Fatty Acid Synthesis and Metabolism Regulation Flashcards
Where does FA synthesis take place?
Cytosol
How many steps are in the synthesis cycle? How many carbons are added per cycle?
Four step cycle
Extended by 2 carbons per cycle
How does fatty acid synthesis work?
Product is palmitic acid–modification leads to longer or shorter and unsaturated fatty acids
Enzymes involved are packaged in a complex called fatty acid synthase
FA synthesis begins from the methyl end and proceeds towards the carboxyl end–C16 and C15 are added first, and are derived directly from Acetyl-CoA. For further extension, acetyl-CoA is first activated to malonyl-CoA by the addition of CO2
What is fatty acid synthase?
Complex enzyme with 2 major units
Synthesizes 2 FAs simultaneously
What are the steps of FA synthesis?
1) Carboxylation of acetyl-CoA to form malonyl-CoA by Acetyl-CoA carboxylase (ACC)
- ACC is a rate limiting enzyme
2) Synthesis of palmitate by the sequential addition of two carbon units to a growing fatty acid chain by fatty acid synthase
What are the substrates for FA synthesis?
Acetyl-ACP and Malonyl-ACP
Both reactions are catalyzed by malonyl/acetyl transferase (MAT)
What is ACC
Acetyl-CoA Carboxylase
active form = polymerized and dephosphorylated
inactivated = phosphorylated monomer
Has 2 isoforms:
1) ACC1- expressed in lipogenic tissues, highly regulated by allosteric modulators and phosphorylation reactions
2) ACC2- expressed in mitochondira of oxidative tissues such as cardiac and skeletal muscle, and liver
- malonyl CoA inhibits acyltransferase 1
- serces a regulatory function in FA oxidation
How is ACC1 regulated?
Activator: citrate, a feed forward activator which promotes polymerization of ACC1
Inhibitor: palmitoyl-CoA, the end product of fatty acid synthesis depolymerizes to inhibit ACC1
Insulin dephosphorylates and activates ACC1
Epinephrine and glucagon phosphorylate and inhibit ACC1
How does fatty acid elongation and desaturation work?
Closely integrated processes occurring in the ER
- important in regulating membrane fluidity
Palmitic acid is converted to palmitoyl-coA for modification
Two carbon units provided by malonyl-CoA for FA elongation is similar to that of FA synthesis
Unsaturated fats are synthesized by enzymes called fatty acid CoA desaturases
Mammals lack the enzymes to introduce double bonds at carbon atoms beyong C9. FAs with double bonds beyond 9 must be supplied by diet and are called Esssential FAs.
How are beta oxidation and FA synthesis regulated
Glucagon and epinephrine inhibit FA synthesis and favor oxidation
Insulin stimulates synthesis and inhibits oxidation
What are the major differences between FA synthesis and beta-oxidation?
1) Different enzymes
2) FA synthesis in cytoplasm; beta-oxidation in mitochondria and peroxisome
3) FA synthesis consumes NADPH; beta-oxidation produces NADH, FADH2
How is FA synthesis regulated (acetyl-CoA cycle)
Fatty acids are synthesized in the cytoplasm from
acetyl-CoA
Acetyl-CoA formed within the mitochondria
Inner mitochondrial membrane is impermeable to
acetyl-CoA
Acetyl-CoA transported into cytoplasm as citrate, which is produced from acetyl-CoA and oxaloacetate
Citrate transported into cytoplasm when β-oxidation
is suppressed, that is, when cell needs little energy
Citrate cleaved to form oxaloacetate and acetyl-CoA
When cell needs energy, FAs are transported into
mitochondria as acylcarnitine derivatives
Acyl-CoA degraded to acetyl-CoA via β-oxidation
How does glucagon stimulate oxidation?
Stimulates CAT-1–presumably carnitine-acylcarnitine translocase
What are the major regulators of FA metabolism?
AMPK, glucagon, epinephrine, citrate malonyl-CoA and palmitoyl-CoA are important regulators of FA metabolism
When is the NADPH required for FA synthesis produced?
NADPH required for FA synthesis is produced by pentose phosphate pathway and during malate to pyruvate conversion
What are the allosteric modulators of FA metabolism?
NADH inhibits β-hydroxyacyl-CoA
dehydrogenase
Acetyl-CoA inhibits thiolase
Malonyl-CoA (ACC product) inhibit CAT-I
In liver, high insulin/glucagon ratio leads to high malonyl-CoA level that cause the inhibition of β-oxidation
High long-chain fatty acid acyl-CoA inhibits ACC (depolymerization)
How are FA synthesis and beta-oxidation regulated by AMP?
High AMP/ATP ratio activates AMPK (AMP kinase)
AMP levels are a sensitive indicator of cellular energy status
Rise in response to stress that deplete ATP levels (nutrient deprivation, hypoxia and prolonged exercise)
AMPK switches off anabolic pathways
- Fatty acid synthesis by phosphorylating ACC1
- Triacylglycerol synthesis by phosphorylating glycerol-3-
phosphate acyltransferase
AMPK switches on catabolic pathways
- Stimulates β-oxidation by activating malonyl-CoA decarboxylase
How does insulin promote fat synthesis?
Promotes fat synthesis by signal transduction
- Activates phosphoprotein phosphatase 2A (dephosphorylates and activates ACC1)
- Trigger GLUT4 to cell surface
Depresses fat mobilization in adipocytes
- Stimulates lipase
How does epinephrin promote lipolysis?
Stimulates dephosphorylation of lipases
Describe transcriptional regulation of FA synthesis/catabolism
Two classes of transcription factors regulate gene expression processes
SERBPs
Insulin upregulates genes that code for enzymes in FA and NADH synthesis
Glucagon and long-chain FA inhibit
PPARs (peroxisome proliferator-activated receptors)
Stimulates fatty acid catabolism in adipose and liver tissues
