Chem 438 - Introductory Biochemistry - Spring 2013

Lecture Notes:

Lipids, cont.

Cholesterol

cholesterol strutural diagram cholesterol spacefilling model

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Lipid Properties

An important consideration for lipids of all sorts is their fluidity. Thus membranes must be fluid enough to allow the diffusion of proteins, transport processes etc. but not so fluid as to weaken the membranes structure. For storage want fat to be fluid enough to flow to fill out body shape at normal operating temperatures. A number of strategies are used by organisms to adjust lipid fluidity:

Fatty acid chain length: longer chains have higher melting points (less fluid at a given temperature).
Unsaturation: double bonds introduce a "kink" in the chain, harder to stack, so less van der Waals contact and thus lower melting points (more fluid).
Branched chains (bacterial only): Again, less van der Waals contact and thus lower melting points (more fluid).
Cholesterol: Its planar shape enables it to stiffen bilayers,

Lipid Bilayers

Detergents & Micelles

Polar heads of detergents and soaps (such as long chain fatty acids) tend to associate with polar solvents such as water, while non-polar "tails" are excluded by water and are forced to associate with themselves making globules known as micelles.

micelles and lipid bilayer images

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Lipid Bilayer

lipid bilayer diagram

The lipid bilayer forms the core for the lipid bilayer membrane as seen in the Fluid Mosaic Model of biological membranes.

Biological Membranes

Fluid Mosaic Model

This model has as its core element lipid bilayer (predominantly glycero-phospholipid). This bilayer makes a very effective barrier for the flow of charged and polar species between aqueous compartments. Within the bilayer itself, however, flow occurs readily - it is a two- dimensional liquid with a viscosity similar to olive oil. Thus we see rapid exchange between adjacent phospholipid molecules on a face of the bilayer, but very rare exchange between faces (the polar "head" groups would have to cross the non-polar bilayer interior). A lipid bilayer membrane thus separates the interior of the cell from the outside.

fluid mosaic model diagram

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Of course a cell also needs to communicate with the outside world - doors and windows are needed. Such communication occurs largely through proteins acting as pores, gates, and shuttles. Note that these proteins "float" in the bilayer. They have unconstrained movement in the two-dimensions of the sheet. Changes in protein conformation can also cause them to "sink" into the hydrophobic interior of the bilayer etc. Protein movement can be constrained by linkage to protein networks (cytoskeleton) within the cell as is exemplified by red blood cells.

RBC membrane diagram

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Membrane Proteins

Integral proteins based both on alpha-helices (Figure 9-22a, p 271) and beta-sheets (Figure 9-22b, p 271). Also has peripheral protein attached via membrane lipids in bilayer (Figure 9-21, p 271).

Membrane Assembly/Protein Targeting

Assembly occurs on scaffolding of previous membrane

Membrane lipids are synthesized in/on membrane (Eukaryotes synthesis on cytosolic face of ER, transport by budding and Phospholipid exchange protein. Signal hypothesis for targeting of many membrane and exported proteins:

Membrane proteins and export proteins synthesized on rER (Figure 22.29, p 691). SRP= signal recognition protein; signal sequence= 13-36 residues with 7-13 residue hydrophobic core flanked by hydrophilic and basic residues near N-terminii; Transmembrane proteins contain an approx. 20 hydrophobic residue "stop transfer" or "membrane anchor" sequence which stays in membrane, other proteins continue through. (Figure 22-32, p 693) Note that this model indicates that the amino terminus would always be extra-cytosolic in membrane proteins (this is not always the case, thus other mechanisms must be operating).

artists rendition of protein transport with nucleus, rER and golgi

1) Nucleus 2) Nuclear pore 3) Rough endoplasmic reticulum (RER) 4) Smooth endoplasmic reticulum (SER) 5) Ribosome on the rough ER 6) Proteins that are transported 7) Transport vesicle 8) Golgi apparatus 9) Cis face of the Golgi apparatus 10) Trans face of the Golgi apparatus 11) Cisternae of the Golgi apparatus

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Mitochondria illustrates more complex situations: Cytosolically synthesized precursor proteins have signal sequence. Hsp 70 helps to unfold precursor protein (ATP required), which can then pass through both membranes of mito. Inside Hsp 70 maintains in partially folded state (ATP required). It is then aided in folding by Hsp 60 ("barrel" chaperon) (ATP required). Finally it is released (ATP required), and the N-terminus is removed to give the mature protein in the matrix.

Proteins are transported in coated vesicles: membranous sacs encased in polyhedral frameworks of clathrin.

Fat Metabolism

Fats come from two main sources: stored body fat and dietary fat. Dietary fat must first be emulsified to increase its surface area for contact with the water soluble lipases. This occurs largely in the duodenum after mixing with the bile acids, a family of cholesterol derived detergents. Triacylglycerols can then be hydrolyzed by pancreatic lipase to free fatty acids and 2-monoacylglycerol:

The fatty acids and monoacylglycerol are absorbed by the intestinal cells, converted to fatty acyl CoA and reassembled into triacylglycerols. The triacyl glycerols then assemble with phospholipids and lipoproteins to form chylomicrons for transport through the lymph and blood to the tissues.

When the chylomicrons reach tissue cells the triacylglycerols are again hydrolyzed by lipoprotein lipase to fatty acids which can be taken up by the peripheral tissue cells. In adipose cells the fatty acids are then converted into fatty acyl CoA's and combined into triacylglycerols for storage. Alternatively the fatty acids can be broken down for energy using the beta-oxidation pathway.

Pathway Diagrams