Lipid Structure and Stereochemistry

Lipid Structure Review

Last lecture focused on lipids and their structures, including different types and melting points.
Melting points are influenced by the presence of double bonds (lower) versus single bonds (higher) due to shape differences.
Discussed micelles and waxes.

Membrane Lipids

Membrane lipids are polar on one side.
Types include glycerolipids and glycerophospholipids which contain phosphate and alcohol groups.
- Glycerolipids can have different sugars attached, like galactose or betaine.

Sphingolipids

Attachment to carbon instead of oxygen (as in glycerolipids).
Glycerolipids attach to glycerol via oxygen, while sphingolipids attach to nitrogen or carbon directly.
- Sphingolipids attached to nitrogen can include phosphocholine (choline is a neurotransmitter).
- They can also have glucose or multiple sugars attached.

Summary Slide Review

Triglycerides: Typical fats with glycerol and fatty acids.
Membrane lipids have sugars (glycolipids) attached.
Sphingolipids have choline or sugar (glycosphingolipids).
Lipid shapes affect membrane properties (micelle vs. bilayer formation).
- Trapezoidal shapes form micelles.
- Cylindrical shapes form bilayers.

Stereochemistry Review

Organic chemistry uses "s" and "r" for configuration; "l" is minus, "d" is plus.
Assignment of groups goes by atomic number.
- Hydrogen has the lowest priority.
- Oxygen has atomic number 8 (highest priority if directly attached to the central carbon).
- For carbons, distinguish by going to the next layer of atoms.
Example Stereochemistry Assignment:
- Prioritization Example:
  1. $OH$ (highest priority due to oxygen)
  2. $CHO$ (aldehyde; double-bonded oxygen counts twice)
  3. $CH_2OH$
  4. $H$ (lowest priority)
- If 1-2-3 is counterclockwise, it's "l", but flip if hydrogen is facing you.
- Fischer projections: Carbon 1 on top, carbon 3 on the bottom; OH on the right indicates "d".
Glycerol is achiral, but chemical modifications can make it chiral.
- Prochiral: Modifying glycerol can introduce chirality.
Deuterium Example:
- Even changing $H$ to deuterium ( $^2H$ ) changes priority due to mass difference.
- Thumb points in direction of $H$ , fingers curl from $OH$ to $CH<em>2O^2H$ to $CH</em>2OH$ to determine handedness.

Chirality and Prochirality

Glycerol is prochiral, meaning it can become chiral upon modification.
Adding a phosphate group ( $PO_4$ ) can make it chiral.
If $OH$ is on the right in the Fischer projection, it's "d" or R configuration.

Glycerol Modifications

Reduction can convert the top group to $CH_2OH$ .
The configuration can flip depending on the modification.

Glycolysis Preview

Glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate are formed.
The lecture previews metabolic pathways.

Enzymes and Stereochemistry

Enzymes typically end in "-ase".
Kinases add phosphate groups (e.g., glycerol kinase).
Glycerol-3-phosphate (G3P) is formed.
Coenzyme A (CoA) carries acetyl groups.
- Acetyl group: Two carbons; "R" can be a long chain in lipids.
Lisophosphatidate forms micelles.

Lipid Synthesis Steps

Acyl groups are added to glycerol.
Hydrolysis uses water to remove phosphate, facilitated by phosphatases.
Acyl transferases add acyl groups, with different names based on their sequential action.

Tetrahedral Shape Importance

Tetrahedral shape is crucial for life's functionality due to its three-dimensional properties.
Enzymes are highly specific to enantiomers.

Enzyme Binding

Enzymes bind specifically to the correct enantiomer through complex formation.
Catalytic activity adds a phosphate group.

Prochiral Carbons and Phosphorylation

Review of stereochemistry with identical groups (no stereocenter yet).
Enzyme orientation determines which group is phosphorylated.
Pro-R group phosphorylation leads to a specific product.

Isoprenoids

Isoprenoids are units shown in red with potential resonance.
Multiple isoprenoid units can connect linearly or in other ways.
Phosphate groups can attach.

Isoprenoid Examples

Farnesyl (C15) with two phosphate groups.
Tail-to-tail attachment to form 30-carbon structures.
Enzymes and pathways involved in synthesis.
Precursors to cholesterol and steroids.

Isoprenoids as Building Blocks

Found in vitamins A, E, K, and D.

Terpenes

Related to isoprenoids and commonly volatile.
Used by insects for attraction or spore dispersal.

Review of Lipid Shapes

Single-chain amphiphiles like detergents.
Double-chain lipids like phospholipids form bilayers.
Cholesterol has a different shape to fit into bilayers.

Lipid Properties Overview

Hydrophobic, but can be modified to be slightly hydrophilic.
Storage lipids: Triacylglycerols.
Glycerolipids and sphingolipids are important for self-assembled bilayers.
Isoprenoid units and stereochemistry are crucial.
Enzymes are involved in lipid metabolism.

Micelle Formation

Amphiphilic molecules (hydrophilic head, hydrophobic tail) in water.
Charged side prefers water; hydrophobic side avoids water.
Micelles form to sequester hydrophobic chains from water.

Thermodynamics of Micelle Formation

Equilibrium between monomers and micelles.
Critical micelle concentration (CMC) is the threshold for micelle formation.
Delta H should be negative (exothermic).
Entropy is negative (less disorder).

Critical Micelle Concentration (CMC)

Concentration of monomer in solution.
Adding detergent lowers the free concentration as micelles form.
Beyond CMC, the monomer concentration remains constant.

Saturation

Similar to saturation in other systems like NaCl or oil in water.
Phase separation of oil and water.
Gibbs free energy (delta G) calculations.

Delta G Calculations

Delta G total = delta G (hydrocarbon in water) - delta G (hydrocarbon in lipid)
Breakdown into logarithmic terms.
Ratio of water-soluble to lipid concentrations.

Equilibrium Constant

Equilibrium constant (Keq) = [products]/[reactants]
Delta G related to Keq via -RTln(Keq).
Can calculate delta G at different concentrations.

Bilayer Formation

Phospholipids form bilayers at saturating concentrations.
Vesicles and liposomes are formed.
Cross-sections show protein incorporation into bilayers.

Liposome Diameters

Varying sizes: small (<25nm), intermediate (100nm), large (250-1000nm).

Micelles vs. Bilayers

Delta G calculations guide formation.
Curvature vs. cylinder shapes depend on lipid properties.

Self-Assembly

Lipids with charged groups self-assemble into amphiphiles in water.
Exclusion of hydrophobic regions.
Thermodynamics driven by enthalpy.
Entropy decreases during micelle formation.

Conserved Domains in Proteins

Conserved domains are unchanged throughout evolution.
Important for function and survival.
ATP synthase is an example of a highly conserved protein.
Conserved domains indicate crucial structural or functional elements.

Aggregate Phase Behavior

Depends on attractive vs. repulsive forces, pH, and concentration.
Shapes can change (hexagonal, micellar, lamellar).
Rheological relevance: Crowding influences shape.

Lipid Bilayer Composition

Complex, containing proteins (integral and peripheral), cholesterol, and glycolipids.
Alpha helices in conserved domains.
Varying lipid composition across different cell types and organelles.

Lipid Types in Cells

Different types and amounts in different organelles.
Glycerophospholipids are predominant, followed by sphingolipids.
Examples: PE, PC, PS, sphingomyelin, cholesterol.

Membrane Synthesis and Distribution

Synthesized in the smooth endoplasmic reticulum (ER).
Cannot cross the cytosol, so concentrations vary.
Lipids can flip-flop between membrane sides.

Diffusion

Flip-flop diffusion measures movement across the membrane.

Recap

This should be a review of structure and shapes, enzymes are coming next.
All above information and explanation should be reviewed.

Exam Review

Chapters 1, 3, 4, 5, 6, 7, 8, and 9 will be covered in the exam.