Polar Lipid Synthesis. Lipids: Role in Signaling.
-
Upload
dominic-hudson -
Category
Documents
-
view
227 -
download
1
Transcript of Polar Lipid Synthesis. Lipids: Role in Signaling.
Polar Lipid Synthesis
glycerol
phosphatidic acid
C
C
C
O
O O X
O
O
-
P
O C R1
O
CR2
O
OHOH
OH
HOOH
CH2 C NH3
COO-
+
CH2CH2NH3
+
CH2CH2N(CH3)3
+
H
H
H
Hwater
ethanolamine
choline
serine
inositol
glycerol CH2CH(OH)CH2OH
glycerophospholipidformula of XX-OH
phosphatidic acid
phosphatidylethanolamine
phosphatidylcholine
phosphatidylserine
diphosphatidylgycerol (cardiolipin)
phosphatidylinositol
CH2CH(OH)CH2O
CH2OCR1
R2COCH
CH2
O
OP
O-
O
phosphatidylglycerol
phosphatidylglycerol
O H
C H2
O H
N H2
+sphinganine
C
C
C
OH
glycerol-3-P
HO
C
C
C
OH
C
C
C
HO
O O-
O
O-
P O O-
O
O-
P
O
O O-
O
O-
P
C
C
C O O-
O
O-
P
O
O C R1
O
O C R1
O
dihydroxacetone-P
1-acylglycerol-3-P 1-acyldihydroxyacetone-P
C
C
C
O
O O-
O
O-
P
O C R1
O
CR2
O
C
C
C
O
OH
O C R1
O
CR2
O
phosphatidic acid
diacylglycerol
glycerol-3-Pacyltransferase
dihydroxyacetone-Pacyltransferase
CoACoA
R1-C-CoA
O
R1-C-CoA
O
R2-C-CoA
O
CoA
CDP-diacylglycerol
CTP
PPi
phosphatidatecytidylyltransferase
ATP
ADP
phosphatidic acidphosphatase
NADPHNADP+
reductase
C
C
C
O
OH
O C R1
O
CR2
O C
C
C
O
OH
O C R1
O
CR2
O
diacylglycerol
C
C
C
O
O OCH2CH2NH3
O
O-
P
O C R1
O
CR2
O
phosphatidylethanolamine
+
C
C
C
O
O OCH2CH2N(CH3)3
O
O-
P
O C R1
O
CR2
O
phosphatidylcholine
+
HOCH2CH2N(CH3)3HOCH2CH2NH3
-O
O
O-
P O
O
O-
POCH2CH2NH3 OCH2CH2N(CH3)3
-O
O
O
P-O
O
O
P O
O
O-
P OCH2CH2N(CH3)3O
O
O-
P OCH2CH2NH3
ethanolamine choline
phosphoethanolamine phosphocholine
CDP-ethanolamine CDP-choline
ethanolaminekinase
cholinekinase
CTP: phosphoethanolaminecytidylyltransferase
CTP: phosphocholinecytidylyltransferase
ATP
ADP
ATP
ADP
CTPCTP
PPiPPi
CMPCMP
cytidinecytidine
CDP-choline:1,2-diacylglycerolphosphocholinetransferase
CDP-ethanolamine:1,2-diacylglycerolphosphoethanolaminetransferase
C
C
C
O
O OCH2CH2NH3
O
O-
P
O C R1
O
CR2
O
phosphatidylethanolamine
+
C
C
C
O
O OCH2CH2N(CH3)3
O
O-
P
O C R1
O
CR2
O
phosphatidylcholine
+
C
C
C
O
O OCH2CH2NH2
O
O-
P
O C R1
O
CR2
O
+
C
C
C
O
O OCH2CH2NH
O
O-
P
O C R1
O
CR2
O
+
S-adenosylmethionine
S-adenosylhomocysteine
S-adenosylmethionine
S-adenosylmethionine
S-adenosylhomocysteine
S-adenosylhomocysteine
CH3
CH3
CH3
C
C
C
O
O O
O
O-
P
O C R1
O
CR2
O
CH2 C NH3
COO-
+
phosphatidylserine
serine serine
ethanolamineethanolamine
CO2
phosphatidylserinedecarboxylase
base exchange reaction
C
C
C
O
O
O C R1
O
CR2
O C
C
C
O
O
O C R1
O
CR2
O
P O
O
O-
CMP
CDP-diacylglycerol
C
C
C
O
O
O C R1
O
CR2
O C
C
C
O
O
O C R1
O
CR2
O
P O
O
O
C
C
C
O
O
O C R1
O
CR2
O C
C
C
O
O
O C R1
O
CR2
O
P
O
O-
O
CH2
C
CH2
P O
O
O-
-O
OH
phosphatidylglycerolphosphate
phosphatidylglycerol
cardiolipin
glycerol-3-phosphate
phosphatase
CMP
glycerophosphatephosphatidyltransferase
Pi
CMP
CDP-diacylglycerol
cardiolipinsynthase
inositol
CMP
phosphatidylinositolsynthase
OHOH
OH
HO
OH
phosphatidylinositol
C
C
C
O
O OCH2CH2NH3
O
O-
P
O R1
CR2
O
1-alkyl-2-acylglycerophosphoethanolamine
+
C
C
C
O
O OCH2CH2NH3
O
O-
P
O
CR2
O
+
C C R1CH2CH2
plasmalogen
NADH H+ NAD+ 2 H2OO2 ++ +
C
C
C
O
O OCH2CH2N(CH3)3
O
O-
P
O
C
O
+
R1CH2CH2C
C
C
HO
O OCH2CH2N(CH3)3
O
O-
P
O
+
R1CH2CH2
H2O
O-C
O
CH3
C
O
CH3 CoA CoA
platelet activating factor1-alkyl-2-lysophosphatidylcholine
desaturase
acetylhydrolase
acetylCoA transferase
C
C
C
O
O OCH2CH2N(CH3)3
O
O-
P
O C
O
C
O
dipalmitoylphosphatidylcholine
+
(CH2)14CH3
CH3(CH2)14
1-palmitoyl-2-acylglycerophosphocholine
1-palmitoyl-2-lysoglycerophosphocholine
phospholipase A2
acyltransferase
O-C
O
R2
CoA
C
O
CH3(CH2)14 CoA
CH3
CoA
O
O
OH
OH
OH
CH2OH
CH2OH
CH2OH
CH2OH
NH3
NH3
+
+
NH
NH
CH3-(CH2)n
CH3-(CH2)n
O
O
C
CH2OH
COO-
H3N H+
NADPH
NADP
fatty acyl-CoA
CoA
CO2CoA
NAD(P)H
NAD(P)
1/2 O2
H2O+
+
+
+
palmitoyl CoA
serine
ketosphinganine
sphinganine
dihydroceramide
ceramide
serinepalmitoyltransferase
ketosphinganinereductase
dihydroceramidesynthase
dihydroceramidedesaturase
+
CH2OH
CH2O_P_O_CH2_CH2-N(CH3)3
OH
NH
O
CH3_(CH2)n
O
O
+
-
sphingomyelin
ceramide
sphingomyelinsynthase
PC
DG
OH
NH
O
CH3_(CH2)n
Cerebroside and ganglioside synthesisOccurs on the lumenal side of the Golgi
Ceramide
UDP-Glc UDP-GalUDP UDP
Glc-ceramide Gal-ceramide
UDP-Gal PAPS UDP-Gal UDP 3’-P-PMP UDP
3-SO3—Gal-ceramide Gal-Gal-ceramide
Gal-Glc-ceramide
UDP-Gal CMP-NeuAc UDP CMP
Gal-Gal-Glc-ceramide NeuAc-Gal-Glc-ceramide
UDP-GalNAc NeuAc UDP-GalNAc UDP UDP
GalNAc-Gal-Glc-ceramide GalNAc-Gal-Glc-ceramide
NeuAc UDP-Gal
UDP
Gal-GalNAc-Gal-Glc-ceramide
Ganglioside and cerebroside catabolism
Gal-GalNac-Gal-Glc-ceramide (GM1)
NeuAc β-galactosidas e [1]
Gal
GalNAc-Gal-Glc-ceramide (GM2) GalNAc-Gal-Ga-l Glc-ceramide
NeuAc β-N-acetylhexosaminidas e A[2] β-N-acetylhexosaminidase
GalNAc GalNAc
NeuAc-Gal-Glc-ceramide (GM3) Ga-l Ga-l Glc-ceramide
Neuraminidase α-galactosidas eA [3]
NeuAc GalGa-l Glc-ceramide
β-galactosidase
Gal
Glc-ceramide
β-glucosidas e[4] Glc
Gal GalGa-l Ga-l ceramide Ga-l ceramide Ceramide
α-galactosidase β-galactosidas e[5] ceramidase [6]
S 4O 2- long-chai n baseArylsulfata seA [7] Fatt y acid
3-SO3-Gal-ceramide
Disease Deficient enzyme activity Reaction
Farber’s lipogranulomatosis ceramidase (6)ceramide = fatty acid + long-chain base
Niemann-Pick disease sphingomyelinase sphingomyelin = ceramide + phosphocholine
Gaucher’s disease B-glucosidase (4)Glc-ceramide = Glc + ceramide
Fabry’s disease a-galactosidase A (3)Gal-Gal-Glc-ceramide = Gal + Gal-Glc-ceramide
Tay-Sachs disease hexosaminidase A (2)GM2 = GM3 + GalNAc
Sandhoff’s disease hexosaminidase A + B (2)GM2 = GM3 + GalNAc
Sulfatide lipidosis arylsulfatase A (7)3’-SO3—Gal-ceramide = Gal-ceramide + SO4
2-
Galactosylceramide lipidosis B-galactosidase (5)Gal-ceramide = Gal + ceramide
GM1 gangliosidosis GM1-B-galactosidase (1)
GM1 = Gal + GM2
Lipids: Role in Signaling
1st messenger (hormone, neurotransmitter, growth factor, etc.)
2nd messenger (calcium, cAMP, IP3, DAG, ceramide)
Signal amplification
Modulator ( G protein, receptor tyrosine kinase)
Enzyme activation (phospholipases, adenylate cyclase)
Enzyme activation (PKA, PKC, phosphatases)
substrates
Discovery of the "phospholipid effect" by Hokin MR et al. : phosphorus incorporation into phospholipids showed a remarkable increase in pigeon pancreas slices on stimulation with acetylcholine (J Biol Chem 1953, 203, 967).
Michell RH in a famous review proposed for the first time that the "phosphoinositide effect” discovered in 1953 by Hokin plays a role in cellular calcium mobilization (Biochim Biophys Acta 1975, 415, 81)
Univ. of Birmingham, UK
A com mon paradigm in the transmission of signals across a cellmembrane by agents such as hormones, neurotransmitters, etc. isthe catabolism of complex membrane lipids. When the lipid substrateis a glycerolipid, catabolism is initiated by a group of enzymes knownas phospholipases that release bioactive lipids. These enzymes arenamed according to their site of cleavage of the complex lipid:
Phospholipases C and D release diacylglycerol (DG) andphosphatidic acid (PA), respectively. The other metabolic products ofthese reactions are a headgroup or its phosphorylated derivative.
Phospholipase A1 and A2 b oth release fatty acids from the par entlipid. In the case of phospholipase A2, t he released fatty acid isusually arachidonic acid (AA) that serves as a precursor forprostaglandin, leukotriene, and thromboxane synthesis.
DG, PA, and AA are all bioactive and capable of activating variouscellular targets. The water-soluble products, which are also releasedby t hese lipases, are typically inactive except for the case of PLCcleavage of PIP2, i n which case the released headgroup, inositoltrisphosphate IP3, also serves as a signaling molecule.
When the lipid substrate is a sphingolipid, catabolism is the result ofcleavage by sphingomyelinase, a specific type of p hospholipase Cthat generates ceramide and phosphocholine. Ceramide is anotherbioactive lipid metabolite that plays an important role in non-proliferative cell biologies such as g rowth arrest, differentiation, andprogrammed cell death (apoptosis).
C
C
C
O
O OX
O
O-
P
O C R1
O
CR2
O
C
C
C
O
OH
O C R1
O
CR2
O C
C
C
O
O OH
O
O-
P
O C R1
O
CR2
O
C
C
C
O
O OX
O
O-
P
OH
CR2
O C
C
C
HO
O OX
O
O-
P
O C R1
O
-O OX
O
O-
P HOX
-O C R1
O
O-CR2
O
phospholipase C phospholipase D
phospholipase A1 phospholipase A2
diacylglycerol phosphatidic acid
monoacylglycerolphosphate monoacylglycerolphosphate
glycerophospholipid
usually acrachidonicacid
QuickTime™ and aPhoto - JPEG decompressor
are needed to see this picture.
QuickTime™ and aPhoto - JPEG decompressor
are needed to see this picture.
Rates of lipid flip-flop across bilayers
Diacylgycerol 0.1 sec
Ceramide 10 min
Phosphatdiylcholine 10 hr
Lysophosphatidic acid >10 hr
Ganglioside >>10 hr
Conclusion: as the headgroup becomes more polar or larger and as the hydrophobic moiety becomes smaller, the lipid flips less readily
QuickTime™ and aAnimation decompressor
are needed to see this picture.
QuickTime™ and aPhoto - JPEG decompressor
are needed to see this picture.
CH2O_P_O_CH2_CH2-N(CH3)3
OH
NH
O
CH3_(CH2)n
O
O
+
-
sphingomyelin
CH2OH
ceramide
OH
NH
O
CH3_(CH2)n
phosphocholine
sphingomyelinase
ceramide
Ceramide-activatedprotein phosphatase(PP2A, PP1)
Ceramide-activated protein kinase
Protein kinase C zeta
Rb dephosphorylation
Growth arrest inflammation
?
?
?
Lipids as receptor agonists
– Platelet-activating factor
– Lysophosphatidic acid
– Sphingosine phosphate
– Lipopolysaccharide
Platelet-activating factor (PAF) or 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine
– an ether analogue of phosphatidylcholine
– causes aggregation of platelets at picomolar concentrations
– acts through a G-protein coupled receptor
Model of G-protein coupled receptor (PAF receptor)signal transduction
Lysophosphatidic acid or 1-acyl-sn-glycerol-3-phosphate (LPA)
–metabolite of phosphatidic acid
–is an important serum mitogen
–acts through the EDG family of G-protein coupled receptors
CH2OP-O-
NH3
OHO-
O
Sphingosine phosphate
–Synthesized by sphingosine kinase
–Acts through the EDG family of G protein coupled receptors
–Also considered to be mitogenic
Bacterial cell wall organization