Membrane Biosynthesis Flashcards
The basis of synthesis
are they made from scratch? where is the process occurring?
Not synthesised from scratch!
- Produced by the expansion of existing membranes:
1) early steps in cytoplasm producing water soluble intermediates
2) final steps through enzymes bound to pre-existing membranes (products incorporated as they’re generated)
Upon formation, membrane lipids must be:
1) Delivered to the correct leaflet of bilayer
2) Distributed to membranes of organelles
3) Distributed to the plasma membrane
Smooth Endoplasmic Reticulum (SEM) in membrane synthesis
Primary site of membrane synthesis:
- produces cholesterol and membrane phospholipids using embedded enzymes in its membrane
- transports newly produced lipids to cellular destinations (as part of a vesicle)
Saturated vs Unsaturated fatty acids
Saturated:
- Single carbon bonds
- Fit closer together, more tightly packed
- Higher melting points (solid at RT)
Unsaturated:
- Double carbon bonds - gives 30 degree kinks to chain
- Less closely packed due to kinks
- Lower melting point (liquid at RT)
Cis and Trans fatty acids (unsaturated)
Cis
- most common
- 2 H atoms on same side of C=C bond hence kink forms
Trans
- H atoms on opposite sides of C=C bond (no kink)
Fatty Acid Synthesis
Acetyl-CoA –> Fatty Acid
1) Pyruvate from glycolysis is decarboxylated to Acetyl CoA
2) Carboxylation of Acetyl-CoA to Malonyl-CoA (irreversible, requires 1x ATP)
3) Malonyl-CoA becomes Palmitate, catalysed by Fatty Acid Synthase (FAS): 2 Carbons provided to fatty acid (Palmitate = C16:0 saturated)
4) Palmitate = Fatty Acid precursor: lengthened to form stearate (C18:0) or longer saturated FAs
- FA elongation occurs in SEM or mitochondria
Producing UNsaturated fatty acids
Fatty Acid Synthesis pathway always produces saturated FAs (Palmitate = Saturated!)
- Desaturase enzymes are required to remove 2 H atoms from a FA allowing a C=C bond to form
- e.g. Oleoyl-CoA formed from Stearol-CoA losing 2x H atoms
Incorporating FAs into phospholipids in the SER membrane
1) 2x FAs esterified to phosphorylated glycerol backbone (Phosphatidic acid)
2) Phosphatase converts phosphatidic acid into diacylglycerol (glyceride made of 2 FAs covalently bonded (ester bonds) to a glycerol)
3) A polar group (e.g. phosporylcholine) is transferred from Cytosine DiPhosphocholine (CDP-choline) onto the exposed hydroxyl group to form a phospholipid
4) Flippases catalyse the integration of the phospholipids into the cytoplasmic leaflet
Sphingolipid Synthesis
Ceramide (precursor) produced in SER
- converted into glycolipids or sphingomyelin in Golgi
Cholesterol Synthesis in Cytosol/ER membrane
1) Cytosol: conversion of Acetly-CoA to HMG-CoA by HMG-CoA synthase
2) ER membrane: HMG-CoA reductase (integral membrane protein) converts HMG-CoA into Mevalonate
3) Mevalonate converted into IPP (5C)
4) 6x IPPs condense to yield Squalene (6x5=30C)
5) Squalene cyclizes: the tetracyclic product is converted into Cholesterol by membrane-bound ER enzymes
HMG-CoA reductase
ER membrane integral protein: 8 transmembrane helices with a cytosolic water soluble catalytic domain
- 5/8 TMDs compose sterol-sensing domain (cholesterol binds to switch off cholesterol synthesis, negative feedback)
- Insig 1/2 bind to induce HMG-CoA reductase degradation (ubiquitination pathway) thus preventing mevalonate and therefore cholesterol production
DRUG TARGET:
- Statins inhibit it, reducing Low Density Lipoprotein (LDL) levels thus promoting increased LDL uptake
Transporting Lipids from SER
Vesicular Transport
Transfer mediated by small, soluble lipid-binding proteins
Direct contact between membranes (mediated by membrane embedded proteins)
Vesicular transport of Lipids from SER
Membrane vesicle buds off SER and fuse with other membranes
- can be selective integration, giving different organelle membrane compositions
Lipid transfer from SER mediated by small, soluble lipid-binding proteins
Cytosolic, water soluble proteins that move lipids from the ER to other membranes
- can only carry one lipid at a time
- Only dissociates from membrane when carrying a lipid (no net transfer can occur between membranes, one in one out)
Different lipid composition across different cellular membranes due to different sites of synthesis
An organelle-produced membrane is different to an imported one (different properties)
- e.g. Cardiolipin (CL) is important in mitochondrial inner membrane so is only made there by mitochondria - CL important for cristae structure/curvature to maximise SA whilst anchoring highly cationic Cyt c
