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FA & Cholesterol reg

Uni of Notts, Signalling & Metabolic Regulation, Year 2, Topic 12

TermDefinition
Reciprocal metabolic states & hormones for fatty acid synthesis & degradation Synthesis is active during carbohydrate-rich meals & driven by insulin; degradation is active during fasting & driven by glucagon/adrenaline
Fatty acid subcellular synthesis & degradation sites + carriers involved Synthesis takes place in the cytosol; degradation takes place inside the mitochondria. Citrate carries acyl from mitochondria to cytosol; carnitine moves them from cytosol to mitochondria
Malonyl-CoA reciprocal inhibition Malonyl-CoA inhibits CPTI to block long-chain fatty acids from entering the mitochondria to prevent newly synthesised FAs being broken down in a futile cycle
Allosteric polymerization of Acc (Ac-CoA carboxylase) Acc is the key regulatory enzyme requiring polymerization by citrate to become active or depolymerization by palmitoyl-CoA to become inactive
Hormonal phosphorylation control of Acc Monomers are inactivated via phosphorylation by AMP, glucagon/adrenaline, & AMPK, or activated via dephosphorylation by insulin/PP2A
Beta-oxidation substrate & hormonal regulation Regulated by substrate supply which depends directly on lipolysis rates in adipocytes controlled by glucagon & adrenaline
AMP-activated protein kinase (AMPK) role (especially in Acc) Functions as an energy sensor activated by high AMP, phosphorylating & inactivating Acc to turn off ATP-consuming fatty acid synthesis
Downstream biological derivatives of cholesterol + where it's synthesised Serves as an essential precursor for bile acids, digestion salts, steroid hormones, & cholecalciferol (vitamin D). Synthesised in the liver cytosol
Cholesterol synthesis: Step 1 2 molecules of acetyl-CoA fuse to form the acid anhydride Acetoacetyl-CoA (4C)
Cholesterol synthesis: Step 2 Acetoacetyl-CoA fuses with another acetyl-CoA & water to form 3-hydroxy-3-methylglutaryl (HMG) CoA
Cholesterol synthesis: Step 3 HMG-CoA is reduced (& the thioester bond is hydrolysed) to mevalonic acid (6C)
Cholesterol synthesis: Step 4 Mevalonic acid is decarboxylated, reduced, & phosphorylated to Isopentanyl pyrophosphate (IPP) (5C)
Cholesterol synthesis: Step 5 2 IPPs are condensed to geranyl (10C) then another is added to make farnesyl (15C) & 2 farnesyl are condensed to a linear squaline (30C)
Cholesterol synthesis: Step 6 Squaline is cyclisised through an epoxy (which becomes the hydroxyl) intermediate to lanosterol. Lanosterol is reduced to cholesterol (27C)
Stoichiometric inputs for cholesterol synthesis Constructing one cholesterol molecule requires 18 molecules of acetyl-CoA, 36 ATP, & 16 NADPH
Protein prenylation definition & attachment Post-translational modification adding a farnesyl (C15) or geranylgeranyl (C20) group via a thioether linkage to a cysteine residue
Prenylation enzymes & cellular targets Farnesyl & geranylgeranyl transferases to anchor small G-proteins like Ras & Rho (don't have intrinsic hydrophobic domains & need to interact with membrane proteins) to cellular membranes for signalling
Peroxisome Proliferator Activator Receptor *Examples* Transcription factor family (PPARs) that controls long-term expression of genes involved in lipid, fatty acid, & cholesterol homeostasis. Alpha upregulates beta-oxidation enzymes & carnitine shuttles; gamma handles adipocyte differentiation & fat storage
Animal inability to degrade cholesterol Animal cells can synthesise & internalise cholesterol but lack metabolic pathways to break the steroid ring skeleton down into CO2 & H2O
Created by: Denny12
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