LIPIDS

### INTRODUCTORY BIOCHEMISTRY

General Characteristics of Lipids

• Definition: Lipids are essential components of all living organisms.
• Solubility: They are water insoluble organic compounds.

- Hydrophobic Nature: Lipids can be categorized as hydrophobic (nonpolar) or amphipathic (containing both nonpolar and polar regions).

Functions of Lipids

• The biological functions of lipids reflect their diverse chemistry.

1. Structural Components: Serve as structural components of biological membranes.
2. Energy Storage and Transport: Function as storage and transport forms of metabolic fuel.
3. Protection: Provide a protective coating on the surface of many organisms.
4. Cell Surface Components: Involved in cell recognition, species specificity, and tissue immunity.
5. Insulation Barriers: Act as insulation barriers.
6. Biochemical Roles: Include some vitamins and hormones.

7. Precursor Role: Serve as precursors of other important substances.

Structural Relationship of Major Lipid Classes

• Major Classes of Lipids:
  • Eicosanoids
  • Fatty Acids
  • Triacylglycerols
  • Waxes
  • Sphingolipids
  • Glycerophospholipids
  • Steroids
  • Lipid Vitamins
  • Terpenes
  • Isoprenoids

- Glycosphingolipids

FATTY ACIDS

Structure and Nomenclature

• Definition: A fatty acid (FA) is a long-chain aliphatic carboxylic acid.
• Key Characteristics:
  • Possess a long hydrocarbon chain and a terminal –COOH group.
  • Differences between FAs:
  1. Length of the hydrocarbon tails.
  2. Degree of unsaturation (presence of double bonds).
  3. Position of the double bonds within the chain.
• Carbon Count: FAs can contain between 4 to 30 carbon atoms, with the most common chain lengths being 12 to 20 carbons and predominating at 16 to 18 carbons.
  • Odd-numbered FAs are found in traces in terrestrial animals and are more abundant in marine organisms.
• Nomenclature:
  • IUPAC nomenclature starts the carboxyl carbon at C-1.

- Common nomenclature uses α, β, γ, δ, ε, etc. starting from C-1, and the carbon farthest from the carboxyl is termed ω.

Common Fatty Acids

| Arachidonate | all cis-5,8,11,14-Eicosatetraenoate| 20 | 4 | -49 | CH3(CH2)4(CH=CHCH2)4(CH2)2COO |

Characteristics of Saturated vs. Unsaturated Fatty Acids

• Unsaturated fatty acids predominate over saturated fatty acids, especially in organisms living in low temperatures.
• Melting Point Influences: Melting points of fatty acids are affected by chain length and degree of unsaturation.
• Classification of Unsaturated Fatty Acids:
  • Monounsaturated fatty acids are called monoenoic, while polyunsaturated fatty acids are termed polyenoic.
  • Generally, one double bond in polyenoic fatty acids is situated between C9 and C10, while additional double bonds occur towards the methyl-terminal end of the chain.
  • Most double bonds in polyunsaturated fatty acids are in the cis configuration.

- Note that the double bonds in polyunsaturated fatty acids are typically separated by a methylene group, indicating that they are not conjugated.

Shorthand Notation

• The position of double bonds is indicated by Δn, where n specifies the lower-numbered carbon of each pair.
• Example: 20:4Δ5,8,11,14 indicates a total number of carbons and double bonds along with their positions.
• Structures of three common C18 fatty acids illustrated:
  • Linolenate: 18:3(Δ9,12,15)
  • Oleate: 18:1(Δ9)

- Stearate: 18:0

Working with Lipids: Gas Liquid Chromatography

• Purpose: Used for analyzing mixtures of fatty acids by separating volatile compounds according to their solubility differences in stationary liquid phase.
• The mobile phase includes an inert gas (such as argon), while the stationary phase consists of a small quantity of liquid within the chromatography column, typically made from a coiled tube.
• Process:
  1. Fatty acids are converted into volatile methyl esters.
  2. The ester mixture is injected into the heated column.
  3. The sample is vaporized and mixes with the inert gas.
  4. The gas mixture moves through the stationary phase under pressure, emerging into a detection device that records the presence and quantities of eluted substances.

Typical Separation

- Representation of a typical separation of volatile methyl esters of fatty acids by gas-liquid chromatography.

TRIACYLGLYCEROLS (TGs)

Structure

• Definition: Triacylglycerols are composed of three fatty acyl residues esterified to a glycerol (a 3-carbon sugar alcohol).
• Types:
  • Simple TG: Contains the same fatty acid in all three positions. For example, triolein has three oleic acid residues.
  • Mixed TG: Most naturally occurring TGs have different fatty acids attached.

Energy Storage and Insulation

• Significance: Triacylglycerols are the most abundant lipid family and serve as vital energy stores, providing 2-3 times the energy compared to proteins or carbohydrates.
• Physical Protection: Provide protection and thermal insulation for various body organs.
• Classification:

- Solids at room temperature are referred to as fats, while liquids are termed oils.

GLYCEROPHOSPHOLIPIDS

Membrane Lipids

• Role: They are the most abundant lipids in biological membranes, also called phosphoacylglycerols, phosphoglycerides, or simply phospholipids.
• Structure: Possess a glycerol-3-phosphate backbone where the -OH group of C-3 is esterified to phosphoric acid, and the other two -OH groups are esterified to fatty acids creating phosphatidates.

Characteristic Properties

• Polar Head Group: The phosphoglycerides have a polar head group, designated as X-OH, where -OH is esterified to the phosphoric acid.
• Amphipathicity: They are polar lipids, differing in the size, shape, and charge of their polar head groups.
• Diversity: Each type has various chemical species depending on the esterified fatty acids.

- Generally, one saturated FA esterified at C-1 and one unsaturated FA at C-2 of glycerol-3-phosphate.

Examples of Glycerophospholipid Structures

• Commonly occurs with heads such as:
  • Phosphatidylethanolamine
  • Phosphatidylserine
  • Phosphatidylcholine

- These molecules exhibit nonpolar tails which are hydrophobic.

Plasmalogens

• Definition: Plasmalogens are ether-linked fatty acids where the C-1 hydrocarbon substituent is attached via a vinyl ether linkage (not an ester linkage).
• Occurrence: Comprising 23% of glycerophospholipids in the human central nervous system.
• Found in peripheral nerve and muscle tissue membranes.

Phospholipases

• Function: Phospholipases are utilized to dissect glycerophospholipid structures.

- Phospholipase A2 is noted for its presence in pancreatic juice and in venoms of certain snakes, bees, and wasps.

SHINGOLIPIDS

Membrane Lipids

• Importance: Serve as crucial membrane components within both plant and animal cells, notably abundant in the central nervous system's tissues.
• Structural Backbone: Sphingosine (trans-4-sphingenine) serves as the structural backbone.

- Ceramides: Fatty acyl groups link to the C-2 of sphingosine via an amide bond, constituting the precursors of sphingolipids.

Types of Sphingolipids

1. Sphingomyelins: Contain phosphocholine or phosphoethanolamine esterified to C-1 of ceramide.
2. Neutral Glycosphingolipids: Feature neutral sugar residues attached via a glycosidic linkage to C-1 of ceramide. The simplest examples are cerebrosides.

3. Acidic Glycosphingolipids: Include oligosaccharide chains that have sialic acid (NeuNAc) attached to ceramide.

Cerebrosides and Gangliosides

• Cerebrosides: Considered the simplest neutral glycosphingolipids, abundant in nerve tissues, comprising about 15% of myelin sheath lipids.
• Gangliosides: Most complex sphingolipids containing oligosaccharide groupings with sialic acid residues.
• Critical to cell surface membranes, gangliosides amount to about 6% of brain lipids and are vital for cell recognition and tissue differentiation, as well as serve as receptors for bacterial toxins.

- Disorders in ganglioside breakdown can lead to hereditary diseases like Tay-Sachs disease due to GM2 accumulation.

WAXES

General Characteristics

• Definition: Waxes are nonpolar esters formed from long-chain fatty acids and long-chain monohydroxylic alcohols or sterols.
• Example: Myricyl palmitate is a major component of beeswax, highly water-insoluble and possessing a high melting point.

- Function: Act as protective waterproof coatings on plant leaves, fruits, animal fur, feathers, and insect exoskeletons.

ISOPRENOIDES

Definition and Role

• Definition: Terpenes are built from multiples of the five-carbon isoprene and may manifest as linear or cyclic compounds.
• Occurrence: Abundant in plants, many having distinct odors and flavors. Terpenes are intermediates in steroid biosynthesis, and lipid vitamins (Vitamins A, D, E, K) are isoprenoid derivatives.

Classifications of Terpenes

• Monoterpenes: Menthol (mint oil), camphor (camphor oil).
• Diterpenes: Phytol (chlorophyll component).
• Triterpenes: Squalene (cholesterol synthesizer).
• Tetraterpenes: Carotenoids like β-carotene (Vitamin A precursor).

- Polyterpenes: Example includes natural rubber.

STEROIDS

• Structure: Steroids are derived from the saturated tetracyclic hydrocarbon perhydrocyclopentanophenanthrene, consisting of four fused rings (three six-carbon rings - A, B, C and one five-carbon ring - D).
• Cholesterol: The most prevalent steroid in animals, is a sterol characterized by a hydroxyl group at C-3 and an 8-carbon branched aliphatic side chain at C-17.

- Role of Cholesterol: Modulates fluidity of mammalian cell membranes, serving as an important determinant for membrane properties. Very hydrophobic.

Cholesterol as a Precursor

• Functions of Cholesterol:
  • Precursor for steroid hormones regulating physiological functions (e.g., testosterone, progesterone).

- Metabolic precursor for bile salts that assist in emulsifying and absorbing lipids in intestines.

Other Sterols

• Plants: Contain little cholesterol; stigmasterol and β-sitosterol are primary sterols.
• Yeast and Fungi: Have ergosterol.

- Prokaryotes: Mainly low sterol content, with exceptions like mycoplasmas.

Cholesteryl Esters

• Formation: Cholesterol converted to cholesteryl esters for cellular storage or transport in blood.

- Characteristics: Cholesteryl esters are more hydrophobic than cholesterol due to C-3 OH being esterified to a fatty acid, transported in blood plasma by lipoproteins.

EICOSANOIDS

• Definition: Eicosanoids are oxygenated derivatives of C20 polyunsaturated fatty acids (e.g., arachidonic acid, 20:4Δ5,8,11,14).
• Produced by almost all mammalian cells, except red blood cells.
• Aspirin's Role: Aspirin irreversibly inhibits cyclooxygenases, alleviating pain, fever, and inflammation by inhibiting prostaglandin synthesis.

Types of Eicosanoids

1. Prostaglandins: Have a cyclopentane ring. For example, Prostaglandin E2 can cause constriction of blood vessels.
2. Thromboxanes: Contain a six-carbon ring with an ether, e.g., Thromboxane A2, involved in blood clot formation.
3. Leukotrienes: Contain three conjugated double bonds; for instance, Leukotriene D4 mediates smooth muscle contraction and bronchial constriction in asthmatics.

Functions of Eicosanoids

• Eicosanoids act as local regulators and perform hormone-like regulatory actions at low concentrations, influencing:
  • Inflammatory responses (e.g., arthritis, psoriasis).
  • Pain and fever production.
  • Induction of labor.
  • Regulation of sleep/wake cycle.

- Blood pressure and clot formation regulation.

LIPOPROTEINS

Overview

• Lipids associate with specific proteins to form lipoprotein systems categorized into two main types: transport lipoproteins and membrane systems.
• In these lipoprotein systems, lipids and proteins are not covalently joined but interact through hydrophobic forces between the lipid's nonpolar portions and protein components.
• Lipoproteins function as transport vehicles in blood plasma for insoluble molecules like triacylglycerols, cholesterol, and cholesterol esters.

Classification of Lipoproteins

• Five categories based on functional and physical properties:
  • Chylomicrons: The largest lipoproteins transport dietary TGs and cholesterol from the intestines to tissues.
  • Very Low-Density Lipoproteins (VLDL): Transport endogenous TGs and cholesterol from the liver.
  • Intermediate Density Lipoproteins (IDL): Involved in transporting cholesterol and triglycerides.
  • Low-Density Lipoproteins (LDL): Known as "bad" cholesterol, can increase atherosclerosis risk by delivering cholesterol to peripheral tissues.
  • High-Density Lipoproteins (HDL): Transport cholesterol from peripheral tissues to the liver, potentially protecting against atherosclerosis.

Molecular and Physical Properties of Lipoproteins

| HDL | 0.18-0.36 | 50-120 | 1.063-1.210 | 45-55 | 5-10 | 15-25 | 25-30 |

Specific Lipoprotein Functions

• Chylomicrons: Largest lipoproteins, transport dietary TGs and cholesterol from the intestine to tissues, present post-meal.
• LDLs: Enriched with cholesteryl esters, deliver lipids tissues while increasing atherosclerosis risk.

- HDLs: Facilitate return of excess peripheral liver, offering protective effects against arterial diseases.

Summary of Lipoprotein Metabolism

• Process:
  1. Dietary lipids enter the intestine.
  2. The liver synthesizes triacylglycerols, cholesterol, and cholesteryl esters.
  3. Chylomicrons transport lipids from the intestine to tissues.
  4. VLDLs, IDLs, and LDLs distribute lipids from the liver to peripheral tissues.
  5. HDLs collect excess lipids and transport them back to the liver.