🧬Biochemistry Unit 5 – Lipids and Biological Membranes

What Are Lipids?

• Lipids are a diverse group of hydrophobic or amphipathic molecules that play crucial roles in biological systems
• Characterized by their insolubility in water and solubility in organic solvents (chloroform, ether)
• Serve as structural components of cell membranes, energy storage molecules, and signaling molecules
• Include fats, oils, waxes, sterols, and phospholipids
• Composed primarily of carbon, hydrogen, and oxygen atoms
• Can be either saturated (single bonds between carbon atoms) or unsaturated (one or more double bonds between carbon atoms)
  • Saturated lipids are solid at room temperature (butter, lard)
  • Unsaturated lipids are liquid at room temperature (olive oil, corn oil)

Types of Lipids

• Fatty acids consist of a carboxyl group attached to a long hydrocarbon chain
  • Can be saturated (no double bonds) or unsaturated (one or more double bonds)
  • Essential fatty acids (linoleic acid, alpha-linolenic acid) cannot be synthesized by the body and must be obtained through diet
• Triglycerides are composed of three fatty acid molecules esterified to a glycerol backbone
  • Serve as the primary form of energy storage in animals
  • Excess triglycerides are stored in adipose tissue
• Phospholipids contain a hydrophilic head group and two hydrophobic fatty acid tails
  • Main component of biological membranes
  • Include phosphatidylcholine, phosphatidylserine, and phosphatidylethanolamine
• Sterols are characterized by a four-ring steroid structure
  • Cholesterol is the most common sterol in animal cells and plays a crucial role in membrane fluidity and signaling
• Sphingolipids consist of a sphingosine backbone linked to a fatty acid and a polar head group
  • Include sphingomyelin and glycosphingolipids
  • Play important roles in cell signaling and recognition

Lipid Structure and Function

• The amphipathic nature of lipids allows them to form bilayers in aqueous environments
  • Hydrophobic tails face inward, while hydrophilic head groups face outward
• Lipids provide a barrier between the cell and its environment, maintaining cellular integrity
• Membrane lipids regulate the fluidity and permeability of the cell membrane
  • Cholesterol helps modulate membrane fluidity by intercalating between phospholipids
• Lipids serve as energy storage molecules, providing twice as much energy per gram compared to carbohydrates
• Some lipids (eicosanoids, steroids) function as signaling molecules, regulating various cellular processes
  • Eicosanoids (prostaglandins, leukotrienes) are derived from arachidonic acid and play roles in inflammation and immune responses
  • Steroid hormones (estrogen, testosterone) are derived from cholesterol and regulate gene expression
• Lipids also serve as precursors for the synthesis of other important biomolecules (bile acids, vitamin D)

Biological Membranes: The Basics

• Biological membranes are composed primarily of lipids and proteins
• The fluid mosaic model describes the dynamic structure of membranes, with lipids forming a fluid bilayer and proteins embedded or associated with the membrane
• Lipid bilayers are held together by hydrophobic interactions between the fatty acid tails of phospholipids
• The thickness of a lipid bilayer is approximately 5-7 nm
• Membranes are selectively permeable, allowing some molecules to pass through while restricting others
  • Small, nonpolar molecules (O2, CO2) can diffuse freely across the membrane
  • Charged or large polar molecules (glucose, amino acids) require specialized transport proteins to cross the membrane
• Membrane proteins can be integral (spanning the entire bilayer) or peripheral (associated with one side of the membrane)
  • Integral proteins include ion channels, receptors, and transporters
  • Peripheral proteins include enzymes and cytoskeletal proteins

Membrane Composition and Organization

• The lipid composition of membranes varies among different cell types and organelles
  • Plasma membranes are enriched in cholesterol and sphingolipids
  • Endoplasmic reticulum membranes have a higher proportion of unsaturated phospholipids
• Lipid rafts are specialized membrane microdomains enriched in cholesterol and sphingolipids
  • Serve as platforms for signaling and protein trafficking
• Membrane asymmetry refers to the different lipid compositions of the inner and outer leaflets of the bilayer
  • Outer leaflet is enriched in phosphatidylcholine and sphingomyelin
  • Inner leaflet contains more phosphatidylserine and phosphatidylethanolamine
• Membrane proteins can be glycosylated, with oligosaccharide chains attached to their extracellular domains
  • Glycoproteins play roles in cell-cell recognition and adhesion
• The cytoskeleton interacts with membrane proteins, providing structural support and regulating membrane dynamics
  • Actin filaments and spectrin help maintain the shape and integrity of the plasma membrane

Membrane Transport

• Passive transport occurs down a concentration gradient and does not require energy input
  • Simple diffusion allows small, nonpolar molecules to cross the membrane
  • Facilitated diffusion involves transport proteins (channels, carriers) that facilitate the movement of specific molecules across the membrane
• Active transport requires energy input (ATP) to move molecules against their concentration gradient
  • Primary active transport uses ATP directly to power the transport process (Na+/K+ ATPase)
  • Secondary active transport couples the movement of one molecule against its gradient to the movement of another molecule down its gradient (Na+/glucose cotransporter)
• Endocytosis involves the invagination of the plasma membrane to bring molecules into the cell
  • Phagocytosis ("cell eating") involves the engulfment of large particles or microorganisms
  • Pinocytosis ("cell drinking") involves the uptake of fluids and dissolved solutes
  • Receptor-mediated endocytosis is a specific form of endocytosis that involves the internalization of ligand-bound receptors (low-density lipoprotein receptor)
• Exocytosis is the fusion of intracellular vesicles with the plasma membrane to release their contents into the extracellular space
  • Plays a crucial role in neurotransmitter release and secretion of hormones and enzymes

Lipid Metabolism

• Fatty acid synthesis occurs in the cytosol and involves the successive addition of two-carbon units to a growing acyl chain
  • Acetyl-CoA carboxylase catalyzes the rate-limiting step, converting acetyl-CoA to malonyl-CoA
  • Fatty acid synthase is a multienzyme complex that catalyzes the elongation of the acyl chain
• Fatty acid oxidation occurs in the mitochondria and involves the sequential removal of two-carbon units from the acyl chain
  • Carnitine shuttle system transports fatty acyl-CoA molecules into the mitochondrial matrix
  • Beta-oxidation spiral generates acetyl-CoA, NADH, and FADH2
• Ketone bodies (acetoacetate, beta-hydroxybutyrate) are produced in the liver during prolonged fasting or low-carbohydrate diets
  • Serve as an alternative energy source for the brain and other tissues
• Cholesterol synthesis occurs in the endoplasmic reticulum and involves a series of enzymatic reactions
  • HMG-CoA reductase catalyzes the rate-limiting step and is the target of statins, a class of cholesterol-lowering drugs
• Lipid metabolism is regulated by hormones (insulin, glucagon) and transcription factors (sterol regulatory element-binding proteins)

Real-World Applications

• Understanding lipid structure and function is crucial for the development of novel drug delivery systems
  • Liposomes are artificial lipid vesicles that can encapsulate and deliver drugs or genetic material to target cells
• Lipid-based biomarkers can be used for the diagnosis and monitoring of various diseases
  • Elevated levels of low-density lipoprotein (LDL) cholesterol are associated with an increased risk of cardiovascular disease
  • Sphingolipid accumulation is a hallmark of several lysosomal storage disorders (Gaucher disease, Niemann-Pick disease)
• Modulating membrane lipid composition can enhance the efficacy of cancer chemotherapy
  • Increasing the proportion of unsaturated fatty acids in tumor cell membranes can sensitize them to oxidative stress induced by chemotherapeutic agents
• Lipid-based vaccines have shown promise in eliciting robust immune responses
  • Lipid nanoparticles containing mRNA encoding viral antigens have been successfully used in the development of COVID-19 vaccines (Pfizer-BioNTech, Moderna)
• Omega-3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid) have been linked to various health benefits
  • Supplementation with omega-3 fatty acids may reduce inflammation, improve cardiovascular health, and support brain function