Section L: Lecture notes: Biological Membranes

Lipids: Objectives

Objectives:

• Biological roles of lipids

• Structure and properties of storage lipids

• Structure and properties of membrane lipids

• Structure and properties of signaling lipids

4 General Types of Membrane Lipids: Phospholipids

Have hydroponic regions composed of two fatty acids joined to glycerol or sphingosine

4 General Types of Membrane Lipids: Glycolipids

Contain a simple sugar or a complex oligosaccharide at the polar ends

4 General Types of Membrane Lipids: Archaeal Tetraether Lipids

Have two very long alkyl chains ether-linked to glycerol at both ends

• Archaebacteria: Bacteria that live in very extreme harsh environments like really high temperatures, really high salt conditions, or pH extremes.

• Their biological membranes need to be extra strong, more than humans, b/c they live in these extreme environments.

4 General Types of Membrane Lipids: Sterols

Compounds characterized by a rigid system of four fused hydrocarbon rings

• Ex: Cholesterol

Glycerophospholipids (phosphoglycerides)

Membrane lipids in which two fatty acids are attached in ester linkage to the first and second carbons of glycerol, and a highly polar or charged group is attached through a phosphodiester linkage to the third carbon

• Most important and abundant structural component of biological membranes

• Similar to TAG (triacylglycerols)

  • But 1 key difference: Glycerophospholipids has the 3rd hydroxyl groups of that glycerol backbone is NOT attached to another fatty acid (see highlighted blue “x” in picture). Instead, an “x” is attached to the phosphate. (x = additional types of chemicals). This is called a “Head-group”.

• Amphipathic molecules => self-assemble & come together in these belayers that form biological membranes.

Platelet-Activating Factor

an ether lipid that serves as a potent molecular signal

• releases from leukocytes called basophils

• stimulates platelet aggregation and serotonin release

• plays a role in inflammation and the allergic response

• Signaling molecule

Sphingolipids

large class of membrane phospholipids and glycolipids

• have a polar head group and two nonpolar tails

  • Sphingosine itself is like a built-in fatty acid

• contain no glycerol

• contain one molecule of the long-chain amino alcohol sphingosine or one of its derivatives

• Fatty acids that get attached are typically saturated FA

• Linkage: amide

• Not all sphingolipids = phospholipids

  • Most of them are not

Glycoplipids

Head group is a sugar

3 Type of Glycolipids: Cerbrosides

Have a single sugar linked to ceramide

• those with galactose are found in the plasma membranes of cells in neural tissue

• those with glucose are found in the plasma membranes of cells in nonneural tissues

3 Type of Glycolipids: Globosides

glycosphingolipids with 2+ (more than 1) sugars, usually D-glucose, D-galactose, or N-acetyl-D-galactosamine

Cerebrosides & Globosides are…

Neutral Glycolipids

• they have no charge at pH 7

*Note: Cerebrosides & Globosides have simple sugars

4 Type of Glycolipids: Gangliosides

JUST KNOW:

• Not neutral

  • Complex branch sugars, where we have this negatively charged head group.

Extra info:

Have oligosaccharides as their polar head groups and 1+ residues of N-acetylneuraminic acid (Neu5Ac), a sialic acid, at the termini

• 1 sialic acid residue = GM (M for mono-) series

• 2 sialic acid residues = GD (D for di-) series

• 3 sialic acid residues = GT (T for tri-) series (and so on)

Sphingomyelins

Subclass of sphingolipids that contains phosphocholine or phosphoethanolamine as their polar head group

Sphingolipids @ cell surfaces are sites of biological recognition

• Glycolipids, with these sugar head-groups, are typically on the outer leaflet of the membrane where sugars would face outside the cell.

• These sugars are recognition sites for different types of molecules to bind

• Some sphingolipids are glycolipids — but not all.

  • (Similar to how some sphingolipids are phospholipids — but not all.)

• Expression of glycosyltransferase (enzyme) = attaches sugars to head-group

  • No expression = no sugar attachment => O-antigen

• Just know: The head-group substituents differ because of this enzyme

Phospholipids & Sphingolipids are degraded in Lysosomes

• phospholipases of the A type remove one of the two fatty acids

• lysophospholipasesremove the remaining fatty acid

• lysosomal enzymes catalyze the stepwise removal of sugar units of gangliosides

• Many types of enzymes that break both Phospholipids & Sphingolipids

Abnormal Accumulations of Membrane Lipids-lysosomal storage diseases

Genetic defects in any of these hydrolytic enzymes leads to the accumulation of gangliosides in the cell

• Need glycospingolipids, BUT they need it at the right amount, right place, at the right time.

• Too much leads to buildup and causes diseases

Sterols Have Four Fused Carbon Rings

• sterols = structural lipids present in the membranes of most eukaryotic cells 

• steroid nucleus: consists of four fused rings; almost planar; relatively rigid

• cholesterol = major sterol in animal tissues

  • amphipathic

  • polar head group

  • nonpolar hydrocarbon body

  • membrane constituents

  • similar to stigmasterol in plants and ergosterol in fungi

Physiological Role of Sterols

• Cholesterol as structural component of membranes

  • modulate fluidity and permeability

  • thicken the plasma membrane

  • no sterols in most bacteria

• Mammals obtain cholesterol from food or synthesizeit de novo in the liver.

• Cholesterol, bound to proteins, is transported to tissues via blood vessels.

  • Cholesterol in low-density lipoproteins (LDL) tends to deposit and clog arteries.

• Many hormones are derivatives of sterols.

  • Male and female sex hormones

Sterols Serve as Precursors for Products with Specific Biological Activities

bile acids = polar derivatives of cholesterol that emulsify dietary fats in the intestine to make them more readily accessible to digestive lipases

Steroid Hormones Carry Messages between Tissues

• Signaling lipids

• Steroids = oxidized derivates of sterols

  • lack the alkyl chain attached to ring D of cholesterol

  • more polar than cholesterol

• Steroid hormones move through the bloodstream (on protein carriers) to target tissues

• Binding to highly specific nuclear hormone receptor proteins in the nucleus triggers changes in gene expression

Steroids Derived From Cholesterol

Testosterone, Cortisol, Prednisone (synthetic steroids), β-Estradiol, Aldosterone, Brassinolide (plants)

Biologically Active Lipids

• Are present in much smaller amounts than storage or structural lipids

• Play vital roles as signaling molecules between nearby cells

• Lipid-soluble vitamins (A, D, E, and K)

Phosphatidylinositol 4,5-Bisphosphate (PIP2)

in the cytoplasmic, inner leaflet of plasma membranes

• serves as a reservoir of messenger molecules that are released in response to extracellular signals

  • phospholipase C hydrolyzes PIP2 to the second messengers IP3 and diacylglycerol (DAG), which in turn control downstream signaling effector enzymes or channels

• Inositol sugar head-group

• Glycerophospholipid

• Signaling lipid

Eicosanoids Carry Messages to Nearby Cells

Paracrine hormones, substances that act only on cells near the point of hormone synthesis instead of being transported in the blood

• Paracrine: act locally on cells near where they’re made

• Signaling lipid

• PUFA (polyunsaturated fatty acids)

• Involved in:

  • reproductive function

  • inflammation, fever, and pain associated with injury or disease

  • formation of blood clots

  • regulation of blood pressure

  • gastric acid secretion

Eicosanoids Are Derived From Arachidonic Acid

4 major classes of eicosanoids:

1. prostaglandins

2. thromboxanes

3. leukotrienes

4. lipoxins

Prostaglandins (PG)

Class of eicosanoids that contain a five-carbon ring

• array of functions:

  • stimulate contraction of the smooth muscle of the uterus

  • affect blood flow to specific organs, the wake-sleep cycle, and the responsiveness of certain tissues to hormones

  • elevate body temperature and cause inflammation and pain

 

Thromboxanes (TX)

Class of eicosanoids that have a six-membered ring containing an ether

• produced by platelets (also called thrombocytes)

• act in the formation of blood clots and reduction of blood flow to the site of a clot

Vitamins A and D Are Hormone Precursors

• vitamins = compounds that are essential to the health of humans and other vertebrates but cannot be synthesized

  • So we get vitamins from diet

• fat-soluble vitamins include the groups A, D, E, and K

  • “Fat kid KADE”

Vitamin D3 Production and Metabolism

calcitrol = hormone that regulates calcium uptake in the intestine and calcium levels in the kidney and bone

All-Trans-Retinoic Acid

• signaling lipid

• vitamin A1 (all-trans-retinol) = acts in processes of development, cell growth and differentiation, and vision

• vitamin A1 or β-carotene can be converted enzymatically to all-trans-retinoic acid

• all-trans-retinoic acid = retinoid hormone that acts through a family of nuclear receptor proteins to regulate gene expression

Vitamins E and K and the Lipid Quinones Are Oxidation-Reduction Cofactors

• vitamin E = collective name for a group of lipids called tocopherols

• tocopherols = hydrophobic compounds that contain a substituted aromatic ring and a long isoprenoid side chain

  • associate with cell membranes, lipid deposits, and lipoproteins

  • biological antioxidants

Vitamin K

vitamin K = contains an aromatic ring that undergoes a cycle of oxidation and reduction during the formation of active prothrombin, a blood plasma protein essential in blood clotting

Ubiquinone and Plastoquinone

Ubiquinone (coenzyme Q) and plastoquinone = isoprenoids that function as lipophilic electron carriers in the oxidation-reduction reactions that drive ATP synthesis in mitochondria and chloroplasts, respectively

Dolichols Activate Sugar Precursors for Biosynthesis

dolichols = isoprenoid alcohols that activate and anchor sugars to cellular membranes

• sugar groups are then used in the synthesis of complex carbohydrates, glycolipids, and glycoproteins

• allow attached sugars to participate in sugar-transfer reactions

Working with lipids:  A Commonly Used lipid Extractant is a Mixture of Chloroform, Methanol, and Water

mixture separates into two phases: methanol/water (top phase) and chloroform (bottom phase)

• lipids remain in the chloroform layer

• more polar molecules (proteins and sugars) partition into the methanol/water layer

Adsorption Chromatography Separates Lipids of Different Polarity

lipids in mixtures can be separated based on their polarity and interactions with polar materials such as silica, using adsorption chromatography methods such as HPLC or TLC

Lipids Summary

• lipids are a structurally and functionally diverse class of molecules that are poorly soluble in water

• triacylglycerols are the main storage lipids

• phospholipids are the main constituents of membranes

• Sphingolipids (& Glycosphingolipids) play roles in structure and in cell recognition

• cholesterol is both a membrane lipid and the precursor for steroid hormones

• some lipids carry signals from cell to cell and from tissue to tissue

Membranes and Transport: Objectives

Objectives:

• The function of biological membranes

• The structure and composition membranes

• Physical properties and dynamics of membranes

• Structure and function of membrane proteins

• Transport across biological membranes

The Lipid Bilayer Is Stable in Water

Membrane = Lipid bilayers

• Glycerophospholipids, Dphingolipids, and Sterols:

  • virtually insoluble in water

  • spontaneously form microscopic lipid aggregates when mixed with water

• Hydrophobic interactions = the clustering of hydrophobic molecule surfaces in an aqueous environment to find the lowest-energy environment by reducing the hydrophobic surface area exposed to water

Vesicle Formation

Vesicle (liposome) = forms spontaneously when a bilayer sheet folds back on itself to form a hollow sphere

• In simpler words: lipids bilayer sphere w/ aqueous cavity

Functions of Biological Membranes

• Compartmentalization

• permit shape changes that accompany cell growth and movement

• permit exocytosis, endocytosis, and cell division

• serve as molecular gatekeepers (selective barrier)

Bilayer Architecture Underlies the Structure and Function of Biological Membranes

Fluid mosaic = pattern formed by individual lipid and protein units in a membrane

• pattern can change while maintaining the permeability membrane

• most membrane proteins can move freely within the lipid bilayer, hence “fluid” in “fluid mosaic”

The Composition of Membranes

• Lipid composition of membranes varies by:

  • organisms

  • tissues

  • organelles

• Ratio of lipid to protein varies

  • type of phospholipid varies

  • abundance and type of sterols varies

  • lack of sterols in prokaryotes

  • cholesterol predominant in the plasma membrane, virtually absent in mitochondria

  • galactolipids abundant in plant chloroplasts but almost absent in animals

Where are Sphingolipids tend to be more enriched?

Outer leaflet in plasma membrane

• sugar groups face outside of cell

Where are Glycerophospholipids tend to be more enriched?

Inner leaflet of plasma membrane facing cytosol

What can pass through membrane?

• Gases

  • CO2

  • N2

  • O2

• Small uncharged polar molecules

  • Ethanol

• Water

• Urea

• Large uncharged polar molecules

  • Glucose

• Ions

  • K+, Mg2+, Ca2+, Cl-, HCO3-, HPO4^2-

• Charges polar molecules

  • Amino Acids

  • ATP

  • Glucose 6-phosphate

Acyl Groups in the Bilayer Interior Are Ordered to Varying Degrees

• liquid-ordered (Lo) state = gel-like state in which all types of motion of individual molecules are strongly constrained

• liquid-disordered (Ld) state = state in which individual hydrocarbon chains are in constant motion (lateral and rotational)

Organisms Can Adjust the Membrane Composition

• Membrane fluidity is determined mainly by the fatty acid composition and melting point.

• More fluid membranes require shorter and more unsaturated fatty acids.

  • Melting temperature decreases as double bonds are added.

  • Melting temperature increases with length of saturated fatty acids.

• At higher temperatures, cells need more long, saturated fatty acids.

• At lower temperatures, cells need more unsaturated fatty acids.

Transbilayer Movement of Lipids Requires Catalysis

• Phospholipids can freely bend/flex, rotate about their    axis, and laterally diffuse in    bilayers

• In contrast, transbilayer (“flip-flop”) movement has a large, positive free-energy change (unfavored)

• membrane proteins facilitate the translocation of individual lipid molecules and maintain asymmetry

*No energy source needed = goes down its concentration gradient

*Energy source needed = goes AGAINST its concentration gradient

Functions of Proteins in Membranes

• Receptors: detecting signals from outside

  • light (opsin)

  • hormones (insulin receptor)

  • neurotransmitters (acetylcholine receptor)

  • pheromones (taste and smell receptors)

• Channels, carriers, transporters, pumps, flippases, etc. (nomenclature can be confusing)

  • nutrients (maltoporin)

  • ions (K-channel)

  • neurotransmitters (serotonin reuptake protein)

• Enzymes

  • lipid biosynthesis (some acyltransferases)

  • ATP synthesis (F0F1 ATPase/ATP synthase)

  • proteases

SNARE Proteins in vesicle fusion

• SNAREs (snap receptors) = family of proteins

  • v-SNAREs = SNAREs in the cytoplasmic face of the intracellular vesicle

  • t-SNAREs = SNAREs in the target membrane with which the vesicle fuses

Membranes: Summary

• Lipids can form micelles, bilayers, and liposomes

• Membranes are composed of various lipids and proteins

• Properties of the bilayer depend on the lipid composition, which varies strongly from:

  • organism to organism

  • tissue to tissue

  • organelle to organelle

• membrane proteins are found in three major classes and play a variety of structural and functional roles, especially in the transport of solutes across the membrane

• Passive transport allows passage with concentration gradient

• active transport of solutes across membranes requires energy but can be accomplished in many different ways