Lipids Flashcards
what are lipids?
hydrophobic molecules include;
phospholipids
glycophospholipids, isoprenoids, eicosenoids
all come from Acetyl CoA
Phospholipids
major comp of cell membranes
glycerophospholipids (glycerol backbone)
sphingolipids (ceramide)
alcohol attached via phosphodiester bond to DAG (diaclyglycerol)
can be sat / unsat
diff head groups
cardiolipin
unusual glycerophospholipid:
two phosphatidic acids eterified to an additional glycerol molecule
found only in inner mito mem (part of ETC0
plsmalogens
glycerophospholipid;
fatty acid at C1 of glycerol is attached via an ether linkage (rather than ester)
most common plsamalogens:
phsphatidalenthanolamine & phsphatidalcholine
30% of glycerphospholipids in brain
reduced levels ~ Alzheimer’s disease
platelet activating factor
ether glycerophospholipid
fatty acid chain on C2 replaced by an acetyl group
platelet aggregation and degranulation, inflammation, analphylaxis
trans vs cis double bond
trans wont put a kink in the fatty acid tail
nature of tails affects fluidity of membrane
C1
C2
C1 generally saturated tail
C2 unsaturated tail
sphingophospholipids
long chain amino alcohol sphingosine as backbone
sphingomyelin is major sphingosine
- choline head group
- myelin sheath
glycerophospholipids are derived from
phosphatidic acid
what is phosphatidic acid synth from?
2 fatty acyl tails + glycerol-3-phosphate (from DHAP)
formation of phosphatidylcholine (PC)
- deP Phosphatidic acid -> DAG + CDP-Choline
- Methlylation of PE ->PC
- PC has 3 methyl grps
- SAM - S-adenosyl-methionine (methly donor) req 3 - Phosphatidylserine -> PC
- decarboxylational; phosphatidylserine DC (PLP)
- or base transfer; phosphatidyl-ethanolamine-serine transferase
Choline; diet or lipid turnover
phosphatidlethanolamine (PE)
deP Phosphatidic acid -> DAG + CDP-ethanolamine
Ethanolamine; diet or lipid turnover
Phosphatidyl inositol (PI)
DAG is activated by UDP
Phosphatiditylserine (PS)
base exchange between serine and PE
sphingolipid synthesis
- palmitoyl CoA + Serine
enz; serine palmitoyl transferase
req NADPH - Spinganine (1 tail) - > Dihydroceramide
enz; Ceramid synthase - Dihydroceramide -> Ceramide (2 tail)
- ceramide sphingomyelin
-transfer of the choline fr PC
-> enz: sphingomyelin synthase
<- enz: sphingomyelinase (SMase)
phospholipase
degrade glycerophospholipids by hydrolize phosphodiester bonds
activate 2nd messengers
-release 1 tail = lysophospholipid (good detergent - alter solubility)
- acyl chains released = intermediates;
PL-A2 -> arachidonic acid -> syn of prostaglandins, leukotriees, thromboxanes
Phospholipase C
PL -C; act by Gprotein coupled receptors, alpha-adrenergic R acts on PIP2 -> DAG + IP3
IP3 -> Ca release
DAG -> act PK-C (also act by Ca)
NE or EP
Constriction of blood vessels - sm mm
Phospholipase A 2
release hydrocarbon tail at 2nd C -> the unsat FA
PL - A2 alpha - specific for those with arachidonic acid
-> generation of prostaglandins, leukotrienes, etc
sphingomyelinase
degrade sphingophospholipids
remove phosphorylcholine = > ceramide
(ceramide further degraded into sphiingosine and free FA)
SMase classified by pH optima
Niemann-Pick disease
lysosomal acid SMase
Neimann-Pick (A,B) disease, AR
lipid buildup in cells
A - more severe, neuro defects, death early
ashkenazi jews
B - 5% fuction, lipid dep in liver
C & D - transporter problem -> build up of lipids inside cells
glycosphingolipids
derived from ceramide (like sphingolipids)
No phosphoester moiety
Polar portion = monosaccharide or oligos attached via O-glycosidic linkage
classified as neutral or acid
neutral glycosphingolipids
neutral charge single sugar (glucose or galactose = glucocerebroside/galactocebroside) or oligosaccharide (globoside)
most common found in mem = galactocerbroside
glucocerbrosides = precursors of more complex glycosphingolipids
acidic glycosphingolipids
neg at phys pH due to:
1. N-acetyleneuraminic acid (NANA aka silaic acid) (note: attached via CMP-NANA)
= gangliosides - ganglion cells of CNS
2. Sulfate = sulfatides
gangliosides
acidic glycosphingolipids w NANA attached
Gm - 1 NANA, cholera toxin interacts here
Gd - 2
Gt - 3
Gq - 4
carb portion stick out from cell surface; communication, bacteria use them as receptor for toxins
sulfatides
cerebrosides containing sulfated galatosyl residues
sulfate donor; (PAPS) 3 phosphoadenosine 5 - phosphosulfate
attached to 3 OH of galactose
where are glycosphingolipids synthesized and how
golgi
sequential attachment of UDP-sugars by glycosyl transferases to the glucose
(similar to glycogen syn)
degradation of glycosphingolipids: where how
endocytosed into lysosomes
lysosomal hydrolases - remove sugars 1 at a time -> ceramide
ceramide -> sphingosine + FA
normal; balance bet syn & deg = constant amt of glycosphingolipids in membrane
1 hydrolase deficient / absent -> buildup of glycosphingolipids in lysosomes
lipidoses
buildup of glycosphingolipids in lysosome due to deficiency/absence of a lysosomal hydrolase
Tay-sachs
lipidoses
defect; hexosaminidase A -> buildup of Gm2
(gangliosides)
rapid, progressive, fatal neurodegen
blindness, cherry red macula, mm weakness, seizures
Gaucher disease
Gaucher diesease = enz beta-glucosidase (aka glucocerbrosidase) -> buildup of glucocerbrosides
most common lysosomal storage disease
hepatospienomegaly
osteoporosis of long bones
CNS inovl in rare infantile/ juvenile forms
eiconsinoids
include: prostaglandins, thromboxanes, leakotrienes
PG/TX - platelet agg, ovulation, gastric acid sec, gastric mucous formation, vasocon/relax
LK - allergic response, asthma, netrophil & eosinophil function, airway dia
all derived from 20C omega-6 FA
- most cases = arachidonic acid - der from linoleic acid, released from mem phospholipids via PL A 2
Prostaglandins and thromboxanes synethesis
PGH synthase (2 catalytic act); takes Arachadonic acid:
1. fatty acid cyclooxygenase (COX) - forms the intermediate PGG2
req O2
2. Peroxidase - converts PGG2 -> PGH2
req glutathione
PGH2 -> converted to a number of diff things dep on cell type (aka the enzymes present)
COX 1
const expressed in all tissue
COX 2
inc induced cytokines/ inflammatory response
COX inhibitors
NSAIDS - non-selective COX inhib
ant-inflammatory (blocks COX-2)
side-affects; stomach upset bc of COX 1 inhibition (dec mucous sec)
selective COX-2 inhib
celecoxib
only COX assoc w anti-inflam response
should have no side-effects
may have adverse cardiovascular effects -> unpredicted side effects
TXA 2
platalet agg
PGI 2
inhibits platelet aggregation
endothelial cells
how do prostaglandins/thromboxanes exert their effects?
via specific G-protein coupled receptors (GCPRs) in target cells
PGI 2 - syn by endothelial cells, ihibits platelet aggregation
TXA2 - syn by platelets and triggers aggregation
Result = limit platelet aggregation to site of injury
aspirin
COX - 1 irreversible (fround in platelets)
COX - 2 reversible
Platelets - anucleated so can’t produce more proteins, so shuts doesn platelet TXA2 production and aggregation
low-dose aspirin therapy more or less platelet specific
leukotriene synthesis
enz; 5-lipoxygenase (5-LOX);
arachadoinc acid -> leukotriene A4 (LTA4)
(intermmediate = 5-hydroperoxyeicosatetranoic acid, 5 HPETE)
not Cyclic (unlike prostaglandins and thromboxanes)
exert effects via GPCR
many contain conj cysteine residue (fr glutathione) = Cysteinyl leukotrienes
- these are the slow-reacting substance of anaphylaxis (SRS-A) - asthma
- inhib of 5-LOX & antagonists of CysLT-1 tx for asthma
