Chapter 1 Notes: The Foundations of Biochemistry
1.1 Cellular Foundations
About $14 imes 10^{9}$ years ago, the universe arose as a cataclysmic explosion of hot, energy-rich subatomic particles. As it expanded and cooled, hydrogen and helium formed; stars formed, some exploded as supernovae, releasing energy to fuse heavier elements. Atoms and molecules formed swirling dust, leading to rocks, planetoids, and planets. Earth and its chemical elements emerged over billions of years.
About $4 imes 10^{9}$ years ago, life arose on Earth: simple microorganisms that could extract energy from chemical compounds and, later, from sunlight, which powered synthesis of diverse biomolecules from simple Earth-surface elements.
We and all living organisms are made of stardust. Biochemistry asks how living organisms’ remarkable properties arise from thousands of biomolecules, and how collections of inanimate molecules interact to sustain life under physical and chemical laws that also govern the nonliving universe.
Central idea: Living organisms organize around a program carried by molecular components; cells are the fundamental unit of life, yet they share striking similarities across diversity.
Life is a dynamic steady state, not an equilibrium with surroundings. Following thermodynamics, living systems extract energy from surroundings to maintain homeostasis and perform work.
Essentially all cellular energy comes from electron flow, driven by sunlight or by metabolic redox reactions.
Cells have the capacity for precise self-replication and self-assembly using genetic information stored in the genome.
A single bacterial cell in a sterile nutrient medium can yield about $10^{9}$ identical daughter cells in 24 hours.
On a larger scale, vertebrate offspring resemble their parents due to inheritance of parental genes.
Evolution over eons produced enormous biodiversity. Despite differences, all forms are fundamentally related through shared ancestry; molecular-level similarities in gene sequences and protein structures reveal this unity.
Earth hosts enormous diversity of organisms across habitats (hot springs, Arctic tundra, intestinal tracts, dormitories, etc.). Biochemical adaptations occur within a common chemical framework.
The introductory chapter emphasizes: cellular, chemical, physical, and genetic backgrounds of biochemistry and the overarching principle of evolution; the chapter encourages revisiting this background material to refresh memory.
1.2 Chemical Foundations
Biochemistry aims to explain biological form and function in chemical terms.
Historical note: early 20th century work showed remarkable chemical similarities in glucose breakdown in yeast and animal muscle—same 10 intermediates and same 10 enzymes. Jacques Monod summarized universality: “What is true of E. coli is true of the elephant.” This underscores biochemical unity across life.
Elements and metabolism:
Fewer than $30$ of the naturally occurring elements are essential to organisms.
Most essential elements have low atomic numbers; only three elements have atomic number above selenium (34).
The four most abundant elements by atom percent are hydrogen (H), oxygen (O), nitrogen (N), and carbon (C). Together they comprise >99% of the mass of most cells and can form one, two, three, and four bonds, respectively; light elements tend to form the strongest bonds.
Trace elements are present in small amounts but are essential (often for proteins/enzymes, e.g., the iron ions that enable hemoglobin to transport oxygen).
Biomolecules are carbon-based with functional groups that give them distinct chemical properties.
Biomolecule chemistry: Carbon versatility governs biology.
Carbon can form single bonds with H and form single, double, and triple bonds with O, N, and C. Carbon can form very stable single bonds with up to four other carbon atoms; two carbons can share two or three electron pairs, yielding double or triple bonds.
Bond lengths and geometry: C–C single bonds are about $0.154 ext{ nm}$; C=C double bonds are about $0.134 ext{ nm}$; a carbon atom typically adopts a tetrahedral arrangement with bond angles near $109.5^
deg$.There is free rotation around each C–C single bond unless bulky or highly charged substituents restrict rotation.
Carbon skeletons can be linear, branched, or cyclic; the bonding versatility of carbon with itself and other elements was likely a key factor in selecting carbon-based chemistry for life.
Functional groups and molecular “personalities.”
Most biomolecules derive from hydrocarbons with functional groups such as: alcohols (–OH), amines (–NH2), carbonyls (aldehydes/ketones), carboxyls (–COOH).
Many biomolecules are polyfunctional (contain two or more functional groups), giving them diverse reactivity.
The “personality” of a molecule depends on the chemistry of its functional groups and their three-dimensional disposition.
Figure references (e.g., Fig. 1-14) illustrate common functional groups and how substituents are represented (R = any substituent).
Acetyl-CoA and metabolic carriers.
Acetyl-CoA is a carrier of acetyl groups in enzymatic reactions; it contains screened functional groups, and the acetyl moiety is linked via a critical thioester bond to CoA (sulfur-containing linkage).
Universal small molecules (cytosol) and metabolism.
Cells harbor a universal set of small organic molecules in the cytosol, with intracellular concentrations spanning from nanomolar to >10 mM; these include amino acids, nucleotides, sugars and their phosphorylated derivatives, and mono-, di-, and tricarboxylic acids.
These metabolites are polar/charged and water-soluble; the plasma membrane impedes their diffusion, so transporters are needed to move them into/out of cells or between compartments.
Conservation of these core metabolites and central metabolic pathways across evolution underlies biochemical unity.
Metabolome and metabolomics.
The entire collection of small molecules in a cell under specific conditions is the metabolome; metabolomics is the systematic study/characterization of the metabolome under defined conditions (e.g., drug administration, hormonal signaling).
Macromolecules and their major classes.
Macromolecules are polymers with molecular weights above roughly $5{,}000$ Da; shorter polymers are oligomers.
Major macromolecule classes: proteins (polymers of amino acids), nucleic acids (DNA and RNA; polymers of nucleotides), and polysaccharides (polymers of sugars).
Proteins can be enzymes, structural elements, signal receptors, or transporters; together they constitute the proteome; proteomics studies the protein complement under particular conditions.
Nucleic acids store and transmit genetic information; some RNA molecules have structural and catalytic roles; the genome is the complete sequence of DNA (or RNA in RNA viruses); genomics studies structure, function, evolution, and mapping of genomes.
Polysaccharides function in energy storage, structural components of cell walls, and extracellular recognition; short oligosaccharides attached to proteins/lipids serve as signals; the glycome is the full set of carbohydrate-containing molecules in a cell.
Lipids are hydrophobic hydrocarbons functioning as membrane components, energy stores, pigments, and intracellular signals; the lipidome is the set of lipid-containing molecules in a cell.
Macromolecules are large: proteins typically range from $5{,}000$ Da to >1,000,000 Da; DNA can be billions of Da; polysaccharides can reach millions of Da; individual lipids are much smaller ($
oughly 750$–$1{,}500)$ Da but can assemble into large noncovalent structures.Cellular membranes arise from massive noncovalent assemblies of lipids and proteins; these informational macromolecules (proteins and nucleic acids) carry information sequences that encode their structure and function; some oligosaccharides also act as informational molecules.
Structural organization and three-dimensional structure.
Three-dimensional structure of biomolecules is described by configuration (stereochemistry at chiral centers and double-bond geometry) and conformation (spatial arrangement of atoms that can change by rotation about single bonds without breaking covalent bonds).
Stereochemistry and biomolecule interactions are highly stereospecific; biological recognition often requires complementary configuration and conformation.
Stereochemistry and stereoisomerism.
Configuration vs. conformation: configuration is fixed by covalent bonds (e.g., chiral centers and double-bond geometry); conformation is the arrangement enabled by rotation about single bonds.
Chiral centers: carbon with four different substituents is asymmetric; asymmetric carbons are called chiral centers.
Enantiomers are mirror-image stereoisomers; diastereomers are not mirror images.
A molecule with one chiral center has two stereoisomers; with $n$ chiral centers, there are up to $2^n$ stereoisomers.
Pasteur’s optical activity: enantiomers rotate plane-polarized light in opposite directions; racemic mixtures show no net rotation.
Box 1-2 (Pasteur): historical example with tartaric acid; later x-ray crystallography confirmed absolute configurations; alanine’s enantiomeric form in proteins is exclusively the L form (R/S details to be discussed in later chapters).
Nomenclature and the RS system.
The RS (Cahn–Ingold–Prelog) system assigns priorities to groups attached to a chiral center; viewing with the lowest-priority group away, if 1→2→3 is clockwise, the center is (R); if counterclockwise, (S).
The D/L system is an alternative for sugars and amino acids; no universal direct correlation exists between D/L and R/S.
Geometric isomers and retinal example.
Geometric isomers (cis/trans) differ around non-rotating double bonds; energy differences prevent interconversion without bond cleavage.
In vision, 11-cis-retinal absorbs light and converts to all-trans-retinal, triggering a neural signal; energy involved is about $E \,\approx\, 250\ \,\mathrm{kJ/mol}$ for the isomerization.
Conformational analysis and steric effects.
Ethane has many conformations due to rotation about the C–C bond; the staggered conformation is most stable; eclipsed is least stable.
Large or charged substituents restrict rotation, reducing the number of accessible conformations.
Molecular recognition and stereospecific interactions.
Biomolecule interactions are often stereospecific; the fit between a reactant and enzyme or a hormone and receptor depends on precise stereochemistry.
Figure 1-22 illustrates glucose fitting into the hexokinase active site and being held by noncovalent interactions.
Stereochemical consequences in pharmacology.
Enantiomeric specificity has practical consequences: some drugs are racemic mixtures, while the active component is one enantiomer (e.g., citalopram: one enantiomer is therapeutically active; a pure enantiomer may have lower effective dose).
Examples: aspartame has different taste properties for enantiomers; Lexapro (escitalopram) is the single active enantiomer, with about half the dose of its racemate.
Summary: Key chemical foundations.
Carbon’s bonding versatility creates diverse carbon–carbon skeletons with various functional groups that define biomolecule personalities.
A nearly universal set of small molecules exists in living cells; their interconversions in central metabolism are evolutionarily conserved.
Proteins and nucleic acids are informational macromolecules; polysaccharides and lipids have structural, energetic, and signaling roles; membranes arise from complex, noncovalent assemblies.
Molecular configuration and conformation govern stereochemical interactions; most biomolecules in life exist predominantly in one chiral form (e.g., L amino acids in proteins; D sugars).
Stereospecificity is a fundamental property of enzymes and biomolecular interactions.
Box 1-1: Molecular weight, molecular mass, and their correct units
There are two common (and equivalent) ways to describe molecular mass:
Molecular weight (relative molecular mass) denoted $M_r$ (dimensionless): the ratio of the mass of a molecule to $1/12^{ ext{th}}$ the mass of a carbon-12 atom.
Molecular mass, denoted $m$, is the mass of one molecule (or molar mass divided by Avogadro’s number).
The molecular mass $m$ is expressed in daltons (Da). A kilodalton is $1\text{ kDa} = 10^3 \text{ Da}$; a megadalton is $1 \text{ MDa} = 10^6 \text{ Da}$.
Example: a molecule with mass $1{,}000$ times that of water can be described as either $M_r = 18{,}000$ or $m = 18{,}000\text{ Da}$ (often written as 18 kDa).
Note: the use of Da is convenient for describing masses of single molecules; polymer masses are often given in kDa or MDa.
Box 1-2: Louis Pasteur and optical activity
Pasteur observed optical activity by separating mirror-image crystals (tartaric acid racemate crystals); each isolated form rotates plane-polarized light in opposite directions, despite identical chemical properties.
His work established that enantiomeric forms are non-superposable mirror images with identical chemical properties but different spatial arrangement.
Later work showed absolute configurations (e.g., (R,R) and (S,S) for tartaric acid; amino acids in proteins are exclusively the (S) isomer (except cysteine).
RS naming convention and D/L system
The RS system assigns priorities to substituents at a chiral center to determine (R) or (S) configuration; the D/L system is used for different biomolecule classes and does not universally map to R/S.
A molecule can be named with RS designations to describe stereochemistry unambiguously; in many biomolecules, only one chiral form is biologically active.
1.3 Physical Foundations
Living organisms operate far from equilibrium and rely on energy flow to maintain homeostasis and perform work; this energy is derived from electron flow powered by light and metabolic redox reactions.
The cellular state is dynamic and regulated by continuous energy input, enabling self-replication, self-organization, and adaptation.
Noncovalent interactions (hydrogen bonds, ionic interactions, van der Waals forces, hydrophobic effects) underpin the formation of macromolecular structures and complexes (e.g., membranes, ribosomes, protein complexes).
The same physical laws that describe nonliving matter apply to living systems; life is constrained by thermodynamics, kinetics, and molecular interactions.
1.4 Genetic Foundations
Cells store information in genetic material (DNA; RNA in some viruses) that directs structure and function.
The genome is the full sequence of genetic material of a cell or organism; genomics studies the structure, function, evolution, and mapping of genomes.
Precise self-replication and self-assembly rely on the information encoded in the genome; inheritance occurs through parental genes, leading to similarity between offspring and parents.
The information content of the genome dictates the synthesis of proteins and other biomolecules, enabling development, metabolism, and adaptation.
1.5 Evolutionary Foundations
Living organisms evolve through gradual changes over time, driven by mutation, selection, and genetic drift, resulting in diversity.
All organisms share a common ancestry, which is reflected at the molecular level in the similarity of gene sequences and protein structures, evidencing biochemical unity across life.
Despite enormous diversity, life exists within a common chemical framework; explores habitats from hot springs to Arctic tundra, from intestines to dormitories; this diversity arises from the same underlying chemistry and evolutionary principles.
While broad generalizations are useful for teaching, exceptions exist and can illuminate special cases; the book emphasizes both generalizations and the notable deviations observed in biology.
Key concepts and recurring themes
Cellular foundations: cells as the basic units of life; a dynamic, energy-dependent, information-driven system that reproduces and evolves.
Biochemical unity: a shared set of chemical intermediates, pathways, and molecular logic across organisms, underpinned by conserved chemistry and core metabolites.
Carbon as the central element: diverse bonding (single, double, triple) and functional groups create a vast landscape of biomolecules.
Functional groups and molecular personality: the reactivity and behavior of biomolecules are determined by their functional groups and three-dimensional arrangement.
Macromolecules and information: proteins and nucleic acids carry information; polymetric assembly and regulation underlie cellular function; lipids and polysaccharides contribute structure, energy storage, signaling, and recognition.
Three-dimensional structure and stereochemistry: configuration and conformation govern molecular interactions; stereospecificity is a hallmark of biochemistry and a key factor in pharmacology and physiology.
Nomenclature and measurement: RS system for stereochemistry; Box 1-1 and Box 1-2 provide units and historical perspectives; mass units (Da, kDa, MDa); optical activity and Pasteur’s legacy.
Real-world relevance: biochemical principles inform medicine, agriculture, nutrition, and industry; the study of metabolism and biomolecular interactions explains both normal physiology and disease.