1.1: Cellular Foundations

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Learning Goals (ChatGPT o3-mini)

Below is a list of learning goals tailored for junior and senior biochemistry majors based on the provided information:

1. Differentiate Cell Types and Organelles

   • Explain the fundamental differences between prokaryotic and eukaryotic cells.
   • Identify and describe the roles of key organelles in a eukaryotic cell, with emphasis on how compartmentalization supports cellular functions.

2. Understand Biomolecular Diversity and Distribution

   • List and characterize the four major classes of biomolecules (lipids, proteins, nucleic acids, and carbohydrates).
   • Trace the “history” of these biomolecules—from synthesis, modification, to degradation—and explain their spatial distribution within the cell.

3. Analyze Metabolic Pathways and Energy Transformations

   • Define metabolism in terms of energy balance, distinguishing between exergonic (energy-releasing) and endergonic (energy-consuming) reactions.
   • Differentiate between catabolic pathways (breakdown of compounds) and anabolic pathways (synthesis of new compounds), including the energy implications of each.

4. Examine Enzyme Catalysis and Regulation

   • Describe the role of enzymes as catalysts in metabolic reactions, including how they lower activation energies and speed up chemical reactions.
   • Compare and contrast the lock and key model with the induced fit model of enzyme-substrate binding.
   • Explain how enzyme activity can be regulated through factors such as allosteric modulation, inhibitors, and environmental changes.

5. Investigate Cellular Transport Mechanisms

   • Outline the mechanisms of molecular transport across cellular membranes, including passive diffusion, facilitated diffusion, and active transport.
   • Discuss the roles of membrane proteins such as transporters, ion channels, pores, and carriers in regulating the intracellular environment.

6. Explore Cellular Organization and Architecture

   • Describe the structure and function of the cytoskeleton and its role in maintaining cell shape, facilitating intracellular transport, and supporting dynamic changes during processes like cell migration.
   • Explain how the crowded intracellular environment influences biomolecular interactions, protein stability, and reaction kinetics.

7. Understand Phase Separation and Cellular Substructures

   • Illustrate how phase transitions (e.g., liquid/liquid demixing) contribute to the formation of cellular substructures such as lipid droplets, membrane rafts, and ribonucleoprotein complexes.
   • Analyze the role of intermolecular forces (ionic interactions, dipole-dipole, ion-dipole, and London dispersion forces) in driving the assembly and function of these structures.

8. Integrate Chemical Principles with Biological Function

   • Connect chemical concepts such as reaction kinetics, thermodynamics, and intermolecular forces to biological processes like signal transduction, metabolism, and cellular homeostasis.
   • Apply this integrated understanding to explain how changes at the molecular level can affect cell function and contribute to disease states or pharmacological outcomes.

These learning goals aim to ensure that students not only grasp the biochemical principles underpinning cell structure and function but also appreciate how these concepts integrate into the broader context of cellular physiology and pathology.

Introduction

You have probably studied the cell many times, either in high school or in college biology classes. Many websites review prokaryotic (bacterial and archaeal cell types) and eukaryotic cells (protists, fungi, plants, and animals). All cells have similar structural components, including genetic material in the form of chromosomes, a membrane-bound lipid bilayer separating the inside from the outside of the cell, and ribosomes responsible for protein synthesis. This tutorial is designed specifically from the viewpoint of chemistry. It explores four classes of biomolecules that are also present in all cell types (lipids, proteins, nucleic acids, and carbohydrates) and describes in a simplified pictorial manner where they are found, made, and degraded in a typical eukaryotic animal cell (i.e., their history). This cell review focuses on the organelle structures common in eukaryotic cells. Subsequent chapters will concentrate on the structure and function of specific biomolecules.

Let’s think of a cell as a chemical factory that designs, imports, synthesizes, uses, exports, and degrades various chemicals (in the case of the cell, these include lipids, proteins, nucleic acids, and carbohydrates). It also must determine or sense the amount of raw and finished chemicals available and respond to its own and external needs by ramping up or shutting off production. Biochemistry is the branch of science that studies the chemical processes within a cell. Understanding these processes can also lend insight into disease states and the pharmacological effects of toxins, drugs, and other medicines within the body.

The building and breaking down of life-sustaining chemicals within an organism is known as Metabolism. Overall, the metabolism involves: (1) the net exergonic, energy-releasing metabolism of food/fuel food to power endergonic, energy-requiring cellular processes; (2) the conversion of food/fuel to building blocks for the synthesis of proteins, lipids, nucleic acids, and other biomolecules and (3) the elimination of waste products. These processes allow organisms to grow, reproduce, maintain structures, and respond to environments.

Metabolic reactions may be categorized as catabolic– the breaking down of compounds (for example, the breaking down of proteins into amino acids during digestion); or anabolic – the building up (synthesis) of compounds (such as proteins, carbohydrates, lipids, and nucleic acids). Usually, catabolism releases energy, and anabolism consumes energy.

Figure 1.1 Catabolic and Anabolic Reactions. Catabolic reactions break molecules into smaller components, whereas anabolic reactions build larger molecules from smaller molecules. Catabolic reactions usually release energy, whereas anabolic processes usually require energy. (CC BY-SA-NC 3.0; anonymous)

The chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed through a series of steps into another chemical, each step often facilitated by a specific enzyme. Enzymes are crucial to metabolism because enzymes act as catalysts, allowing a reaction to proceed more rapidly. In addition, enzymes can provide a mechanism for cells to regulate the rate of a metabolic reaction in response to changes in the cell’s environment or to signals from other cells through the activation or inhibition of the enzyme’s activity. Enzymes can also allow organisms to drive desirable reactions that require energy that will not occur by themselves by coupling them to spontaneous reactions that release energy. Enzyme shape is critical to the enzyme's function as it determines the specific binding of a reactant. This can occur by a lock and key model where the reactant is the exact shape of the enzyme binding site or by an induced fit model, where the contact of the reactant with the protein causes the shape of the protein to change to bind to the reactant. The catalytic mechanisms, kinetics, and regulatory pathways of enzymes will be studied in detail within this text.

Figure 1.2 Mechanisms of Enzyme-Substrate Binding. (A) In the Lock and Key Model, substrates fit into the enzyme's active site without further modifications to the enzyme's shape. (B) In the Induced Fit Model, substrate interaction causes the enzyme's shape to change to better fit the substrate and mediate the chemical reaction. Figure 1.2A was modified from Socratic, and Figure 1.2B was modified from Concepts in Biology

Within eukaryotic cells, the metabolic machinery allows for the construction of membrane-bound organelle structures that help compartmentalize cellular functions. Therefore, organelles, having discrete cellular functions, can be considered ‘little organs’ within the cell. The figure of the cell below and in the other linked sites based on it was made available with the kind permission of Liliana Torres. For more detailed information, click on the blue hyperlinks for some organelles.

Figure 1.3 Structure of a Typical Eukaryotic Animal Cell. The original figure was acquired from Liliana Torres at: http://torresbioclan.pbworks.com/w/page/22377234/Spikefish%20About%20Cells Use with permission from Liliana Torres. Also at www.animalport.com/animal-cells.html

Design – The design for a cell primarily resides in the blueprint for the cell, the genetic code, which comprises the DNA in the cell nucleus and a small amount in the mitochondria. The DNA blueprint must be read out (transcribed) by DNA readers (DNA-dependent RNA polymerases) to form RNA.  Since DNA and RNA are nucleic acids comprised of deoxynucleotide (for DNA) and nucleotides (for RNA) monomers, this process is called transcription.  A type of RNA, messenger RNA, is then decoded to form a new kind of polymer, a protein, with amino acid monomers.  This process is called translation (analogous to converting an English sentence into a Spanish one).  In a nanomachine, the ribosome, which contains RNA and protein subunits, interacts with the messenger RNA and incoming transfer RNA connected to individual amino acids to create a protein. The genetic code has the master plan that determines the sequence of all cellular proteins, catalyzing almost all cell activities, including catalysis, motility, architectural structure, etc. In contrast to DNA, RNA, and protein polymers, the length and sequence of polysaccharide polymers and lipids are not driven by such a template but rather by the enzymes that catalyze the synthesis.

Import/Export: Many of the chemical constituents of the cell arise not from direct synthesis but from the import of both small and large molecules. The imported molecules must pass through the cell membrane and, in some cases, through additional membranes if they need to reside inside membrane-bound organelles. Molecules can move into the cell by passive diffusion across the membrane, but their movement is usually “facilitated” by a membrane transporter protein. Molecules can also move against a concentration gradient in a process called “active transport.” Given the amphiphilic nature of the bilayer (polar head group exterior, nonpolar interior), you would expect that polar molecules like glucose would have difficulty moving across the membrane by passive diffusion. Typically, only small nonpolar molecules move across the membrane via passive transport. Membrane-bound transport proteins are involved in the movement of both nonpolar and polar molecules.

• transporters, carrier proteins, and permeases: These membrane proteins move specific ligand molecules across a membrane, typically down a concentration gradient. Click the image below for a computer (molecular dynamics) simulation of the facilitated diffusion of lactose across the membrane by a membrane protein (lactose permeate).

Morten Ø. Jensen et al.  Sugar Transport across Lactose Permease Probed by Steered Molecular Dynamics.  Open Archive.  DOI:https://doi.org/10.1529/biophysj.107.103994. Theoretical and Computational Biophysics Group, Beckman Institute, Urbana, Illinois USA.  Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois USA Creative Commons licensing

https://www.cell.com/cms/10.1529/bio...329ed/mmc2.mp4 

• ion channels: These membrane proteins allow the flow of ions across membranes. Some are permanently open (nongated), while others are gated open or closed depending on the presence of ligands that bind the protein channel and the local environment of the protein in the membrane. The flow of ions through the channel proceeds in a thermodynamically favored direction, which depends on their concentration and voltage gradients across the membrane.

Fatemeh Khalili-Araghi et al. Dynamics of K⁺ Ion Conduction through Kv1.2.  Open ArchiveDOI:https://doi.org/10.1529/biophysj.106.091926.   Theoretical and Computational Biophysics Group, Beckman Institute, Urbana, Illinois USA.  Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois

• pores: Some membranes (nuclear, mitochondria) assemble proteins (such as porins) to form large but regulated pores. Porins are found in mitochondrial membranes, while nucleoporins are found in the nuclear membrane. Small molecules can generally pass through these membrane pores, while large ones are selected based on their tendency to form transient intermolecular attractive forces with the pore proteins. The following link shows the diffusion of water through aquaporin. animation of water diffusion through the aquaporin channel,

Water Transport in Aquaporins.  https://www.ks.uiuc.edu/Research/aquaporins/.  Theoretical and Computational Biophysics Group, Beckman Institute, Urbana, Illinois USA.  Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois

• endocytosis: Very large particles [for example, Low-Density Lipoproteins (LDL) and viruses] can enter a cell through endocytosis. Initially, the LDL or virus binds to a receptor on the cell's surface. This triggers a series of events that leads to the invagination of the cell membrane at that point. This eventually pinches off to form an endosomal vesicle surrounded by clathrin, a protein. “Early” endosomes can pick up new proteins and other constituents and shed them as they move and mature through the cell. During this maturation process, protein pumps in the endosome lead to a decrease in the endosomal pH, which can lead to conformation changes in protein structure and protein shedding. Eventually, the “late” endosome reaches and fuses with the lysosome, an internal organelle that contains degradative enzymes. Undegraded components like viral nucleic acids or cholesterol are delivered to the cell. This transport can also go in the reverse direction (called exocytosis) and recycle receptors to the cell membrane. Likewise, vesicles pinched off from the Golgi complex can fuse with endosomes, with some components surviving the process to reenter the Golgi.

 

Alexey Solodovnikov (Idea, Producer, CG, Editor), Valeria Arkhipova (Scientific Сonsultant).  Endocytosis. For example, coronavirus binds to the ACE2 receptor of the epithelial cell. CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons

Synthesize/Degrade: Cells must synthesize and degrade small molecules and larger polymeric proteins, carbohydrates, lipids, and nucleic acids. The anabolic (synthetic) and catabolic (degradative) pathways are often compartmentalized in time and space within a cell. For example, fatty acid synthesis occurs in the cytoplasm, while fatty acid oxidation occurs in the mitochondria. Proteins are synthesized in the cytoplasm or completed in the endoplasmic reticulum (for membrane and exported proteins).  They are degraded in the lysosome or, more importantly, in a large multimolecular structure in the cell called the proteasome.

Key Characteristics of a Cell

Let’s consider some key cell characteristics as a prelude for later chapters.

Cells and their internal compartments have regulated concentrations of ions and hydronium ions.

As expected the pH of the cytosol (the aqueous substance surrounding all the organelles within the cell) varies from about 7.0-7.4, depending on the metabolic state of the cell. Some organelles have proton transporters that can significantly alter the pH inside an organelle. For example, the pH inside the lysosome, a degradative organelle, is about 4.8. Furthermore, creating a pH gradient across the inner mitochondrial membrane is sufficient to drive the thermodynamically unfavored synthesis of ATP.

Compared to the extracellular fluid, the concentration of potassium ions is higher inside the cell. In contrast, sodium, chloride, and calcium ion concentrations are higher outside the cell (see table below). Ion transporters and channels maintain these concentration gradients and require energy expenditure, ultimately in the form of ATP hydrolysis, to do so. Changes in these concentrations are integral to the signaling system used by the cell to sense and respond to changes in its external and internal environments. The table below shows approximate ion concentrations in the cell.

Table 1.1 Average Cellular and Extracellular Ion Concentrations

Ion	Inside (mM)	Outside (mM)
Na^+	140	5
K^+	12	140
Cl-	4	15
Ca^2^+	1 uM	2

Cells have an internal framework that provides architectural and internal structural support

The “cytoskeletal” architecture of a cell (with molecular “cables”- and “girder-like” structures) is superficially similar to that of a factory. The cell's internal framework, the cytoskeleton, is composed of microfilaments, intermediate filaments, and microtubules. These, in turn, are built from proteins that self-assemble to form the internal architecture. Parts of the cytoskeleton can be seen in Figure 1.4.

Figure 1.4 Cellular Architecture. The architecture and organization of structural components within a cell (right picture) are analogous to the organization seen within a warehouse (left picture). In the right image, bovine pulmonary artery endothelial cells have been stained to indicate the nucleus (blue color), tubulin cytoskeletal proteins (fluorescent green color), and F-actin cytoskeletal proteins (fluorescent red color). Source of the factory picture: http://www.cybercom.net/~copters/trips/pictures/factory_inside.jpg Source of the fluorescent cell picture: http://en.Wikipedia.org/wiki/File:FluorescentCells.jpg

Microfilaments of actin monomers (stained with a red/orange fluorophore) and microtubules, which offer more structural support made of tubulin monomers (stained green) and the blue-stained nucleus, are shown in the image. Organelles are supported and organized by the cytoskeleton (primarily microtubules). Actin (stained orange) and spectrin microfilaments support the cell membrane underneath the inner leaflet. Motor proteins like myosin (that moves along actin microfilaments) and dynein and kinesin (that move along tubulin microtubules) carry cargo (vesicles, organelles) directionally. The cell is not a disorganized collection of molecules and organelles. Instead, it is highly organized to optimize chemical production, use, and degradation.

Cells have various shapes. Some circulating immune cells must slip through the cells that line capillary walls to migrate to sites of infection. The same process occurs when tumor cells metastasize and escape to other sites in the body. To do so, the cell must drastically change shape, a response that requires the dissociation of the cytoskeleton polymers into monomers, which are later available for polymerization. The following video shows the mobility and flexibility of a Killer T-cell as it attacks and kills a cancerous cell.

Video 1.1 Killer T Cell Attacking Cancer. Video available on YouTube through Creative Commons by Cambridge University

The cell is an amazingly crowded place

In chemistry labs, we typically work with dilute solutions of solute molecules in a solvent. You have probably heard that the body is composed of 68% water, but the water concentration depends on the cellular environment. Solute molecules like protein and carbohydrates are densely packed. Cells are so crowded that the space between larger molecules like proteins is typically smaller than that of a single protein. Studies have shown that the stability of a protein is increased in such conditions, which would help keep the protein in the correctly folded, native state. Another consequence of high intracellular concentrations is that it limits the diffusion of molecules throughout the cell, as expected from an equilibrium perspective in dilute solutions. Thus, cytoplasmic cellular functions can be highly localized within specific cell regions, creating unique microenvironments and higher differentiation potential within a single cell.

Hence, the study of biomolecules in dilute solutions in the lab may not reveal the actual complexities of interactions and activities of the same molecule in vivo. Recently, investigators have added a neutral copolymer of sucrose and epichlorohydrin to cells in vitro. These particles induced the organization of extracellular molecules secreted by the cell, forming an organized extracellular “matrix,” which induced the organization of the microfilaments on the inside and induced changes in cell activity.¹ Furthermore, in vitro enzyme activity of a key enzyme in glycolysis dramatically increases under crowded conditions.² Another result of crowding may be the spatial and temporal association of key enzymes involved in specific metabolic pathways, allowing for the coordinated passage of substrates and products within the colocalized enzyme system.

Figure 1.5: The Crowded Cytoplasm of E. Coli. The computer simulation used 50 different types of the most abundant macromolecules of the E. coli cytoplasm and 1008 individual molecules. Rendering of the cytoplasm model at the end of a dynamics simulation. RNA is shown as green and yellow. This figure was prepared with VMD. Figure adapted from: Ufrom McGuffee SR, Elcock AH (2010) PLoS Comput Biol 6(3): e1000694. doi:10.1371/journal.pcbi.1000694 (open source journal)

Cell components undergo phase transitions to form substructures within the cell.

A perplexing question is how substructures form within a cell. This includes the biogenesis of organelles like mitochondria and smaller particles such as polysaccharide granules, lipid droplets, protein/RNA particles (including the ribosome), and the nucleolus of the cell nucleus. It might be easiest to consider this problem using two examples from the lipid world: lipid droplets and membrane rafts. Phase transitions occur when a sparingly soluble nonpolar liquid is added to water. At a high enough concentration, the solubility of the nonpolar liquid is exceeded, and a phase transition occurs, as evidenced by the appearance of two separate liquid phases. The identical process occurs when triglycerides coalesce into lipid droplets with proteins associated on their outside. Another example occurs within a cell membrane when lipids with saturated alkyl chains self-associate with membrane cholesterol (which contains a rigid planar ring system) to form a lipid raft membrane microdomain. Lipid rafts are characterized by greater packing efficiency, rigidity, and thickness than other membrane parts. These lipid rafts often recruit proteins involved in signaling processes within the cell membranes. This phase separation process is called liquid/liquid demixing, as two “liquid-like” substances separate.

Similarly, it appears that proteins that interact with RNA are composed of less diverse amino acid sequences and have more flexible (“more liquid-like) structures, allowing their preferential interaction with RNA to form large RNA-protein particles (like the ribosome and other RNA processing structures) in a fashion that mimics liquid/liquid demixing. All of these interactions are just manifestations of the various intermolecular forces that can exist between molecules. These include ionic interactions, ion-dipole interactions, dipole-dipole interactions, and London dispersion forces.  A review of intermolecular forces can be found in a Kahn Academy video on YouTube.

Summary

Chapter Summary

This chapter offers an integrative overview of cellular biochemistry by framing the cell as a dynamic chemical factory. It emphasizes that, although cells have been traditionally studied from a biological perspective, a chemical viewpoint reveals the intricate processes that drive cellular life. Key points include:

• Cellular Structure and Biomolecules:
  The chapter begins by reviewing the fundamental organization of cells, distinguishing between prokaryotic and eukaryotic types. It highlights the common presence of major biomolecules—lipids, proteins, nucleic acids, and carbohydrates—and outlines their synthesis, distribution, and degradation within eukaryotic animal cells.

• Metabolic Processes:
  Metabolism is portrayed as the orchestrated series of chemical reactions that power cellular functions. This includes:

  • Catabolic Reactions: Breaking down complex molecules to release energy.
  • Anabolic Reactions: Building complex biomolecules from simpler units using energy.
  • The integration of these processes is crucial for energy balance, growth, and response to environmental changes.

• Enzyme Catalysis and Regulation:
  Enzymes are introduced as essential catalysts that accelerate metabolic reactions. Two primary models of enzyme-substrate interactions are discussed:

  • Lock and Key Model: Emphasizing a perfect fit between enzyme and substrate.
  • Induced Fit Model: Highlighting structural changes in the enzyme upon substrate binding. These models illustrate how enzyme structure is key to function and regulation, allowing cells to respond to internal and external signals.

• Cellular Compartmentalization and Transport:
  The chapter explains how the compartmentalization of metabolic processes into distinct organelles (such as the nucleus, mitochondria, endoplasmic reticulum, and lysosomes) enhances efficiency and regulation. It also covers various transport mechanisms—including passive diffusion, facilitated diffusion, and active transport—that allow selective import and export of molecules, thereby maintaining internal homeostasis.

• Cellular Architecture and Crowding:
  An analogy to a factory is used to describe the cytoskeleton—a network of microfilaments, intermediate filaments, and microtubules—that provides structural support and facilitates intracellular transport. The crowded cellular environment is noted for influencing biomolecular interactions, protein stability, and localized reaction dynamics.

• Phase Transitions and Subcellular Organization:
  Finally, the chapter discusses how phase separation phenomena, such as liquid/liquid demixing, lead to the formation of specialized cellular substructures. Examples include the formation of lipid droplets and membrane rafts, which are driven by intermolecular forces like ionic and dipole interactions.

Overall, the chapter sets the stage for deeper exploration into the structure, function, and regulation of specific biomolecules by connecting fundamental chemical principles with cellular physiology and highlighting their relevance to health and disease.