22B Fatty Acid Synthesis Flashcards
Where does Fatty Acid Synthesis occur?
Cytoplasm
What are Fatty Acids Synthesized from?
Acetyl CoA’s from the matrix of Mitochondria
Activation of Acetyl CoA in Fatty Acid Synthesis
Addition of CO2 in the form of HCO3- (CO2 in aqueous solution dissociates into HCO3- and H+)
Acetyl CoA Carboxylase
Carboxylation (addition of CO2)
Acetyl CoA + ATP + HCO3- -> Malonyl CoA + ADP
- Commited Step in Fatty Acid Synthesis=REGULATED
- Requires ATP
- Prosthetic Group=Biotin
How is biotin attached to the enzyme Acetyl CoA Carboxylase
E amino group of Lysine
What three enzymes has Biotin as Prosthetic group?
Acetyl CoA Carboxylase
Propionyl CoA Carboxylase
Pyruvate Carboxylase
Acetyl Transacylase
Exchanges CoA for ACP on acetyl group forming Acetyl ACP
Acetyl CoA-> Acetyl ACP
Malonyl Transacylase
Transfer malonyl group from CoA to ACP
ACP
-structure
Acyl Carrier Protein
- 77 amino acids
- Acyl Group Attaches to serine R group ( same as Coenzyme A)
Elongation Phase of Fatty Acid Synthesis:
-1st Step
Condensation
Acetyl ACP + Malonyl ACP -> AcetoAcetyl ACP + ACP + CO2
- catalyzed by Acyl-maloynl ACP condensing enzyme
- Decarboxylation reaction which provides the energy (decreases in free energy)
Elongation Phase of Fatty Acid Synthesis:
-2nd Step
Reduction
AcetoAcetyl ACP-> D-3-hydroxybutryl ACP
catalyzed by B-Ketoacyl ACP reductase
NADPH is oxidized to NADP+
Elongation Phase of Fatty Acid Synthesis:
-3rd Step
Dehydration
D-3-hydroxybutryl ACP (4C)-> Crotonyl ACP(4C) + H2O
catalyzed by 3-hydroxyacyl ACP dehydrates
Elongation Phase of Fatty Acid Synthesis:
-4th Step
REduction Crotonyl ACP (4C) -> Butyryl ACP
catalyzed by Enoyl ACP reductase
-NADPH oxidized to NADP+
Acetyl CoA Carboxylase
-Structure
Contains all enzymes from elongation step Dimer: 3 domains with 7 activites 1) Domain 1-substrate entry and condensation unit -AT=acetyl transacylase -MT-Malonyl Transacylase -CE= Acyl-Malonyl ACP condensing enzyme 2) Domain 2-reduction unit -KR=B-ketoacyl ACP reductase -DH=3-hydroxyacyl ACP dehydratase -ER=Enoyl ACP reductase 3) Domain 3-palmitate release -TE-Thioesterase
Palmitate synthesis requires
8 Acetyl CoA
14 NADPH
7 ATP’s
How Are acetyl CoA transported from Mitochondria to Cytoplasm for Fatty Acid Synthesis?
Acetyl CoA can’t cross the inter membrane of Mt
* When Acetyl CoA and OAA concentration is High, Citrate is synthesized and transported to cytoplasm for Fatty Acid Synthesis
Steps:
1) Acetyl CoA + OAA -> Citrate in Krebs cycle
2) Citrate transported across the inter membrane of mitochondria and through porons of the outer mitochondrial membrane into the cytoplasm
3) Citrate-> Acetyl CoA + OAA
- catalyzed by ATP citrate lipase
- occurs in cytoplasm
- acetyl CoA can now undergo Fatty Acid Synthesis
4) OAA -> Malate
- catalyzed by Malate Dehydrogenase
- OAA is reduced to Malate
- NADH is oxidized to NAD+ to be used in glycolysis and fermentation
5) Malate-> Pyruvate
- catalyzed by NADP+ linked malate enzyme
- oxidizes malate to pyruvate
- Synthesizes ONE NADPH per acetyl unit
What is the source of NADPH in Fatty Acid Synthesis?
1) Oxidation of Malate to Pyruvate by NADP+ Linked malate enzyme
2) Pentose phosphate pathway
Acetyl CoA Carboxylase Regulation
High Activity when: there is a high concentration of
- Carbohydrates concentration=represented by citrate
- High Energy Charge (ATP)
Turned ON:
1) dephosphorylation by Protein Phosphatase 2A
2) Allosterically by: Citrate which facilitates polymerization of dimers of Acetyl CoA carboxylase
Turned OFF:
1) Phosphorylation by AMP dependent Protein Kinase
- stimulated by AMP and Inhibited by ATP
2) Palmitoyl CoA
- faciliates depolymerization of Acetyl CoA carboxylase polymers
- Inhibits Citrate translocase
- Inhibits Glucose 6-Phosphate in Pentose Phosphate Pathway
Hormonal Control of Acetyl CoA Carboxylase
Turns ON:
1) Insulin- well fed state
-activates Protein Phosphatase 2A which converts carboxylase into dephosphorylated form (Active form)
Turned OFF:
1) Glucagon and Epinephrine
-Maintains carboxylase in Phosphorylated State by AMP-dependent Protein Kinase
Adaptive Control
1) regulation due to dietary changes
- Fasting animals then switch to high carbohydrate state (Fed state), low fat diets exhibit increase conc of Acetyl CoA Carboxylase and Fatty Acid Synthase
2) Transcriptional Level
- up regulate the synthesis of mRNA for the enzymes apart of Fatty Acid Synthesis
Synthesis of >16 Carbon Fatty acids
Enzymes located on cytoplasmic side of smooth ER
Adds two carbon units to carboxyl end of saturated and unsaturated fatty acids from Malonyl CoA
-energy provided by decarboxylation of Malonyl CoA
Synthesis of Unsaturated Fatty Acids
Enzymes located on cytoplasmic side of smooth ER
Double Bonds inserted by multi enzyme complex
1) NADH cytochrome b5 reductase
- FAD prosthetic group
2) cytochrome b5
- Heme prosthetic group with Iron
3) Desaturase
- Non heme iron
- Molecular O2 which accepts 4 electrons- 2 from NADH and 2 from single bond of fatty acyl substrate
- NADH provides 2 electrons
Synthesis of Unsaturated Fatty Acids in Mammals
Mammals lack the enzyme to introduce double bonds at carbon atoms beyond C9:
Essential Fatty Acids-Linoleate and Linolenate both have double bonds after C9 this is why they are essential to mammals
Arachidonate
20:4 Fatty acid is precursor for synthesis of Eicosanoid Hormones
Eicosanoid Hormones: contain 20 carbons
- Prostaglandins
- Prostacyclins
- Thromboxanes
- Leukotrienes
