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IMS: Biochemistry > Lipids > Flashcards

Lipids Flashcards

1
Q

Classes of Lipids

A
  1. Glycerolipids
    • Triacylglycerols
    • Phospholipids
  2. Sphingolipids
    • Sphingophospholipids
    • Sphingoglycolipids
  3. Isoprenoids
  4. Eicosanoids
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2
Q

Phospholipids

A
  • Major lipid component of cell membranes
  • Composed of an alcohol attached via a phosphodiester bond to either:
    • Diacylglycerol (DAG) ⇒ glycerolphospholipid
      • DAG is an intermediate of TAG synthesis
    • Ceramide ⇒ sphingophospholipid
      • An amino alcohol spingosine with a fatty acid esterified to the amino group
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3
Q

Triacylglycerol Synthesis

A
  • Glucose or glycerol used to synthesize glycerol-3-phosphate
  • Fatty acid tails added via esterification to glycerol-3-phosphate to produce triacylglycerol.
  • Phosphatidic acid (aka DAG-P) can be dephosphorylated to DAG then acylated to form TAG.
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4
Q

TAG Functions

A
  • An intermediate for glycerolphospholipid synthesis
  • Energy storage medium
  • Structural component of lipoproteins
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5
Q

Glycerophospholipids

A

The major class of phospholipids.

Phosphatidic acid is the simplest glycerophospholipid.

All others are derived from it by esterification of an alcohol.

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6
Q

Cardiolipid

A

Two phosphatidic acids esterified to an additional glycerol molecule.

  • Class of glycerophospholipids
  • Found only in the inner mitochondrial membrane
  • Required for functioning of the mitochondrial ETC
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7
Q

Plasmalogens

A

Glycerophospholipid where fatty acid at C-1 of glycerol is attached via an ether linkage.

  • Most common plasmalogens are:
    • Phosphatidalethanolamine
    • Phosphatidalcholine
      • -al suffix instead of -yl
  • Almost 30% of glycerophospholipids in the brain are plasmologens
  • Reduced levels of plasmologens associated with Alzheimer’s disease
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8
Q

Platelet-activating Factor

(PAF)

A

Ether glycerophospholipid with the fatty acid chain on C-2 replaced with an acetyl group.

  • PAF is a mediator of many physiological processes including:
    • Platelet aggregation and degranulation
    • Inflammation
    • Anaphylaxis
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9
Q

Head Groups

A

Various alcohols which can be esterified to phosphatidic acid:

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10
Q

Glycerophospholipid Charge

A
  • Net charge on a glycerophospholipid depends upon the head group.
  • Charge affects the nature of the membrane surface.
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11
Q

Glycerophospholipid

Acyl Tails

A
  • Acyl tails can vary from lipid to lipid and cell type to cell type
  • Acyl tails effect the ability to pack lipids and thus membrane fluidity:
    • Inc length = dec fluidity
    • Double bonds = inc fluidity
      • Unsaturated FA usually at C-2
      • Saturated FA usually at C-1
  • Naturally occuring lipids have saturated or cis-DB
  • Changing membrane fluidity effects:
    • Transport
    • Signal transduction
    • Etc.
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12
Q

Sphingophospholipids

A
  • Use the long chain amino alcohol sphingosine as a backbone to which FA are attached
  • Ceramide is a sphingosine with an extra FA attached
  • Major sphingophospholipid in humans is sphingomyelin
    • Has a choline head group
    • Sometimes ethanolamine found instead
  • Sphingomyelin is a major component of the myelin sheath
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13
Q

Phosphatidic Acid Synthesis

A
  • Glucose ⇒ DHAP ⇒ Glycerol-3-Phosphate

or

  • Glycerol ⇒ Glycerol-3-Phosphate
  • Two fatty acyl tails attached to glycerol-3-phosphate using fatty acyl CoA substrates
  • Water esterified as phosphate headgroup to form phosphatidic acid
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14
Q

Phospholipid Synthesis

from

Phosphatidic Acid

A
  1. Phosphatidic acid is dephosphorylated to diacylglycerol (DAG)
  2. CDP is used to activate choline or ethanolamine.
  3. DAG is condensed with CDP-activated alcohols to form phospholipids.
    • DAG + CDP-choline ⇒ Phosphatidylcholine (PC aka lecithin)
    • DAG + CDP-ethanolamine ⇒ Phosphatidylethanolamine (PE)

OR

  1. Phosphatidic acid is dephosphorylated to diacylglycerol (DAG)
  2. DAG is activated by CDP forming CDP-DAG
  3. CDP-DAG is condensed with inositol to form Phosphatidylinositol (PI)
  4. CDP-DAG is condensed with glycerol to form Phosphatidylglycerol (PG)
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15
Q

Phospholipid Interconversion

A

PC can be made through methylation of PE using SAM.

PS can be made from PE through base exchange of ethanolamine for serine.

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16
Q

Glycerolphospholipid

Grand Scheme

A
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17
Q

Phospholipases

A
  • Phospholipases hydrolyze phosphodiester bonds.
  • Different phospholipases cleave specific phosphodiester bonds.
  • Functions to:
    • Degrade glycerolphospholipids
    • Generate secondary messengers
    • Release acyl chains which serve as intermediates in the synthesis of biologically-active molecules
  • PL-A1 : cleaves at C-1 producing a lysolipid
  • PL-A2: cleaves at C-2 producing arachidonic acid
    • serves as a precursor for eicosanoids
    • Cortisol’s anti-inflammatory action via PL-A2 inhibition
  • PL-C: cleaves at ester bond on C-3
    • can be activated by specific GPCR’s
    • acts on PIP2 to produce DAG and IP3
18
Q

Pulmonary Surfactant

A
  • Type II pneumocytes synthesize and secrete dipalmitoyl PC (DPPC) which is the main component of surfactant.
  • Surfactant prevents alveoli collapse during expiration and reduces pressure needed to inflate alveoli during inspiration.
  • DPPC synthesis markedly increases around 32 weeks.
  • Lack of surfactant main cause of infant respiratory distress syndrome (IRDS)
  • An amniotic fluid lecithin-sphingomyelin (L/S) ratio > 2 indicative of sufficient surfactant synthesis
19
Q

Synthesis of Plasmalogens

A
  • Ether lipids synthesized from:
    • DHAP
    • Fatty acids
    • Fatty alcohols
  1. Fatty acid esterified at C-1
  2. FA exchanged with a long chain fatty alcohol in peroxisomes
    • Patients with Zellweger disease are unable to synthesize plasmalogens
20
Q

Sphingomyelin Synthesis

A
  1. Palmitoyl-CoA condensed with serine to produce sphinganine by Serine Palmitoyl Transferase.
    • Reaction requires PLP and NADPH
  2. Second acyl tail is added from a fatty acyl-CoA to produce ceramide.
  3. Choline is transfered from PC to ceramide producing sphingomyelin.
21
Q

Sphingomyelin Degradation

A
  1. Sphingomyelinase (SMase) removes phosphorylcholine from sphingomyelin producing a ceramide.
    • Several isoforms of SMase classified according to pH optima.
    • Defects in lysosomal acid SMase leads to type A and B Niemann-Pick Disease
  2. Ceramide degraded into sphingosine and free fatty acid.
22
Q

Niemann-Pick Disease

A

Caused by a deficiency of lysosomal acid SMase.

Autosomal recessive.

Results in build-up of sphingomyelin in liver, spleen, and CNS.

  • Type A has < 1% enzyme activity.
    • Extensive developmental disability
    • Neurodegeneration
    • Death in early childhood
  • Type B has ~ 5-10% enzyme activity.
23
Q

Glycosphingolipids

A
  • Derived from ceramide
  • Do not have a phosphoester moiety
  • Polar portion provided by a monosaccharide or oligosaccharide attached via an O-glycosidic linkage
  • Depending on number and type of sugar attached, glycosphingolipids subclassified as:
    • neutral glycosphingolipids
    • acidic glycosphingolipids
24
Q

Acidic Glycosphingolipids

A
  • Negatively charged at physiological pH due to the presence of:
    • N-acetylneuraminic acid (NANA, a sialic acid) in gangliosides
    • Sulfates in sulfatides
  • Gangliosides
    • Primarily found in ganglion cells of CNS
    • Named based on number of NANA moieties attached
      • Mono - GM series
      • Di - GD series
      • Tri - GT series
      • Quarto - GQ series
    • Carbohydrate moiety protrudes from cell surface
      • Cell recognition
      • Cell-cell communication
      • “receptors” for bacterial toxins
        • Cholera toxin interacts with GM1
25
Sulfatides
Cerebrosides containing sulfated galactosyl residues.
26
Glycosphingolipid Synthesis
* Sequential attachment of UDP-sugars by *glycosyl transferases* to glucose in glucocerebrosides. * Occurs primarily in Golgi
27
Sulfatide Synthesis
* _Ceramide_ condensed with _UDP-galactose_ to produce a galactocerebroside. * _Sulfate_ groups attached to 3' OH of _galactose_ by *sulfotransferase* using _PAPS_ as sulfate donor
28
Glycosphingolipid Degradation
* Glycosphingolipids internalized by endocytosis into lysosomes * Sugars removed one at a time by family of ***lysosomal hydrolases*** producing _ceramide_ * If a hydrolase is absent or reduced, gluycosphingolipid will accumulate in lysosomes ⇒ _lipidoses_ * Ceramide degraded into _sphingosine_ and _free fatty acid_ * Synthesis & degradation normally balanced so glycosphingolipid concentration in membranes relatively constant
29
Tay-Sachs Disease
* Caused by a defect in **β​-*****hexosaminidase A*** * Leads to a build-up of **GM2**
30
Gaucher Disease
* Caused by a defect in ***β-glucosidase*** * Leads to build-up of **glucocerebrosides**
31
Krabbe Disease
* Defect in ***β-galactosidase*** * Results in accumulation of **galactocerebrosides**
32
Fabry Disease
* Defect in ***α-Galactosidase*** * Accumulation of **globosides**
33
Eicosanoids
* Derived from 20-carbon unsaturated ω-6 fatty acids * Most derived from arachidonic acid (20:45,8,11,14) * Made from dietary linoleic acid * Arachidonic acid released from membrane phospholipids by PL-A2 * Inhibited by cortisol Includes * **Prostaglandins & Thromboxanes** * Act through G-protein coupled receptors * Involved in inflammation * Affect gastric acid and mucosal secretion * Platelet aggregation * Ovulation * Control of blood vessel diameter * **Leukotrienes** * Regulate neutrophil and eosinophil function * Play a role in allergic response and airway diameter
34
Prostaglandins & Thromboxanes Synthesis
1. _Arachidonic acid_ converted to _PGH2_ by ***PGH Synthase***, an enzyme with two catalytic activities. * Arachidonic acid converted to _PGG2_ intermediate by ***fatty acid cyclooxygenase*** (COX) activity in an _O2-_requiring reaction * PGG2 converted to _PGH2_ by ***peroxidase*** activity in a _glutathione_-requiring reaction 2. PGH2 converted to a number of products depending on cell type: * Endothelial cells ⇒ PGI2 (prostacyclin) * Platelets ⇒ thromboxane A2 (TXA2) * Other cells: PGF2 and PGE2
35
PGH Synthase
PGH synthase exists in two isozymes: * **_COX-1_** * Constitutively-expressed in most tissues * NSAIDS such as aspirin, indomethacin, and ibuprofen irreversibly inhibit COX-1 * Action on all tissues leads to side-effects * **_COX-2_** * Induced by cytokines in cells associated with the inflammatory response * Celecoxcib (Celebrex) selectively inhibit COX-2 * Liked to adverse cardiovascular events thought to be linked to PGI2​ inhibition * Aspirin is a reversible inhibitor of COX-2
36
TXA2 | (Thromboxane A2)
* Produced by COX-1 primarily in **platelets** * **Promotes platelet aggregation** * **Vasoconstriction** * Mobilizes intracellular calcium * Selective contraction or relaxation of smooth muscle
37
PGI2 (Prostacyclin)
* Produced by COX-2 primarily in endothelium of vessels * Vasodilation * Inhibits platelet aggregation
38
PGE2 | (Prostaglandin E2)
* Produced by most tissues, espcially kidney * Vasodilation * Relaxes smooth muscle * Relaxes cervix & contracts uterus inducing labor * Required for fever response * Maintains patent ductus arteriosis
39
PGF2α​ | (Prostaglandin 2α)
* Produced by most tissues * Vasoconstriction * Contraction of smooth muscle * Stimulates uterine contractions * Used to induce labor
40
Aspirin
* Irreversible inhibitor of COX-1 * Platelets anucleated and incapable of synthesizing new COX-1 * Effects are more or less platelet specific * Decreases risk of CAD * Reversible inhibitor of COX-2
41
TXA2 and PGI2 Actions
* TXA2 synthesized by platelets and triggers platelet aggregation. * PGI2 synthesized by endothelial cells and inhibits platelet aggregation and vasodilation. * Opposing actions limit platelet aggregation to the site of vascular injury while preventing it downstream of the injury.
42
Leukotriene Synthesis
Some tissues contain the enzyme ***5-lipoxygenase*** (5-LOX) instead of COX. * _Arachidonic acid_ is converted to 5-hydroperoxyeicosatranoic acid (5-HPETE) then to **_leukotriene A4 (LTA4)_** * Non-cyclical molecule * LTA4 is then converted to: * Leukotrienes (LTC4, LTD4 LTE4) which contain a conjugated _cysteine_ residue from glutathione * Termed **cysteinyl leukotrienes** in mast cells and eosinophils. * Form the **slow-reacting substance of anaphylaxis** (SRS-4) * Mediate allergic and asthmatic responses. * Act through GPCRs * Inhibitors of 5-LOX and antagonists of CysLT1 receptors used for asthma prophylaxis. * **LTB4** in neutrophils and monocytes * Induces activation and adhesion of leukocytes on endothelium * Acts as chemoattractant for neutrophils to areas of tissue damage

IMS: Biochemistry (10 decks)

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