongate FA
When is the synthesis of FA process ending? (When does the cycle of adding 2 C each time stopped?)
When the FA reaches the palmitate length (16C), it leave the FA synthetase.
Is there a difference between C16 and C15(near glycerol) compared to the rest of the C on the FA synthesized?
C16 and C15 are derived from methyl and carboxyl carbon from an acetyl CoA.
The other carbons on the FA are from the acetyl CoA via the malonyl CoA.
How is the synthesis of other FA (longer or unsaturated) made from palmitate? Which type of FA can it not do?
Long-chain FA are produced in ER (also in mitochondria)
Palmitate is the precusor for long chain FA to be prod. in body. (stearate (18:0))
Palmitate and stearate are desaturated– they will produce unsaturated FA that we find in our bodies by FATTY ACYL-COA DESATURASE by oxidative reactions (it adds double bonds through oxidation process, by removing H+)
Palmitoleate (16:1) and oleate (18:1) have bonds at C9-10. Oleate can be synthesized by our cells.
Linoleate.. Which is in the omega family CANNOT be synthesized by us (only by plants)
If we cannot make linoleate (omega family) through palmitate, how can we? What can be made from linoleate?
Linoleate (18:2delta9, 12) cannot be synthesized in mammals; this is an essential FA: linoleate is made by plants, so we need it in diet!
Arachidonate (20: 4delta5, 8, 11, 14) is synthesized by linoleate. Arachidonate is a precursor to cholesterol. So linoleate needs to be eaten so that it can be elongated to arachidonate in mammals.
What are activators and deactivators of FA biosynthesis?
- Insulin: pathway has phosphatase that dephosphorylates ACC (ACTIVATOR)
- Acetyl-CoA carboxylase (ACC) is the rate limiting enzyme/step. So, if ACC acts upon acetyl CoA to make malonyl, then it can only go to FA synthesis = ACTIVATOR.
- Citrate from mitochondria is an ACTIVATOR of ACC
- Malonyl CoA inhibits b-oxidation of Fatty Acyl-CoA (mit.; b-oxidation rate limiting step)), and it will make FA in cyt.
- INHIBITED by phosphorylation (by epinephrine and glucagon signal)
- Palmitoyl-CoA is a FEEDBACK INHIBITOR; FA synthesis start with ACC until goes to FA synthase, which makes palmitoyl CoA (before palmitate). Palmitoyl CoA stops reaction from continuing.
Basically, what are the reactions that occur in the mitochondria? Cytosol? ER?
Mit:
- b-oxidation
- AcetylCoA prod.
- ketone body synthesis
- FA elongation
Cyt:
- Phospholipids and sterols synthesis
- FA elongation
- FA desaturation
ER:
- NADPH prod (pentose phosphate pathway)
- sterol synthesis
- FA synthesis
What molecules are produced in catabolism of FA? Used in Anabolism of FA?
Catabolism of FA
Produces Acetyl CoA
Produces e- donors (NADH)
Occurs in the mitochondria
Anabolism of FA
Requires acetyl-CoA and malonyl-CoA
Requires e- donors (NADPH)
Occurs in the cytosol in animals
What are sources of Acetyl-CoA?
PROBLEM: the inner mitochondrial membrane is not permeable for Acetyl-CoA. How can it get out to the cyt.?
Pyruvate carboxylation (end prod. of glycolysis in mit.) or aa catabolism (mitocondria) are sources of Acetyl-CoA.
Acetyl CoA needs a transportation process to get it out to cyt.
- Citrate is the acetyl CoA form that can be transported–acetyl-CoA + oxaloacetate = citrate (uses CITRATE SYNTHASE paired with citrate transporter, in mitochondria).
-When in cytoplasm, citrate can be converted back to acetyl-CoA + oxaloacetate (uses CITRATE LYASE in cyt.)
- Acetyl CoA is where we needed it to be, but oxaloacetate, no; oxaloacetate (cyt.)– malate (uses MALATE DEHYDROGENASE in cyt.)
- Malate can go into the mit. Through malate-alpha-ketoglutarate TRANSPORTER OR malate in cyt. can also be CONVERTED TO pyruvate in cyt.(using malic enz.)
How are TG made? (for storage of FA)
Step 1: G-3-P uses acyl transferase (add FA chains to G-3-P) to form phosphatidic acid
Step 2: Phophatidic acid can be synthesized as glycerophospholipid (which is used in the membrane, such as PIP2) OR form TG (using phsophatidic acid phosphatase and acyl transferase).
Insulin promotes/stimulates synthesis of TG (E storage), by stimulating acyl transferase; ANABOLISM
How is cholesterol made (biosynthesis)? Where?
Occurs in cyt. or microsomes (membrane-bound structure)
- Acetate starts with condensation using intermediate HMG CoA ; (acetate to HMG-CoA synthase to HMG CoA to HMG CoA reductase to form mevalonate).
- Phosphorylation of mevalonate form an activated isoprene.
- polymerization (long chain to form squaline)
- and finally, cyclization (3 6 carbon rings + 1 5 C ring)= cholesterol.
What is the rate-limiting enzyme of cholesterol biosynthesis? What activates or inhibits this enzyme?
HMG-CoA reductase is rate limiting enzyme:
1) AMP-dependent prot kinase (AMPK) -When AMPK rises, kinase phospholyrates the enzyme= inhibiton
2) Glucagon, epinephrine -Cascades lead to phosphorylation= inhibition
3) Insulin -Cascades lead to dehosphorylation, which activates activity.
4) Insig (insulin-induced gene prot.) sense cholesterol levels -Triggers ubiquination (always triggers prot. degradation) of HMG-CoA reductase.
What can be made from cholesterol?
Vitamin D, Sterols, Bile acids
