Biol2174 Cell Physiology in Health & Disease. Lecture 3: Simple diffusion. Kiaran Kirk. Research School of Biology

Transcription

1 Biol2174 Cell Physiology in Health & Disease Lecture 3: Simple diffusion Kiaran Kirk Research School of Biology

2 Learning objechves To understand: The barrier properhes of the lipid bilayer The factors influencing the rate of diffusion of solutes across the lipid bilayer How the phenomenon of simple diffusion underpins a number of clinical examples

3 Diffusion rate and the oil/water parhhon coefficient It has been known for a century that there is a relahonship between the rate at which small molecules diffuse across lipid bilayers and their hydrophobicity, as measured by their oil/water parhhon coefficient, K. K = Equilibrium constant for the parhhon of the solute between oil and water = [Solute] oil / [Solute] water The more hydrophobic a compound is, the more readily it dissolves in oil and the higher its oil/water parhhon coefficient, K.

4 Diffusion rate and the oil/water parhhon coefficient

5 Diffusion across the human red blood cell membrane Fig. 2.1 from Stein - Transport and Diffusion Across Cell Membranes "

6 Size- dependence of diffusion The apparent size- dependence of the permeahon rate reflects the size- dependence of diffusion within the lipid region of the membrane. This is shown (for the human red cell membrane) in the following figure which graphs the rate of diffusion within the membrane bilayer against the size (molecular volume) of the diffusing solute Fig. 2.4 from Stein - Transport and Diffusion Across Cell Membranes

7 Size- corrected diffusion rate Using the data on the previous slide to calculate 'Size- corrected Permeability' gives the following, much- improved correlahon with the parhhon coefficient. Fig. 2.5 from Stein - Transport and Diffusion Across Cell Membranes

8 Summary of the factors affechng simple diffusion across membranes We can understand the rate at which solutes diffuse across the lipid component of membranes in terms of the need for them to: (i) Par--on from the aqueous phase into the oily interior of the membrane bilayer, as reflected in their oil/water parhhon coefficient; (ii) Diffuse from one side of the bilayer to the other, as reflected in the size- dependence of the diffusion rate. Consequently, the rate of diffusion of small solutes through the lipid phase of biological membranes is determined largely by its hydrophobicity (which determines its oil/water parhhon coefficient) and its size (which determines its rate of diffusion within the membrane bilayer). Specifically, the basal membrane permeability, P, increases with increasing solute hydrophobicity and decreases with increasing solute size.

9 Two examples of the importance of simple diffusion in a clinical context

10 1. The anhmalarial achon of chloroquine

11 Chloroquine is a weak base NH N Cl N

12 Chloroquine is a weak base NH + N H Cl N H +

13 The malaria parasite has an acidic digeshve vacuole ph 7.4 Haemoglobin ph ~5 ph 7.3 PepHdes Haemozoin Amino acids Haem" ATP H + H + ADP DigesHve Vacuole Parasite RBC

14 Chloroquine accumulates in the vacuole by weak base trapping ph 7.4 Haemoglobin ph ~5 ph 7.3 CQ PepHdes Amino acids Haem" CQ H + CQ CQH + H + CQH 2 2+ Haemozoin DigesHve Vacuole Parasite RBC

15 Summary: Chloroquine delivery The delivery of chloroquine at high concentrahons to its site of achon within the parasite is dependent upon: (i) The ability of the uncharged, hydrophobic chloroquine molecule to diffuse through the various membranes to reach the interior of the food vacuole. (ii) The inability of the charged (and therefore hydrophilic) form of the chloroquine to escape from the acidic vacuole.

16 2. Treatment of an inherited disorder CircumvenHon of defechve neutral amino acid transport in Hartnup disease using tryptophan ethyl ester' (Jonas & Butler (1989) J. Clin. Invest. 84, )

17 Hartnup disease An autosomal recessive condihon characterized by defechve uptake of neutral amino acids in the gut and the kidney (i.e. it is a defect in a membrane transporter). One of the neutral amino acids, tryptophan is a precursor for the neurotransmiqer serotonin. Symptoms: dermahhs, diarrhea, ataxia, neuropsychiatric symptoms.

18 Hartnup disease: Case study Three year old child Growth failure, developmental delay, hyperachvity, chronic diarrhea, weakness

19 Hartnup disease: Case study "No side effects were observed other than a faint smell of alcohol on his breath."