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Biochemistry The Molecular Basis of Life, International Edition TRUDY MCKEE JAMES R. MCKEE Chapter 2 Living Cells 1  Online Video Self-Assembly: T...

Biochemistry The Molecular Basis of Life, International Edition TRUDY MCKEE JAMES R. MCKEE Chapter 2 Living Cells 1  Online Video Self-Assembly: The Power of Organizing the Unorganized Section 2.1 The process of self-assembly, or when unordered parts come together in an organized structure. How we see self- assembly at work in biology and chemistry – and even in our future technologies. 2 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Online Video Motor Proteins Section 2.1 The two-legged molecules known as motor proteins are what get the job of living done in most of your cells. 3 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Online Video A Day in the Life of a Motor Protein Section 2.1 A motor protein has to transport its package to the right destination in the nerve cell, illustrating the relevance and mechanisms of proper intracellular transport in the nervous system. 4 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Online Video Endocytosis and Exocytosis Section 2.3 How larger compounds are transported in vesicles across a cell membrane. 5 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Online Video The Golgi Apparatus Section 2.3 The Golgi apparatus is essentially a factory that synthesizes and/or processes a diverse group of proteins and lipids. These biomolecules are then sorted for transport to their final destination. 6 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Living Cells Chapter 2 Overview Section 2.1: Core Biochemistry Concepts Section 2.2: Structure of Prokaryotic Cells Section 2.3: Structure of Eukaryotic Cells 7  Overview Cells are the basic unit of life, since they are the smallest entities that are actually alive. - Cells can sense and respond to their environment, transform matter and energy, and reproduce themselves. The human body contains about 200 types of cells. This great variation reflects the variety of functions that cells can perform. No matter what their shape, size, or species, cells are also amazingly similar. - They are all surrounded by a membrane that separates them from their environment. - They are all composed of the same types of molecules. 8 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.1: Basic Themes Understanding of the biological context of biochemical processes is enhanced by examining the following key concepts: 1. Water 2. biological membranes 3. self-assembly 4. molecular machines 5. macromolecular crowding 6. Proteostasis 7. signal transduction: - calcium ions as a signaling device - the relationship between signal transduction and metabolism. 9 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.1: Basic Themes Water Unique polar structure Among its most important properties is interaction with a wide range of substances Figure 2.1 Hydrophobic Interactions Between Water and a Nonpolar Substance 10 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.1: Basic Themes Biological Membranes Thin, flexible, and stable sheet-like structures Selective physical barrier Phospholipid bilayer with integral and peripheral membrane proteins Figure 2.2 Membrane Structure 11 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.1: Basic Themes Self-Assembly Many of the working parts of living organisms are supramolecular structures. According to the principle of self-assembly, most molecules that interact to form stable and functional supramolecular complexes are able to do so spontaneously because they inherently possess the steric information required. Examples: - ribosomes: the protein-synthesizing devices that are formed from several types of protein and RNA - large protein complexes such as the sarcomeres in muscle cells - proteosomes: large protein complexes that degrade proteins. - In some cases, self-assembly processes need assistance. For example, the folding of some proteins requires the aid of molecular chaperones. - https://www.youtube.com/watch?v=2Lfm1uRPqo8 Figure 2.3 Self-Assembly The information that permits the self-assembly of biomolecules consists of the complementary shapes and distributions of charges and hydrophobic groups in the interacting molecules. Large numbers of weak interactions are required for supramolecular structures to form. In this diagrammatic illustration, several weak noncovalent interactions stabilize the binding of two molecules that possess complementary shapes. 12 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.1: Basic Themes Molecular Machines Many multisubunit complexes containing motor proteins are involved in cellular processes where they function as molecular machines Molecular machines ensure that precisely the correct amount of applied force results in the appropriate amount and direction of movement required for a specific task to be completed. Figure 2.4 Biological Machines Proteins perform work when motor protein subunits bind and hydrolyze nucleotides such as ATP. The energy-induced change in the shape of a motor protein subunit causes an orderly change in the shapes of adjacent subunits. In this diagrammatic illustration, a motor protein complex moves attached cargo (e.g., a vesicle) as it “walks” along a cytoskeletal filament. 13 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.1: Basic Themes Macromolecular Crowding The interior space within cells is dense and crowded. The term crowded rather than concentrated is used because macromolecules of each type usually are present in low numbers. Estimates of the volume occupied by macromolecules, called the excluded volume, in individual cell types vary between 20 and 40%. Figure 2.5 Volume Exclusion Macromolecules and small molecules are depicted with large balls and small balls, respectively. Within each square, macromolecules occupy 30% of available space. (a) An introduced small molecule can penetrate into virtually all of the remaining 70% of the space. (b) Steric repulsion between macromolecules (open circles) limits the ability of these molecules to approach each other. Although the macromolecules occupy only 30% of the volume, the introduced macromolecule is excluded. 14 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.1: Basic Themes Proteostasis Each type of living cell has its own characteristic set of proteins, referred to as its proteome, which changes constantly in response to environmental conditions. Mammalian cells have an average of 10,000 types of protein, most of which are produced in multiple copies Cells in which protein quality control is high are said to be in a state of protein homeostasis, or proteostasis. The processes that monitor and restore proteostasis are referred to as the proteostasis network (PN). 15 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.1: Basic Themes Signal transduction Living organisms require both energy and information to create order. - Survival requires that organisms process information from their environment. Information, or signals, come in the form of molecules (e.g., nutrients), physical stimuli (e.g., light) and mechanical force. Although organisms are bombarded with signals, they can adapt to changing environmental conditions only if they can recognize, interpret, and respond to each type of message. The process that organisms use to receive and interpret information is referred to as signal transduction. Examples of eukaryotic signal molecules include neurotransmitters (products of neurons), hormones (products of glandular cells), and cytokines (products of white blood cells). 16 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.1: Basic Themes Signal transduction All information-processing mechanisms can be divided into four phases: 1. Reception: A signal molecule, called a ligand, binds to and activates a receptor. 2. Transduction: Ligand binding triggers a change in the three-dimensional structure of the receptor, which results in the conversion of a primary message or signal to a secondary message, often across a membrane barrier. 3. Response.: Once initiated, the internal signal causes a signaling cascade, a series of reactions that involve covalent modifications (e.g., phosphorylation) of intracellular proteins. Results of this process include changes in enzyme activities and/or gene expression, cytoskeletal rearrangements, cell movement, or cell cycle progression (e.g., cell growth or division). 4. Termination: The efficiency and effectiveness of signal mechanisms require that they be terminated in a timely manner. Living organisms use a variety of signal termination methods. For example, signaling molecules may be destroyed or removed (e.g., neurotransmitters such as acetylcholine and serotonin, respectively), activated proteins are inactivated by changes in covalent modification (e.g., removal of phosphate groups), and nonprotein signals are degraded by enzymes. 17 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.1: Basic Themes Signal transduction CALCIUM IONS (Ca2+): A UNIVERSAL SIGNALING DEVICE - Cells respond to external stimuli by increasing their cytoplasmic Ca2+ concentrations, which are normally kept quite low by ATP-driven pump complexes in the plasma membrane and in eukaryotes in the membrane of organelles such as the endoplasmic reticulum SIGNAL TRANSDUCTION AND METABOLISM - Signal transduction mechanisms in living organisms are vital. - They detect relevant information in cell environments in which there is a profusion of stimuli, integrate this information, and then execute an appropriate response. - Such responses involve precise alterations in gene expression and the flow of metabolites in biochemical pathways. 18 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press Prokaryotes: The Basics Section 2.2 Some basic knowledge about prokaryotes. From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.2: Structure of Prokaryotic Cells A detailed, enlarged view of a portion of a a bacterial cell Figure 2.6 Structure of a Typical Bacterial Cell All living cells contain vast numbers of densely packed and interacting molecules, each of which performs specific tasks that, taken together, are required for life. The enlargement indicates relative sizes and shapes of the major biomolecules in a bacterial cell. 20 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.2: Structure of Prokaryotic Cells Prokaryotes include bacteria and archaea They have common features: cell wall, plasma membranes, circular DNA, and no membrane-bound organelles https://www.youtube.com/watch?v=8Cw-NrnT5ic 21 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.2: Structure of Prokaryotic Cells Cell Wall The prokaryotic cell wall is a complex semi-rigid structure primarily for support and protection The cell wall’s strength is largely caused by the presence of a polymeric network made up of peptidoglycan The thickness and chemical composition of the cell wall and its adjacent structures determine how avidly a cell wall takes up and/or retains specific dyes. 23  Section 2.2: Structure of Prokaryotic Cells Cell Wall The lipid component of the outer membrane is lipopolysaccharide instead of phospholipids. Lipopolysaccharide acts as an endotoxin. So called because they are released when the cell disintegrates, endotoxins are responsible for symptoms such as fever and shock in animals infected by Gram-negative bacteria. The outer membrane is relatively permeable, and small molecules move across it through porins, transmembrane protein complexes that contain channels. 24  Section 2.2: Structure of Prokaryotic Cells Figure 2.7 Bacterial Plasma Membrane Plasma Membrane (Cytoplasmic membrane) Directly inside the cell wall is the plasma membrane It is a phospholipid bilayer that is reinforced with hopanoids, a group of relatively rigid molecules that resemble sterols (e.g., cholesterol) that stiffen membranes in eukaryotes. A diverse group of proteins are embedded in the lipid bilayer. A selectively permeable membrane that may be involved in energy transduction processes such as photosynthesis or respiration 27 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.2: Structure of Prokaryotic Cells Cytoplasm Prokaryotic cells do have functional compartments Nucleoid, which is centrally located and contains the circular DNA (chromosome) Also contains small DNA plasmids they are not required for growth or cell division but provide the cell with a biochemical advantage Figure 2.8 Bacterial Cytoplasm (a) Cytoplasm is a complex mixture of proteins, nucleic acids, and an enormous variety of ions and small molecules. For clarity, the small molecules appear only in the upper right corner. (b) Close-up view of the nucleoid. Note that DNA is coiled and folded around protein molecules (brown). 28  Section 2.2: Structure of Prokaryotic Cells Cytoplasm Inclusion bodies are large granules that contain organic or inorganic compounds - Some species use glycogen as carbon storage polymers. - Polyphosphate inclusions are a source of phosphate for nucleic acid and phospholipid synthesis. The remaining space in the cytoplasm is filled with ribosomes (molecular machines composed of RNA and proteins that synthesize polypeptides) Figure 2.8 Bacterial Cytoplasm (a) Cytoplasm is a complex mixture of proteins, nucleic acids, and an enormous variety of ions and small molecules. For clarity, the small molecules appear only in the upper right corner. (b) Close-up view of the nucleoid. Note that DNA is coiled and folded around protein molecules (brown). 29  Section 2.2: Structure of Prokaryotic Cells Pili and Flagella - Many bacteria have external appendages Pili are fine, hair-like structures - allow cells to attach to food sources and host tissues. - Sex pili are used by some bacteria to transfer genetic information from donor cells to recipients, a process called conjugation. Flagella are a flexible corkscrew-shaped protein filament that is used for locomotion. - The filament of the flagellum is anchored into the cell by a protein complex. Motor proteins in this complex convert chemical energy into rotational motion. https://microbiologynotes.com/differe 30 nces-between-flagella-and-pili/  Eukaryotes Section 2.3 The animal cell that is responsible for all the cool things that happen in our bodies. From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Eukaryotic cells are structurally complex The most obvious features of eukaryotic cells are their large sizes (diameters of 10–100 ) in comparison to prokaryotes. Membrane-bound organelles and the endomembrane system increase surface area for chemical reactions https://www.youtube.com/watch?v=cj8dDTHGJBY Figure 2.9 Animal Cell Structure 32 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Eukaryotic Cells Important structures: plasma membrane, endoplasmic reticulum, Golgi apparatus, nucleus, lysosomes, mitochondria, chloroplasts, ribosomes, and the cytoskeleton Each organelle within the cell contains a characteristic set of biomolecules and is specialized to perform specific functions. - The biochemical processes within an organelle proceed efficiently because of locally high enzyme concentrations and because they Figure 2.9 Animal Cell Structure can be individually regulated. 33 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Plasma Membrane Isolates the cell from the outside environment and is selectively permeable It is composed of a lipid bilayer and an enormous number and variety of integral and peripheral proteins. Channels and carriers within the plasma membrane regulate Figure 2.11 the passage of various ions and Plasma Membrane of an molecules in and out of the cell. Animal Cell Receptors play key roles in signal transduction. 34 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Plasma Membrane Outside the plasma membrane are the glycocalyx and the extracellular matrix The carbohydrate molecules play important roles in cell–cell recognition and adhesion, receptor specificity, and self- identity (an immune system requirement). Figure 2.11 The basic blood group antigens Plasma Membrane of an (A, B, AB, or O) are an example Animal Cell of this self-identity function. 35 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Plasma Membrane The inner surface of the eukaryotic plasma membrane is reinforced by a three-dimensional meshwork of proteins called the membrane skeleton, which is attached to the membrane by extensive noncovalent bonding to peripheral proteins. In animal cells, this protein Figure 2.11 network—composed of actin, Plasma Membrane of an several types of actin-binding Animal Cell proteins, and spectrin - provides mechanical strength to the plasma membrane and determines cell shape. 38 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Figure 2.11 The Plasma Membrane of an Animal Cell The plasma membrane (PM) is composed of a lipid bilayer in which a wide variety of integral proteins are embedded. Note that numerous integral proteins and lipid molecules are covalently attached to carbohydrate. Peripheral proteins are attached by noncovalent bonds to the cytoplasmic surface of the PM. Specialized cells of the connective tissue of higher animals called fibroblasts synthesize and secrete proteins into the extracellular matrix (ECM; e.g., elastin and collagen). The inner surface of the PM is reinforced by the membrane skeleton, which is composed of a meshwork of actin microfilaments and other proteins linked to the 39 cell’s cytoskeleton. From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Endoplasmic Reticulum (ER) is a series of membranous tubules, vesicles, and flattened sacks The internal space is the ER lumen Figure 2.13 Endoplasmic Reticulum 40 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Two types: Rough ER functions include protein synthesis, folding, and glycosylation Smooth ER functions include lipid biosynthesis and Ca2+ storage Figure 2.13 Endoplasmic Reticulum 41 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells ER stress: the failure of polypeptides to fold within the RER, resulting in an accumulation of misfolded molecules. It is caused by: - environmental factors such as metabolic stress (changes in metabolism triggered by injury, illness, or infection) - oxidative stress (from oxygen radicals) - activated inflammatory signaling processes - genetic factors. Figure 2.13 Endoplasmic Reticulum 42 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells ER associated protein degradation (ERAD) is a cellular mechanism that targets misfolded polypeptides and transports them into the cytoplasm, where they are degraded by proteasomes If stress is severe, the RER initiates the unfolded protein response (UPR) in an attempt to restore proteostasis. -Signals sent to the nucleus result in the inhibition of protein synthesis, with the exception of additional molecular chaperones. Figure 2.13 Endoplasmic Reticulum 43 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells In addition to proteosomal protein destruction, autophagy (controlled digestion of damaged or unnecessary organelles or other cell components; can be utilized in an attempt to prevent cell death. If protein homeostasis cannot be achieved within a certain time period, apoptosis, a programmed cell death process can be initiated. Figure 2.13 Endoplasmic Reticulum 44 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Hepatocyte SER performs a wide variety of functions, which include biotransformation and synthesis of the lipid components of very low density lipoproteins (VLDL). Biotransformation reactions convert an enormous variety of water-insoluble metabolites and xenobiotics (foreign and potentially toxic molecules) into more soluble products that can then be excreted. Figure 2.13 Endoplasmic Reticulum 45 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Golgi Apparatus The Golgi apparatus is formed of large, flattened, sac-like membranous vesicles Processes, packages, and distributes cell products The primary role is the glycosylation to proteins and lipids. Sulfation and phosphorylation reactions also occur. Figure 2.14 The Golgi Apparatus 46 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Golgi Apparatus Has a cis and a trans face (cisterna) 47 Section 2.3: Structure of Eukaryotic Cells Secretory products concentrated at the trans Golgi into secretory vesicles are delivered to the plasma membrane Exocytosis is a process in which secretory vesicle fuse with the plasma membrane allowing the release of secretory product molecules Figure 2.15 Exocytosis 48 Section 2.3: Structure of Eukaryotic Cells Vesicular Organelles and Lysosomes: The Endocytic Pathway: Vesicular Organelles The eukaryotic cell has vesicles Vesicles originate in the ER, Golgi and/or via endocytosis Figure 2.16 Receptor-Mediated Endocytosis 49 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Vesicular Organelles and Lysosomes: The Endocytic Pathway: Endocytic cycle is used for recycling and remodeling of membranes Endocytosis is a cellular process in which plasma membrane protein receptors bound to specific substances such as lipoproteins are taken into cells. Lysosomes are vesicles that contain digestive enzymes Enzymes are acid hydrolases Lysosomes Degrade debris in cells and involved in autophagy 50 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Nucleus The nucleus is the most prominent organelle Contains the hereditary information Site of transcription Nuclear components: Nucleoplasm Chromatin (genome) Nuclear matrix Nucleolus Nuclear envelope Figure 2.18 Eukaryotic Nucleus 52 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press Section 2.3: Structure of Eukaryotic Cells The nuclear envelope surrounds the nucleoplasm The nuclear envelope has nuclear pores referred to as nuclear pore complexes Structures through which pass most of the molecules that enter and leave the nucleus Figure 2.19 The Nuclear Pore Complex 53 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Mitochondria The mitochondria (mitochondrion) are recognized as the site of Figure 2.23 The Mitochondrion aerobic metabolism Mitochondria are the principle source of cellular energy Have inner and outer membrane surrounding the matrix Have DNA and ribosomes 54 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Mitochondria Mitochondria form stable contact sites with regions of the ER called mitochondria-associated membranes (MAMs). These contacts have several functions that together regulate mitochondrial dynamics: 1. Calcium signaling 2. Lipid exchange 3. Mitochondrial fission regulation. Figure 2.22 Mitochondrial Fission and Fusion 55  Section 2.3: Structure of Eukaryotic Cells Peroxisomes The peroxisome is a small organelle containing oxidative enzymes Peroxisomal enzymes are involved in a variety of anabolic and catabolic pathways: - synthesis of certain membrane phospholipids and other lipids, purine and pyrimidine bases, and bile acids - degradation of long-chain fatty acids, branched chain fatty acids, polyamines, and purine bases. - Detoxifies peroxides (e.g., H2O2): generation and breakdown of toxic molecules known as peroxides. Hydrogen peroxide (H2O) is generated when molecular oxygen (O2) is used to remove hydrogen atoms from specific organic molecules Peroxisomes use H2O2 to oxidize toxic molecules such as formaldehyde or alcohol. 56 From McKee and McKee, Biochemistry, 7th Edition, © 2020 by Oxford University Press  Section 2.3: Structure of Eukaryotic Cells Cytoskeleton The cytoskeleton is an intricate supportive network of fibers, filaments, and associated proteins Three main components: Microtubules Microfilaments Intermediate filaments Main functions include: 1. cell shape and structure 2. large- and small-scale cell movement 3. solid-state biochemistry 4. signal transduction Figure 2.25 The Cytoskeleton 57 (a) microtubules, (b) microfilaments, (c) intermediate filaments