T17 - Glycerophospholipids and Lipid Signaling Flashcards
Describe the relationship between phospholipids, surfactant, and premature birth.
phospholipid-rich surfactant, which reduces surface tension, is necessary for infants to breathe
in premature infants, surfactant is not produced, meaning alveoli are collapsed and baby cannot breathe properly → neonatal respiratory distress syndrome (RDS)
Describe what an X-ray of an infant with neonatal respiratory distress syndrome would look like.
would see white space that indicates alveolar collapse (normally, should be black to indicate presence of air)
In embryological development, when is surfactant synthesis initiated?
initiated in fetal lungs after 75% of gestation is complete (~24 weeks)
In embryological development, when do the lungs start to develop?
3 weeks
Which cell in fetuses is responsible for storing lung surfactant? When does this cell start to actually secrete surfactant?
Type II cells, containing lamellar bodies, store surfactant (these cells appear at 24 weeks)
start to actually secrete surfactant at 30 weeks
What clinical test is used to determine whether there is sufficient surfactant in a fetus?
lecithin:sphingomyelin (L/S) ratio — samples amniotic fluid, into which surfactant is secreted
Describe how the lecithin:sphingomyelin (L/S) test is carried out.
lecithin = another name for phosphatidylcholine, the major phospholipid component of surfactant
sphingomyelin is used as a baseline (derived from fetal cells sloughed into amniotic fluid)
Describe the composition of surfactant.
80% glycerophospholipid
10% cholesterol
10% protein
What is the major/active component of surfactant? Describe its structure.
dipalmitoylphosphatidylcholine (DPPC)
contains two saturated fatty acids (C16:0) at sn-1 and sn-2 positions
Why is dipalmitoylphosphatidylcholine (DPPC) in surfactant highly surface-active?
because DPPC molecules line up efficiently at alveolar air-liquid interface and block hydrogen bonding of H2O with one another (i.e. reduces surface tension)
What is the most common glycerophospholipid?
phosphatidylcholine
Describe the structure of a glycerophospholipid.
glycerol backbone
sn-1 O esterified to saturated, long-chain FA (i.e. stearic or palmitic)
sn-2 O esterified to polyunsaturated FA (i.e. arachidonic or linoleic)
C-3 OH esterified to phosphate
Describe the polarity of glycerophospholipids.
Glycerophospholipids are highly amphipathic
Give an example of a glycerophospholipid serving as a component of plasma lipoproteins.
phosphatidylcholine (lecithin) — serves as the substrate for lecithin-cholesterol acyltransferase (LCAT), which forms HDL particles
Describe the function of glycerophospholipids as membrane anchors for proteins.
phosphatidylinositol used to tether proteins/enzymes to plasma membrane
Describe the function of glycerophospholipids as bioactive molecules.
used in platelet-activating factor (PAF)
Describe the function of glycerophospholipids as reservoirs for prostaglandin precursors.
arachidonic and linoleic acids (prostaglandin precursors) are released from sn-2 position by phospholipases
Describe the function of glycerophospholipids as reservoirs for second messengers.
phosphotidylinositol-containing compound (PIP2) can be converted into the second messengers DAG and IP3.
What enzyme liberates arachidonic or linoleic acid from the sn-2 position of glycerophospholipids?
phospholipase A
Describe how plasmalogens differ structurally from glycerophospholipids.
have an alkenyl ehter moiety in sn-1 position
Give an example of a molecule that has an alkyl chain at the sn-1 position of the glycerol backbone (instead of a saturated fatty acid).
PAF
What is the precursor molecule for all glycerophospholipids?
phosphatidic acid
One of the two products of phosphatidic acid is diacylglycerol. Diacylglycerol can be further converted into which compounds?
phosphatidylcholine
phosphatidylethanolamine
triacylglycerol
One of the two products of phosphatidic acid is CDP-diacylglycerol. CDP-diacylglycerol can be further converted into which compounds?
phosphatidylinositol
cardiolipin
phosphatidylgclyerol-phosphate
Describe how phosphatidylserine is formed.
phosphatidic acid → diacylglycerol → phosphatidylcholine + phosphatidylethanolamine → [base exchange] → phosphatidylserine
What enzyme converts phosphatidic acid to diacylglycerol?
PAPase
What enzyme converts phosphatidic acid to CDP-diacylglycerol?
CTP:phosphatidate cytidyltransferase
Draw out the pathway of phosphatidic acid/phosphatidate formation.
Draw out a diagram that shows how phosphatidic acid is further converted to other glycerolipids.
What enzyme is the key regulator in glycerophospholipid synthesis?
PAPase — exists in inactive cytosolic form and active membrane-associated form
What enzyme esterifies fatty acids to the sn-1/sn-2 positions of the glycerol backbone?
acyltransferase
Quantitatively speaking, which phospholipids are most important in mammalian cells? (2)
PC
PE
What is the major pathway to synthesize PE and PC, the two most important phospholipids?
Kennedy/base activation pathway
Write out the pathway for phosphatidylcholine synthesis.
choline → [choline kinase, ATP] → phosphocholine → [CTP:phosphocholine cytidylyltransferase, CTP] → CDP-choline → [+ DAG, phosphotransferase] → phosphatidylcholine
Write out the pathway for phosphatidylethanolamine synthesis.
ethanolamine → [ethanolamine kinase, ATP] → phosphoethanolamine → [CTP:phosphoethanolamine cytidylyltransferase, CTP] → CDP-ethanolamine → [+ DAG, phosphotransferase] → phosphatidylethanolamine
What is the regulated step in phosphatidylcholine/ethanolamine synthesis?
CTP:phosphocholine cytidylyltransferase — exists in inactive monomeric cytosolic form and active tetrameric membrane-associated form [much like PAPase]
What activates CTP:phosphocholine cytidylyltransferase? (2)
long chain fatty acids
fatty acyl-CoAs
Draw out a diagram illustrating phosphatidylserine synthesis. What is the name for this type of reaction?
base exchange reaction
The synthesis of phosphatidylserine requires what cofactor/coenzyme/vitamin/molecule/ion?
Requires the presence of Ca2+
What is the committed step in glycerophospholipid synthesis?
phosphatidic acid + CTP → CDP-diacylglycerol (mediated by CTP:phosphatidate cytidylyltransferase)
How does CDP-diacylglycerol become phosphatidylglycerol-phosphate?
CDP-glycerol + glycerol-3-phosphate → phosphatidylglycerol phosphate → [can be further metabolized] → phosphatidylglycerol
How does CDP-diacylglycerol become phosphatidylinositol?
CDP-diacylglycerol + myo-inositol → phosphatidylinositol
How does CDP-diacylglycerol become cardiolipin?
phosphatidylglycerol + CDP-diacylglycerol → cardiolipin
Phospholipase A2 is produced by
the pancreas
What is the function of phospholipase A2?
digestion of dietary phospholipids
Explain what gives rise to the deadly nature of snake venom. (4)
phospholipase A2 causes release of arachidonic acid from host cell membranes → metabolized to prostaglandins, causing pain + inflammation → released phospholipids are powerful detergents that digest host cell membranes → edema and hydrolysis
What two enzymes are responsible for metabolic turnover of glycerophospholipids in mammalian cells?
phospholipase A2 and phospholipase C
Draw out a diagram of a generic glycerophospholipid, and indicate where the 4 major phospholipases (A1, A2, C, D) cleave the molecule.
Describe how phosphatidylcholine is remodeled to create DPPC.
phospholipase A2 cleaves off the unsaturated fatty acid of PC, forming lysophosphatidylcholine, which then reacts with palmitoyl-CoA to form DPPC
Draw a diagram showing the signaling pathway that occurs when a hormone such as epinephrine binds to a GPCR. Identify molecules that inhibit parts of the pathway.
What are the normal calcium levels in the cytoplasm?
10-6 M
What are the normal calcium levels in the extracellular fluid?
10-3 M
What effects can increased free calcium in the cytosol have on a cell? (4) How does calcium carry out these effects? (2)
changes in cell shape/motility
contraction of muscle cells
release of secretory proteins
activation of regulatory enzymes
binds to calcium-binding proteins such as calmodulin in non-muscle cells and troponin C in striated muscle cells
What is the effect of activating PKC?
PKC activation → activation of transcription factor AP-1 → regulation of genes that promote cell proliferation
What is the composition of the transcription factor AP-1?
heterodimer of c-Fos and c-Jun cellular protooncogene products
List the steps of the pathway that begins with insulin and ends with activation of Akt. (9)
insulin → activate receptor tyrosine kinase → IRS proteins dock and are phosphorylated → PI3 kinases bind to phosphorylated IRS → PI3Ks then phosphorylate PIP2 → PIP3 → activation of PDK1 → phosphorylation/activation of Akt/PBK → activates GLUT4 uptake
Phospholipase A2 is activated by
increased Ca2+ levels
Phospholipase C mediates what cleavage reaction?
PIP2 → DAG + IP3
PIP2 → DAG + IP3 is mediated by what enzyme?
phospholipase C
