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Four step sequence that adds 2 carbons to an existing acyl chain (Skeleton):
(addition and modification of malonyl-CoA ) Existing acyl chain + malonyl-CoA, 2 carbons + 3 carbons = 4 carbons???? Decarboxylation removes 1 carbon as CO2 (the same carbon we added to create malonyl-CoA, same added as removed). Fatty acid synthesis requires that Malonyl-CoA is activated and fatty acid synthase, a large complex. Sequence: (1) condensation, 3C + 2C à 4C + CO2 leaves (2) reduction, NADPH + H+ is oxidized to NADP+, double bond is removed (3) dehydration, H2O leaves and another double bond is created somewhere else (4) reduction, NADPH + H+ is oxidized into NADP+ à saturated acyl group, lengthened by two carbons.
Four step sequence that adds 2 carbons to an existing acyl chain (Detail):
Step 1: Condensation of Acetyl + Malonyl groups à Acetoacetyl-ACP. Acetyoacyl bound to –SH of ACP pantothenate. CO2 is produced: originally from HCO3 (-), same CO2 is attached and removed- makes overall reaction favored. This condensation also makes overall reactions favored.
Step 2: Reduction of the carbonyl group. Carbonyl of Acetoacetyl-CoA is reduced à D-beta-hydroxybutyryl-ACP. Electron/proton donor is NADPH, ANABOLIC.
Step 3: Dehydration. H2O is produced from groups removed from C2 and C3. Produces a double bond.
Step 4: Reduction of double bond. Product – a butyryl-ACP. NADPH is electron/proton donor (reducing agent).
- Formation of palmitate by repeating the 4 reactions: butyryl (4-carbon) group is transferred from the –SH group of ACP to
- the –SH group of KS. Another malonyl group is added to the ACP (re-charging). The four reactions proceed, using existing butyryl group. 7 rounds of condensation yield palmitoyl-ACP. Palmitate is released (16:0). A hydrolysis reaction using 1 H2O releases palmitate from ACP.
How many reducing equivalents, molecules of electron carriers, and ATP molecules are needed for the addition of 2 carbons:
Each round adds two carbons (net) and requires 4 H+ and 4 e-.
Balance sheet for palmitate synthesis:
8 acetyl-CoA + 7ATP + 14NADPH + 14H+ à Palmitate + 8CoA + 6H2O + 7ADP + 7Pi +17NADP+
Ketoacyl synthase (KS) and Acyl Carrier Protein (ACP) Charging:
Both thiols KS and ACP must be bound with the correct groups. (1) Acetyl group (of acetyl-CoA) is transferred to the Cys of KS (2) Malonyl group (of Malonyl-CoA) is transferred to the –SH of ACP.
What is the specific (longest) product of fatty acyl chain synthesis?:
Palmitate is the specific longest product of fatty acyl chain synthesis.
How can the newly synthesized acyl chain be made longer, if necessary?:
the fatty acid elongation system, adds acetyl groups (2 carbon units), operates in mitochondria and (smooth) endoplasmic reticulum- coenzyme A is acyl carrier (not ACP), and the mechanism is the same one used for making palmitate. “Elongation of fatty acids does not involve fatty acid synthase”.
How is shorter acyl chains synthesized?:
How we can obtain the shorter acyl chains is through diet as we cannot make them.
Acyl chain bonds desaturated:
Double bond is introduced by oxidation: mixed funtion oxidase (fatty acyl-CoA desaturase). Oxidases are also in fatty acif oxidation. They require NADPH, cytochrome b5, and FADH2. Double bonds between C9 and C10 can be introduced in mammals (mammals cannot desaturate between C10 and methyl end of fatty acid).
The function of Acyl Carrier Protein:
it may serve as a flexible arm and thioester hydrolysis is highly exergonic – drives the condensation reaction. Acyl carrier protein is a thiol group.
What is the “important” secondary function of Malic Enzyme?
The important secondary function of malic enzyme is the production of NADPH + H+ when malate converts to pyruvate and CO2 via that enzyme.
Where does fatty acyl chain synthesis happen in eukaryotes and in plants?:
In eukaryotes, FA chain synthesis happens in the cytosol. Segregation of these anabolic processes from the catabolism in the mitochondria.
Regulations of fatty acid synthesis:
- (1) Allosteric control of acetyl-CoA carboxylase:
- Palmitoyl-CoA is a feedback inhibitor, inhibits malonyl-CoA synthesis.
- Citrate is an allosteric activator; citrate also inhibits PFK-1 – inhibits glycolysis and prevents buildup of unnecessary energy.
- (2) Phosphorylation:
- Regulation can also be by phosphorylation. Glucagon and epinephrine cause inactivation by phosphorylation.
- Active Acetyl-CoA carboxylase polymerizes into filaments. Inactive enzyme is depolymerized.
- (3) Regulation by substrate:
- Beta-oxidation is blocked by Malonyl-CoA; inhibits carnitine acyltransferase.
- Another example of futile cycling.
The basic precursors for making eicosanoids:
Strategy for making eicosanoids:
no energy is required.