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General Biochemistry II MOLB4610/5610: Biosynthesis of Membrane Phospholipids

This document provides an overview of membrane phospholipid biosynthesis in both prokaryotes and eukaryotes. Key points include: phospholipids are synthesized through different pathways in bacteria versus eukaryotes; phosphatidylserine and phosphatidylethanolamine are produced from CDP-diacylglycerol in bacteria but through different mechanisms in mammals; cardiolipin contains four acyl chains and is important in mitochondrial membranes; and sphingolipids are synthesized via a multi-step pathway producing molecules like cerebrosides and sphingomyelin. The lecture also discusses how lipids must be trafficked between organelles since free diffusion is unlikely.

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14 views

General Biochemistry II MOLB4610/5610: Biosynthesis of Membrane Phospholipids

This document provides an overview of membrane phospholipid biosynthesis in both prokaryotes and eukaryotes. Key points include: phospholipids are synthesized through different pathways in bacteria versus eukaryotes; phosphatidylserine and phosphatidylethanolamine are produced from CDP-diacylglycerol in bacteria but through different mechanisms in mammals; cardiolipin contains four acyl chains and is important in mitochondrial membranes; and sphingolipids are synthesized via a multi-step pathway producing molecules like cerebrosides and sphingomyelin. The lecture also discusses how lipids must be trafficked between organelles since free diffusion is unlikely.

Uploaded by

Maria Angelina Bunawan
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PPT, PDF, TXT or read online on Scribd
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General Biochemistry II MOLB4610/5610

Lecture 10 Biosynthesis of membrane phospholipids


Lehninger Ch. 21 pg. 791 - 799

Todays lecture
Membrane behavior Distribution of phospholipids Phospholipid synthesis in bacteria Phospholipid synthesis in eukaryotes Plasmalogen synthesis Lipid trafficking

Membrane phospholipids
PS PE PC PG PI DPG Phosphatidylserine Phosphatidylethanolamine Phosphatidylcholine (= lecithin) Phosphatidylglycerol Phosphatidylinositol Diphosphatidylglycerol (=Cardiolipin)

Why are there so many different phospholipids ?


Membranes contain mainly proteins and lipids Phospholipid composition dictates membrane behavior Membranes requiring movement within membrane
More unsaturated fatty acids (PE and PS often have higher amounts of polyunsaturated fatty acids) Lower packing densities (kinks decrease density) Shorter fatty acid tails - fewer hydrophobic interactions Higher membrane fluidity

Cell compartment specific membrane composition


cardiolipin found exclusively at the inner mitochondrial membrane - decreased leakage

Distribution of membrane lipids


Animals:
major components are PE, PS, PC (= lecithin), & cholesterol cell membranes of the central nervous system contain additional lipids such as sphingomyelin, myelin, cerebrosides, gangliosides

Plants
PE and PC predominate PI and PG are present as well cholesterol is absent but replaced by phytosterols

Bacteria
major components are PE and PG PC is rarely present, sterols are absent

Phospholipid synthesis in E. coli


pyrophosphate linkage

Phosphatidate

Requires an activated component


CDP-diacyglycerol + PPi

Phosphatidate + CTP

Both phosphate groups in PPi come from CTP

CDP-diacylglycerol can be converted to:


a) Phosphatidylserine (PS) and subsequently to PE b) Phosphatidylglycerol-3-phosphate (PG)

Synthesis of phosphatidylserine (PS) & phosphatidyl- ethanolamine (PE)


1) Phosphatidylserine synthase reaction
PS synthase CDP-diacyglycerol + serine CMP Phosphatidylserine

2) Phosphatidylserine decarboxylase reaction


PS decarboxylase Phosphatidylserine H+ Lehninger pg. 793 CO2

Phosphatidylethanolamine

Synthesis of phosphatidylglycerol (PG)


1) Phosphatidylglycerol 3-phosphate synthase
PG-3-P synthase CDP-diacyglycerol + glycerol-3-P

CMP Phosphatidylglycerol-3-P

2) Phosphatidylglycerol 3-P phosphatase


PG-3P phosphatase Phosphatidylglycerol-3-P H2O Pi Phosphatidylglycerol

Synthesis of cardiolipin
Cardiolipin synthase reaction (Bacteria vs. eukaryotes)
BACTERIA 2 PGs glycerol + cardiolipin

EUCARYOTES

CDP-diacyglycerol + PG* CMP + cardiolipin


* Phosphatidylglycerol is made exactly as in bacteria

Eucaryotic synthesis of phosphatidylinositol (PI)

EUCARYOTES
CDP-diacylglycerol + inositol
CMP + Phosphatidylinositol PI and phosphorylated PI derivatives play an important role in signal transduction PI kinase

Eucaryotic PS synthesis
IN YEAST

PS

PE

In yeast PS is synthesized like in bacteria from CDPdiacylglycerol In mammals PS is NOT derived CDP-diacylglycerol ! Instead it is derived from PE via a displacement of headgroups (Serine - ethanolamine) A
Q: Where does PE come from in mammals?

PE synthesis Mammals vs. Bacteria


MAMMALS ATP ADP

1) Ethanolamine
CTP 2) Phosphorylethanolamine Diacylglycerol 3) CDP-ethanolamine

Phosphorylethanolamine
PPi CDP-ethanolamine CMP Phosphatidylethanolamine

EUCARYOTES & BACTERIA


PS decarboxylase Phosphatidylserine CO2 Phosphatidylethanolamine

PC synthesis in yeast
The amino group of the phosphoglyceride is methylated 3 times using S-adenosylmethionine as the methyl donor.
PE This reaction also takes place in bacteria (Stryer pg 718) and in the liver of mammalian cells. Although yeast is a eucaryote it shares share several reactions with bacteria.

PC synthesis in mammals
1) Choline kinase mediated phosphorylation of choline 2) Activation of phosphocholine by CTP via CTP -choline cytidylyl transferase 3) Replacement of CMP by diacyglycerol resulting in PC. This mechanism used in most mammalian cells.

Plasmalogen
Ether lipid

CH2-O-CH=CH-(CH2)n-CH3 CH-O-CO-(CH2)n-CH3
(-)

CH2-O-PO3-CH2-CH2-N(CH3) 3

(+)

Ether: R1-O-R2 Ether-linked alkene: CH2-O-CH=CH-(CH2)n-CH3

~ 1/2 of heart phospholipids produced mainly in peroxisomes Other ether lipids (platelet-activating factor)

Plasmalogen synthesis
Step-by-step summary of reactions backbone = DHAP Acylation of C1 in DHAP by fatty acyl CoA Exchange of an alcohol saturated fatty alcohol for the carboxylic group at C1 Reduction by NADPH Acylation by a second acyl CoA at C2 Headgroup (ethanolamine) attachment at C3 Oxidation to alkene via mixed function oxidase

Plasmalogen synthesis

Platelet activating factor (PAF)


Ether lipid
Acetyl group at C2 of DHAP backbone instead of fatty acid

Synthesis similar to plasmalogen


from DHAP backbone

subnanomolar concentration of PAF


induce aggregation of blood platelets induce muscle contractions activate the immune system also the mediator of anaphylactic shocks

Sphingolipid synthesis
Four stages:
1. Synthesis of sphinganine Requires palmitoyl-CoA + serine (backbone) Reduction of keto group with NADPH 2. Attachment of a fatty acid to form N-acylsphinganine 3. Desaturation of sphinganine to yield N-acylsphingosine 4. Attachment of the headgroup to produce a sphingolipid a) Cerebroside (head group e.g. Glucose)
Glycosidic linkage instead of phosphodiester bonds

b) Sphingomyelin (head group e.g. choline)

Lipid trafficking
Lipids that are synthesized at smooth ER need to relocate to target organelle
Free diffusion is unlikely due to hydrophobic nature of lipids

Specific transport to target compartments


Requires vesicles that bud from the Golgi complex

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