Introduction to Lipids and Fatty Acids

Functions of Lipids

Lipids are a diverse group of biomolecules essential for cellular structure, energy storage, and signaling.

• Energy Storage: Lipids, especially triacylglycerols, store energy efficiently due to their hydrophobic nature.

• Structural Components: Lipids form the basis of biological membranes (phospholipids, cholesterol).

• Signaling Molecules: Some lipids act as hormones or second messengers (e.g., steroid hormones).

• Insulation and Protection: Lipids provide thermal insulation and protect organs.

Structure of Fatty Acids

Fatty acids are carboxylic acids with long hydrocarbon chains. Their properties depend on chain length and degree of saturation.

• Saturated Fatty Acids: No double bonds; straight chains; higher melting points.

• Unsaturated Fatty Acids: One or more double bonds; kinked chains; lower melting points.

• Mono-unsaturated: One double bond.

• Poly-unsaturated: Two or more double bonds.

• Cis Fatty Acids: Hydrogen atoms on the same side of the double bond; causes chain bending.

• Trans Fatty Acids: Hydrogen atoms on opposite sides; straighter chains, higher melting points.

IUPAC Naming: Fatty acids are named based on chain length and number/location of double bonds. Numbering can start from the carboxyl (Δ) or methyl (ω) end.

• Example: Oleic acid is 18:1Δ9 (18 carbons, 1 double bond at carbon 9).

Melting Temperature (Tm): Increases with chain length and decreases with unsaturation.

Triacylglycerols and Phospholipids

Triacylglycerols

Triacylglycerols (TAGs) are esters of glycerol and three fatty acids, serving as the main energy storage form in animals.

• Structure: Glycerol backbone with three fatty acid chains.

• Energy Storage: Highly reduced, yielding more energy per gram than carbohydrates.

• Melting Temperature: Depends on fatty acid composition; more saturated = higher Tm.

Glycerophospholipids

Major components of cell membranes, consisting of glycerol, two fatty acids, and a phosphate-containing head group.

• Common Head Groups: Choline, ethanolamine, serine, inositol.

Phospholipases

Enzymes that cleave specific bonds in phospholipids, important in membrane remodeling and signaling.

• Site of Action: Phospholipase A1, A2, C, and D each target different bonds.

Major Classes of Lipids

• Plasmalogens: Ether-linked phospholipids, abundant in heart and brain.

• Sphingolipids: Based on sphingosine backbone; important in neural tissue.

• Ceramides: Sphingosine + fatty acid; precursor to sphingolipids.

Cholesterol and Lipoproteins

Structure and Function of Cholesterol

Cholesterol is a sterol with a rigid ring structure, essential for membrane fluidity and precursor to steroid hormones.

Lipoprotein Particles

Lipoproteins transport cholesterol and other lipids in the blood.

• Basic Composition: Core of triglycerides and cholesterol esters, surrounded by phospholipids and apolipoproteins.

• Types:

  • Chylomicrons: Transport dietary lipids from intestine.

  • LDL (Low-Density Lipoprotein): Delivers cholesterol to tissues; "bad cholesterol".

  • HDL (High-Density Lipoprotein): Removes cholesterol from tissues; "good cholesterol".

Biological Membranes

Functions and Structure

Membranes compartmentalize cells, regulate transport, and facilitate signaling.

• Forces Holding Membranes: Hydrophobic effect, van der Waals forces.

• Monolayers vs Bilayers: Bilayers form spontaneously due to amphipathic nature of phospholipids.

• Self-Annealing: Membranes can repair themselves.

• Lateral vs Transverse Diffusion: Lateral (within leaflet) is fast; transverse (flip-flop) is slow.

• Limited Permeability: Only small, nonpolar molecules cross easily.

• Asymmetry: Different lipid composition in inner vs outer leaflet.

• Factors Affecting Fluidity: Fatty acid length, saturation, cholesterol content.

Concentration and Charge Gradients

Membrane Gradients

Membranes generate concentration and charge gradients essential for cellular function.

• Free Energy of Transport: Calculated using concentration and charge differences.

Equation:

• R: Gas constant

• T: Temperature

• z: Charge of ion

• F: Faraday constant

• \Delta \Psi: Membrane potential

Membrane Transport

Types of Transport

Membrane transport can be passive or active, involving various proteins.

• Simple Diffusion: Movement of small, nonpolar molecules.

• Protein Carriers, Channels, and Pores: Facilitate transport of larger or polar molecules.

• Selectivity: Potassium channels are highly selective due to their structure.

• Gating: Channels open/close in response to signals.

• Facilitated Transport: Protein-assisted movement down a gradient.

• Passive vs Active Transport: Passive does not require energy; active uses ATP or gradients.

• Primary vs Secondary Transport: Primary uses ATP directly; secondary uses gradient established by primary transport.

Transport Terms

• Uniport: Single substance, one direction.

• Symport: Two substances, same direction.

• Antiport: Two substances, opposite directions.

Signal Transduction

Hormones and Signaling

Hormones regulate cellular processes via signal transduction pathways.

• Three-Step Model: Reception, transduction, response.

• Key Terms: First messenger (hormone), receptor, transducer, effector enzyme, second messenger (e.g., cAMP).

• GPCR: G-protein coupled receptors activate G-proteins, which act as molecular switches.

• Pathways: GPCR/cAMP and Tyrosine kinase/PIP3.

• Regulation: Signals must be terminated to prevent overstimulation.

Concepts in Metabolism

Terminology and Energy Flow

Metabolism encompasses all chemical reactions in cells, divided into catabolism and anabolism.

• Intermediate Metabolism: Pathways connecting catabolism and anabolism.

• Catabolism: Breakdown of molecules; exergonic/oxidative.

• Anabolism: Synthesis of molecules; endergonic/reductive.

• Metabolite: Intermediate or product of metabolism.

• Autotrophs vs Heterotrophs: Autotrophs synthesize organic molecules; heterotrophs consume them.

• Regulatory Strategies: Feedback inhibition, feedforward activation, compartmentalization.

Oxidation-Reduction Reactions

Redox in Metabolism

Redox reactions involve electron transfer, crucial in glucose metabolism, gluconeogenesis, and the pentose phosphate pathway.

• Reducing Reaction: Gain of electrons.

• Oxidizing Reaction: Loss of electrons.

• Electron Carriers: NADH, NADPH, FADH2.

• Oxidation States: Carbon atoms in metabolites can be assigned oxidation numbers to track electron flow.

"High Energy" Bonds

ATP and Energy Coupling

ATP is the primary energy currency, with high-energy phosphoanhydride bonds.

• Phosphoanhydride Bond: Releases significant energy upon hydrolysis.

• Adenylate Energy Charge: Reflects cellular energy status.

• Coupled Reactions: ATP hydrolysis drives endergonic reactions.

• ΔGo' vs ΔG: Standard vs actual free energy change.

• High Energy Thioesters: e.g., Acetyl-CoA.

Example Table: Energy of phosphate compounds (inferred):

Basis of Metabolic Regulation

NADH and NADPH Cycles

NADH and NADPH are used in catabolic and anabolic pathways, respectively.

• Regulation of Opposing Pathways: Prevents futile cycles.

• Regulating Far-from-Equilibrium Reactions: Key control points in pathways.

• Free Energy and Reaction Quotient:

Reactions of Glycolysis

Phases and Enzymes

Glycolysis consists of two phases: energy investment and energy payoff.

• Energy Investment: ATP consumed.

• Energy Payoff: ATP and NADH produced.

• Enzyme Classes: Kinases, isomerases, dehydrogenases, etc.

• Overall Energetics: Net gain of 2 ATP and 2 NADH per glucose.

Anaerobic Glycolysis

Fate of Pyruvate

Under anaerobic conditions, pyruvate is converted to lactate to regenerate NAD+.

• Lactic Acid Fermentation: Pyruvate + NADH → Lactate + NAD+ (enzyme: lactate dehydrogenase).

• Cory Cycle: Lactate transported to liver, converted back to glucose.

Glycogen Metabolism

Synthesis and Breakdown

Glycogen is a storage form of glucose, regulated by hormones.

• Glucose-6-Phosphate Fates: Glycolysis, pentose phosphate pathway, glycogen synthesis.

• Glycogen Synthesis: Glycogen synthase, branching enzyme.

• Glycogen Breakdown: Glycogen phosphorylase, debranching enzyme.

• Reciprocal Regulation: Insulin promotes synthesis; glucagon promotes breakdown.

• Signal Transduction: Insulin and glucagon activate respective pathways via second messengers.

Pentose Phosphate Pathway

Function and Products

An alternative fate of glucose-6-phosphate, producing NADPH and ribose-5-phosphate.

• Oxidative Phase: Generates NADPH for biosynthesis.

• Products: NADPH, ribose-5-phosphate, CO2.

Gluconeogenesis

Necessity and Steps

Gluconeogenesis synthesizes glucose from non-carbohydrate precursors, essential during fasting.

• Unique Steps: Four steps require unique enzymes (e.g., pyruvate carboxylase, PEP carboxykinase).

• Reverse Steps: Most steps are reverse of glycolysis.

Basics of Glucose Regulation

Regulation Principles

Reciprocal regulation ensures efficient control of glycolysis and gluconeogenesis.

• Mechanisms: Allosteric regulation, covalent modification, substrate availability.

• Regulated Steps: Glucose uptake (GLUT), glucokinase, phosphofructokinase-1, pyruvate kinase.

• Energy Charge: High ATP inhibits glycolysis.

• Fructose-2,6-bisphosphate: Key regulator of glycolysis and gluconeogenesis.

Fructose-2,6-Bisphosphate Regulation

Role and Synthesis

F2,6BP is a potent allosteric activator of phosphofructokinase-1, promoting glycolysis.

• Synthesis/Degradation: Bifunctional enzyme (PFK-2/F-2,6-BPase).

• Regulation: Phosphorylation state responds to insulin and glucagon.

Insulin and Glucagon

Hormonal Regulation

Insulin and glucagon coordinate central metabolism, affecting liver, kidney, and muscle.

• Signal Transduction: Distinct pathways for insulin (promotes storage) and glucagon (promotes mobilization).

• Glycogen Regulation: Insulin stimulates synthesis; glucagon and epinephrine stimulate breakdown.

• Coordination: Ensures proper balance between glycolysis, gluconeogenesis, and glycogen metabolism.

Example: In muscle, epinephrine triggers glycogen breakdown for rapid energy.