Block A: Membrane Biology & Biochemistry Lipid signalling and sphingolipid function 02.-06.11.2015 Gerhild van Echten-Deckert Tel. 73 2703 E-mail: [email protected]
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Block A: Membrane Biology & Biochemistry
Lipid signalling and sphingolipid function
02.-06.11.2015
Gerhild van Echten-Deckert
Tel. 73 2703E-mail: [email protected]
Programme of the weekMonday Monday - General discussion: cellular signalling- Phosphoinositids as signalling moleculesp g g- Bioactive fatty acid derivatives: eicosanoids (and endocannabinoids)- Sphingolipids: structure and function
T d Tuesday - Sphingosine-1-phosphate and neurodegeneration (Morbus Alzheimer) - Neural-targeted deletion of SPL and its impact on cognitive skillsNeural targeted deletion of SPL and its impact on cognitive skills
Thursday- The amyloid cascade hypothesis: pros and cons
- Sphingolipids: Critical Players in Alzheimer’s Disease
Friday- General discussion: what did you learn?- Take home messages
- QuestionsQuestions
Phosphoinositides as Signal Transducersp g
- Phospholipase C: different isoforms are activated by different signalsthat bind either GPCR or RTK
- PI-3 kinase pathway
Signal transduction from GPCRs to effector proteins
Lodish et al. Molecular Biology of the Cell
Signal transduction from RTKs to effector proteins
Lodish et al. Molecular Biology of the Cell
Intracellular signallingb h h i itidby phosphoinositids
Nature has used several possible variations of theinositol head group to createinositol head group to createhighly specific docking sites for lipid binding proteins
Wymann & Schneiter, Nature, 2008
Modification of a common phospholipid precursor generates several d h i f D G d IPsecond messengers: synthesis of DAG and IP3
Lodish et al. Molecular Biology of the Cell
Phospholipase C Isoforms
Berg, Tymoczko, Stryer: Biochemistry, 2002
PLC-induced release of Ca2+ from the ER is mediated by IP3
Löffler, Petrides, Biochemie und Pathobiochemie
PLC is an effector targeted by GPCRs
Short term effects on cell metabolism and movementLong term effects on gene expression
PLC1 is an effector targeted by RTKs1 g y
The activated EGF receptor recruits the cytosolic phospholipase C The activated EGF-receptor recruits the cytosolic phospholipase C-1(substrate PIP2) via its SH2-domain and activates the enzyme by phosphorylation.
Phosphatases terminate this process.
Proteinkinase C
Berg, Tymoczko, Stryer: Biochemistry,
PI 3-phosphates recruit and activate protein kinase B (PKB)
PH: pleckstrin homologyPDK: PI‐dependent kinase
PI-3 kinase generates phosphatidylinositol 3-p p yphosphates, which arebinding sites for varioussignal-transduction proteins,usually triggering survival.
PTEN: the first tumour suppressor with phosphatase activity
PTEN phosphatase has ab d f b broad specificity but its major function in cells isto reverse the PI-3 kinase
t l d ti catalyzed reaction.
PTEN is deleted or mutatedin multiple types of humanin multiple types of humancancer (glioblastoma, prostate cancer, endometrial tumour)endometrial tumour).
Overexpression of PTENpromotes apoptosis in promotes apoptosis in cultured mammalian cells.
www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi...
Wymann & Schneiter, Nature, 2008
Arachidonic acid
Prostaglandines:derivatives of the hypothetic ypprostanoic acid
Ulf von Euler 1930Ulf von Euler, 1930(in human seminal fluid)
Regulate physiological processes:Regulate physiological processes:‐ platelet aggregation‐ uterine contractions
i i (f )‐ pain, pyrexia (fever)‐ inflammation‐ secretion of mucins that protect thegastric mucosa from acid and proteasesin the stomach
Voet, Voet: Biochemistry
Metabolism of arachidonic acid
Berg, Tymoczko, Stryer: Biochemistry
The cyclic fate of arachidonic acid
Voet, Voet: Biochemistry
Benjamin Wäschle - comment 2012
The effects of cyclic endoperoxidases (facilitated by COX1 and COX2)
COX1 Stomach (PGE1) Mucous membrane production Acid productionKidney (PGE2) Perfusion Water excretiony ( 2)Thrombocytes (TxA2) Aggregation Vasoconstriction
COX2 Uterus Tone (labor pains, period pain)V l (PGI ) V dil i P biliVessels (PGI2) Vasodilation PermeabilityThrombocytes (PGI2) AggregationNociceptors SensitivityNociceptors SensitivityFever (PGE2) Thermoregulation hypothalamus
Benjamin Wäschle - comment 2012
What is the problem of selective COX2 inhibitors? ...
Benjamin Wäschle - comment 2012
Inhibition of COX2 facilitated prostacyclin biosynthesis and no interference with thromboxan A2 biosynthesis leads to:‐ Higher thrombocyte aggregation thrombosis
myocardial infarction
... They kill you. And make cute girls cry.
X-ray structure of PGH synthase (PGHS) from sheep seminal vesicles in complex with flurbiprofen which
Diagram of the left PGHS subunit (green).van der Waals surface of active site channel
seminal vesicles in complex with flurbiprofen which forms an ion pair with Arg120
HemeHeme
TTyr
Ser 530
Tyr385
Arg 120
Page
964
Arg
g
P
Voet, Voet: Biochemistry (4.ed)
PGH2-Synthase has 2 catalytic activities:2 catalytic activities:
Cyclooxygenase (COX)
The various effects of Aspirin are based on the inhibition of COX activity
Peroxidase
Voet, Voet: Biochemistry
Some nonsteroidal anti-inflammatory drugs (NSAIDs).( id ff d i hibi i f b h i f COX)(side effects due to inhibition of both isoenzymes of COX)
Page
965
P
Voet, Voet: Biochemistry (4.ed)
Selective COX-2 inhibitors (coxibs).
Withd f h ti l k tWithdrawn from pharmaceutical marketdue to unanticipated cardiac side effectsarising from attenuation of PGI2 formation!
Page
966
P
(to large to enter COX-1 active site channel, th t i 20 % ll i l th th t f COX 2)
Voet, Voet: Biochemistry (4.ed)
that is 20 % smaller in volume than that of COX-2)
Metabolism of the endocannabinoid anandamide
Kendall & Nicolaou, Prog Lipid Res, 2013
Metabolism of the endocannabinoid arachidonoyl glycerol
Kendall & Nicolaou, Prog Lipid Res, 2013
Mode of action of the nuclear receptor superfamily PPAR
L: fatty acids and d i ti derivatives
PPAR: peroxisomeproliferator-
PPAR, liver & adipose tissue, turns on genes proliferator
activated receptor
RXR: retinoid X receptor
for lipid synthesis, differentiation of fibroblasts into adipocytes
PPAR, hepatocytes,turns on genes for FA - PPAR, liver & muscle
i
adipocytes.
turns on genes for F oxidation and ketone body formation duringfasting.
tissue, turns on genes for -oxidation and for energy dissipation through uncoupling of
.through uncoupling ofmitochondria (prevents obesity).
Diet regulates the expression of genes central to maintaining body mass
Metabolic integration by PPAR isoforms
General mechanism by which lipophilic compounds regulate gene expression
Lipophilic ligands:steroid hormones thyroid hormones,retinoids (vit. A) vitamin D
Nelson, Cox: Lehninger Biochemistry,
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