Lipid Membranes and Drug Targets Flashcards
(47 cards)
1
Q
Hydrophobic Effect
A
Effect of Oil-drop in Water
- Non-polar molecules stick together in polar media (water)
- in a way to MAXIMIZE # of POLAR interactions
- =EXOERGIC
- in a way to MAXIMIZE # of POLAR interactions
2
Q
Free Energy Aspects
of Amphiphile Aggregation
A
- Ordered Water molecules that have fewer interactions with other molecules @ surface of Nonpolar solute
- –> are squeezed out
-
Formation of lipid aggregate (ampiphatic complexes)
-
Favorable both enthapically & Entropically
- VDW
- Enthalpic - interaction amoung water
- Entropic - water ordering
-
Favorable both enthapically & Entropically
3
Q
Phospholipid Aggregates
Different Forms
A
-
Micelle / Hexoganal Phase
-
individual units are WEDGE-shape
- head + 1 tail
-
individual units are WEDGE-shape
-
Bilayer
-
indiv units are CYLINDRICAL
- head + 2 tails
-
indiv units are CYLINDRICAL
-
Liposome
- aqueous cavity
4
Q
Critical Micelle Concentration
CMC
A
- Specific CONC at which a monomeric amphiphile begins to form micelles
- typically 10-10M for membrane phospholipids
-
HIGHER CMC Values caused by:
- Shorter chains
- Greater negative charge
5
Q
Phospholipid Structure
A
-
Polar HydroPHILIC head
- Choline - Phosphate - Glycerol =
-
Non-polar hydroPHOBIC tail
- = 2 hydrocarbon tails
6
Q
Sphingolipid
*not found in bacteria
A
- A Polar Membrane Lipid
- a Glycolipid
- Have mostly saturated fatty acid chains
- –> TIGHTER packing in bilayers
- Presence of HB amide bonds –> more rigid
- Consist of:
- Sphingosine + FA + Mono/Oligosaccharide
7
Q
Glycerophospholipids
A
-
Glycerol
- 2 FA’s + (PO + Alcohol)
- Not very rigid compared to sphingolipids
- more UNSATURATED = kinks
- BLOOD GROUP ANTIGENS
8
Q
Galactolipids (Sulfolipids)
A
- Polar Membrane Lipid - Glycolipid
-
Glycerol
- 2 FA + (Mono/disaccharide + SO4)
9
Q
Triacylglycerols
A
- neutral Storage Lipid
-
Glycerol
- 3 FA’s
10
Q
Blood Groups differ by presense & Type of what?
A
Glycosyl Transferase
- Blood group antigens are GLycosphingolipids
11
Q
Cholesterol
A
-
Eukaryotic membrains contain Cholesterol
- *not found in bacteria
- Orientated w/ -OH facing the aqeuos phase
-
Polycyclic Structure
- –> imparts RIGIDITY to membranes w/ a lot of cholesterol
- Found most in Plasma Membrane
12
Q
PhosphatidylCHOLINE (PC)
A
-
found only in prokaryotes
- mainly in Mito
- Inner Membranes
- mainly in Mito
-
distributed @ the OUTER MONOLAYER
- along with sphingomyelin
13
Q
Cardiolipin
A
- Lipid found mostly in MITOCHONDRIA
14
Q
PhosphatidylEthanolamine (PE)
A
- PE found in both prokaryotes & eukaryotes
- mainly in Mitochondria
-
Negatively charged phospholipid
- located @ INNER leaflet of bilayer
-
involved in RECRUITMENT of POSitive signaling proteins
- to the membrane surface
-
involved in RECRUITMENT of POSitive signaling proteins
- located @ INNER leaflet of bilayer
15
Q
Flippase
A
-
Catalyzes TRANSVERSE DIFFUSION
- “FLIP-FLOP” of phospholipid
- from facing outer membrane to inner membrane
- very slow –> very fast
-
Lateral diffusion occurs very fast UNCATALYZED
- also rotation along molecular axis is fast
16
Q
Liquid-Crystalline Phase
(fluid state)
A
-
Biological membranes MUST STAY liquid-crystalline
-
TO BE FUNCTIONAL
- Need to be ABOVE transition temperature
-
TO BE FUNCTIONAL
-
if below transition temperature
-
–> GEL STATE (non functional)
- aka paracrystalline state
-
–> GEL STATE (non functional)
17
Q
How do bacteria adapt to lower temperatures?
A
- they use more unsaturated fatty acids
- like OLEIC ACID (unsaturated = MORE BENT)
- Enable bacteria membrant to REMAIN liquid crystalline
18
Q
Traits of Phospholipids with
More Unsaturated Bonds
A
-
Thinner Bilayers compared to saturated chains
- Cis-double bonds are shorter
- Shorter & Occupy LARGER SURFACE AREA
19
Q
Passive transport is fastest for molecules with moderate hydrophobicity. Why?
A
We want the molecule to readily enter the membrane but we also do not want it to leave so quickly
20
Q
Membranes are refractory to polar molecules.
Why?
A
Phosphoplipid membrane has polar heads
polarity will block molecule from entering
21
Q
Topology of membrane proteins can be predicted from hydropathy indices.
What’s that?
A
22
Q
2 Dimentional Liquid
or
Liquid Crystalline State
A
- Rapid conformational & rotational changes in:
- ALKANE chains & head group orientation
- Planar bilayer is maintained
- NO LATERAL Movement observed within 5Nanoseconds**
23
Q
Uncatalyzed lateral Diffusion
A
- A motion in liquid-crystalline bilayers
- LATERAL
- occurs very FAST
- because the forces VDW are very weak
24
Q
Uncatalyzed Transverse Diffusion
“flip-flop”
A
- Motion in liquid-crystalline bilayer
-
occurs very SLOW
- during transit, e- charged head group must be stripped of solvating water molecules
- *there is also fast rotation along the molecular axis
25
**Glycophorin A**
Integral Membrane Protein
* Contains a Single Helical transmembrane segment
* **hydrophobic AA side chains allow the segment to sit between the phospholipid bilayer**
* **Heavily glycosilated @ extracellular part**
* w/ NEGATIVELY charged sialic acid
* --\> ensure that eruthrocyte do not adhere to walls of blood vessels
26
**Membrane Pore / Channel**
Integral Protein
* Formed by assemblies of either **a-helical / b-sheeted proteins**
* Responsible for:
* **signaling**
* **ligand gated channels**
* **voltage gated ion channels**
* **membrane transporters**
27
**Bacteriorhodopsin**
Integral Protein
* **Seven-Pass Membrane receptor**
* important for **cell signaling**
* **GPCR =** great target for drug design
* regulate processes from sensing to neuronal transmission
* **Proton Pump**
* allow **H+ to leave cell**
28
**Hydropathy Indices**
* number representing the **hydrophobic or hydrophilic** properties of a **AA** sidechain
* **GLU / ASP = most polar**
* **PHE / TRP = most hydrophobic**
* ****Used to **PREDICT TRANSMEMRANE DOMAINS**
* ****Bacteriorhodopsin = 7 hydrophobic domains
* Glycophorin = 1 hydrophobic domain
29
Membrane Permeability:
## Footnote
**Hydrophobic Molecules**
* Easily cross the membrane
* **O2 / CO2 / N2 / Benzene**
30
Membrane Permeability:
## Footnote
**Small Uncharged POLAR Molecules**
* Membranes are permeable to **small noncharged molecules**
* Ex. **Water, Urea, Glycerol**
* Must have *LOW POLARITY*
* ****800 Daltons = Upper MW limit** to cross cell membrane passively
* those greater than this need a transporter system
* **low MW is a necessary but insufficient condition of BV**
31
Membrane Permeability:
## Footnote
**IONS**
* CHARGED molecules can NOT cross bilayer
* **especially NEGATIVE**
32
**Simple Diffusion**
**Non-Polar Compounds Only**
**Down Concentration Gradient**
* **\<800 daltons**
* Low MW is necessary but insufficient condition of BV
33
**Fascilitated Diffusion**
**Down Electrochemical gradient**
**uses a transporter**
34
**Primary Active Transport**
**AGAINST electrochemical gradient**
**USES ENERGY**
35
**Secondary Active Transport**
**SYMPORTER**
**AGAINST electrochemical gradient**
Driven by **ION moving down the gradient**
both molecules move in SAME direction
*antiporter = two molecules in opposite directions*
36
**Ion Channel**
**Down Electrochemical gradient**
***may be gated by a ligand or ion***
37
**Ionophore-mediated ion transport**
**Down electrochemical gradient**
38
**Membrane Bound GLUCOSE transporter**
* HydroPHILIC / phobic properties of **a-helices**
* **polar surface** of the channel pore
* Asn / Ser / Thr
* interact w/ **polar -oh groups of glucose**
39
Selective Serotonin Reuptake Inhibitors
## Footnote
**SSRI**
* Key in antidepressants ~ **Paroxetine**
* Block Serotonin transporter w/ **Ki** **=0.34 nm**
* **Toggles between outward / inward facing conformations**
* **Outward = open extracellularly**
* **Inward = open to cytosol**
* ******Symporter**
* hydrogen and ligand go in the SAME direction
40
**Drug Transport Predictors**
* Factors that help determine Bioavailability
* ******Octonol / Water Partioning = logP**
* **Artifical Membranes**
* **Cell Culture Systems - Cell Monolayer**
* ****passive transport
* Cell assisted transport
* ****transcellular / paracellular (inbetween)
* Carrier mediated transport
* Transport proteins
41
**Lipid Partitioning Vs Membrane Permeation**
**logD = 1-2 is MOST ideal, HIGHEST FLUX**
**(**pH 7.4)
* flux = mass transfer via artifical membrane %
* **bimodal relationship**
* ****lipophilicity vs mass transfer
* Very lipoPHILIC drugs can penetrate membrane
* but CAN NOT LEAVE
* Very hydroPHILIC drugs cannot get solubized in membrane
42
Lipid Partitioning vs Membrane Permeation
**k1 & k2**
* **k1 =** rate constant of transport from:
* **Aqueous --\> liquid phase**
* **INCREASES** as logD Heightens
* **k2 =** REVERSE of K1
* *DECREASES as logD Heightens*
43
**Passive Vs Carrier-Mediated Transport**
* **Carrier Mediated Transport = LIMITED by transporter**
* Levels off at **Vmax**
* high **km** = weak binding
* when concentration = half maximum velocity
* Overall Transport is a sum of the two components
44
**Passive Transport**
* **Linearly dependent on concentration**
* Non-saturable, unlike *carrier mediated transport*
* *_NOT SUBJECT TO INHIBITION_*
* Less structure specific than carrier mediated
* general dependence on LIPOPHILICITY
* Less cell-type specific than carrier mediated
45
**Carrier-Mediated Transport**
* *Non-Linearly dependent on concentration*
* ***SATURABLE***
* ****SUBJECT TO INHIBITION**
* MORE structure specific
* dependence on lipophilicity could be identified in narrow chemical series
* **Cell type specific**
* requires expression of transporter
46
**Efflux Pumps**
* **can Work AGAINST the gradient (ATP)**
* **pump drug out of the cell**
* ****cytosol --\> out of cell
* _Blocking efflux pump is a strateg_y:
* for maintaining higher drug conc. after administration
47
