Cell Bio Lecture 3

Alanine

Ala A

Arginine

Arg R

Asparagine

Asn N

Aspartate

Asp D

Cysteine

Cys C

Glutamate

Glu E

Glutamine

Gln Q

Glycine

Gly G

Histidine

His H

Isoleucine

lle I

Leucine

Leu L

Lysine

Lys K

Methionine

Met M

Phenylalanine

Phe F

Proline

Pro P

Serine

Ser S

Threonine

Thr T

Tryptophan

Trp W

Tyrosine

Tyr Y

Valine

Val V

D vs L Amino Acids

• Proteins are composed almost exclusively of L-amino acids

• D- vs L- refers to the stereochemistry (orientation) around the α-carbon, NOT the amino acid identity

• Aspartate (Asp) vs Leucine (Leu) = different amino acids

• D vs L = mirror-image forms of the SAME amino acid

Important Notes:

• L-amino acids → used in ribosomally synthesized proteins

• Some D-amino acids have biological functions, but are NOT incorporated into human proteins

  • Examples:

    • Bacterial cell walls (peptidoglycan)

    • Neurotransmission/modulation (rare in humans)

Exam Tip 🧠:

If the question is about protein structure or synthesis → choose L-amino acids

Glycine

(Gly, G) Nonpolar, hydrophobic

• R-group: -H (just hydrogen - simplest/smallest amino acid)

• Achiral (only amino acid without chirality - has 2 H's on α-carbon, no stereoisomer)

• Provides extreme flexibility in protein

• Helix breaker - too flexible, lacks side chain for stability

• Found at tight turns and loops in proteins

• Inhibitory neurotransmitter in CNS

• Precursor for heme and purine biosynthesis

• Small size + flexibility allow extreme conformational freedom

• Enriched in collagen (allows tight packing at center)

Alanine

(Ala, A)Nonpolar, hydrophobic

• R-group: -CH₃ (methyl - smallest side chain after glycine)

• Chiral (unlike glycine)

• Slightly more bulk → favors α-helices (provides stability)

• Precursor for pyruvate (energy production)

• Found in extraterrestrial samples

• Key difference: Glycine = flexibility (turns); Alanine = stability (helices)

Valine

(Val, V) Nonpolar, hydrophobic

• R-group: Branched aliphatic (isopropyl)

• Essential amino acid (must come from diet)

• BCAA (branched-chain amino acid)

• Glucogenic (converts to glucose)

• Stabilizes hydrophobic cores

• Muscle protein synthesis

• Promotes glucose uptake by muscles

• Energy production during prolonged exercise

• Prevents muscle wasting

Leucine

(Leu, L) Nonpolar, hydrophobic

• R-group: Branched aliphatic (isobutyl)

• Essential amino acid (must come from diet)

• BCAA (branched-chain amino acid)

• Coded by 6 codons (most redundant)

• Activates mTOR pathway (muscle growth, autophagy)

• Can convert to ketone bodies (ketogenic)

• Especially stimulates muscle protein synthesis (key BCAA player)

• Used in athletic supplements for performance

Isoleucine

• R-group: Branched aliphatic (sec-butyl)

• Essential amino acid (must come from diet)

• BCAA (branched-chain amino acid)

• Dual metabolic role: Glucogenic AND ketogenic (unique!)

• Promotes glucose uptake by muscles

• Helps maintain blood sugar levels

• Energy production during prolonged exercise

Methionine

• Nonpolar, hydrophobic

• R-group: -CH₂-CH₂-S-CH₃ (thioether - contains sulfur)

• Essential amino acid (must come from diet)

• START codon (AUG) for protein synthesis (every protein begins with Met)

• Sulfur is polarizable → adaptable interactions

• Reversibly oxidized → protective buffer during oxidative stress

• Precursor for SAM (S-adenosylmethionine) - main methyl donor in biology

• Methylation of DNA, epigenetic regulation

• Soft and polarizable sulfur gives flexibility

Phenylalanine

• Nonpolar, hydrophobic

• R-group: Benzyl (benzene ring)

• Essential amino acid (must come from diet)

• Large, bulky, hydrophobic

• Precursor for tyrosine

• Protein-protein interactions

• Aromatic ring allows π-π stacking

Tryptophan

• Nonpolar, hydrophobic

• R-group: Indole (largest aromatic side chain)

• Essential amino acid (must come from diet)

• Bulkiest amino acid of all 20

• Precursor for serotonin (mood, sleep)

• Precursor for niacin (Vitamin B3)

• Pellagra disease (deficiency): 4 D's - Dermatitis, Diarrhea, Dementia, Death

• Pathway: Tryptophan → Niacin (Vitamin B3)

• Historical: Early 1900s American South - corn-based diets low in tryptophan

• Corn's niacin is bound (unavailable)

• Lesson: Essential amino acids = public health issue

Proline

• Nonpolar, hydrophobic

• R-group: Cyclic (forms ring back to backbone nitrogen)

• α-helix breaker - too rigid, lacks H-bond donor for helix backbone

• Restricts phi (φ) rotation - locked position, limits flexibility

• Creates rigid kinks in protein structure

• Enriched in collagen (provides rigidity)

• Can be hydroxylated to hydroxyproline (requires Vitamin C)

• Vitamin C deficiency → scurvy (defective collagen)

• Cannot be in membrane-spanning helix (breaks helix structure)

• Opposite of glycine: rigid vs flexible

Serine

• Polar, uncharged HYDROPHILIC

• R-group: -CH₂-OH (hydroxyl)

• Small, polar, hydrophilic

• Phosphorylation site (Ser-OH → Ser-OPO₃²⁻)

• Important in cell signaling cascades

• Precursor for glycine and cysteine

• Part of "Phosphorylation Trio" (S, T, Y)

• Post-translational modification site

Threonine

• Polar, uncharged HYDROPHILIC

• R-group: -CH(OH)-CH₃ (secondary alcohol)

• Essential amino acid (must come from diet)

• Phosphorylation site

• Has 2 chiral centers (α-carbon + β-carbon)

• Part of "Phosphorylation Trio" (S, T, Y)

• Post-translational modification site

• Cell signaling regulation

Cysteine

• Polar, uncharged HYDROPHILIC

• R-group: -CH₂-SH (thiol/sulfhydryl)

• Forms disulfide bonds (Cys-S-S-Cys)

• Ionizable side chain: pKa ~8.3

• At pH 7.4: mostly protonated (free -SH form)

• CRITICAL DISTINCTION - Cysteine vs Cystine:

  • Cysteine: Reduced form (free -SH)

  • Cystine: Oxidized form (two cysteines linked by -S-S-)

  • NOT two different amino acids - just redox states

• Context trap - Cellular Environment:

  • Inside cell (cytoplasm): Reducing → favors cysteine (free -SH)

  • Outside cell/ER lumen: Oxidizing → favors cystine (disulfide bonds)

• Disulfide bonds stabilize protein structure (especially extracellular proteins)

• Most disulfides form in ER lumen or outside cell

• Can break/reform during folding and stress

• Hair perm: breaks and reforms disulfides to hold curls

• Exam hints:

  • Oxidation → cystine formation

  • Protein stability → disulfide bonds

  • Extracellular protein → assume cystine present

  • Redox chemistry/metal binding → cysteine

Tyrosine

• Polar (aromatic) HYDROPHILIC

• R-group: Phenolic (benzene-OH)

• Aromatic AND polar (both categories)

• Phosphorylation site (receptor tyrosine kinases - RTKs)

• Ionizable side chain: pKa ~10.1 (phenol)

• At pH 7.4: mostly uncharged (pH < pKa)

• Can be hydroxylated

• Precursor for neurotransmitters: dopamine, norepinephrine, epinephrine

• Precursor for thyroid hormones (T3, T4)

• Part of "Phosphorylation Trio" (S, T, Y)

• Critical for cell signaling (kinase cascades)

Asparagine

• Polar, uncharged HYDROPHILIC

• R-group: -CH₂-CONH₂ (amide)

• Polar, neutral at all physiological pH

• Can form hydrogen bonds

• Similar to Asp but uncharged (amide vs carboxyl)

• The amide group prevents ionization

Glutamine

• Polar, uncharged HYDROPHILIC

• R-group: -CH₂-CH₂-CONH₂ (amide - one more CH₂ than Asn)

• Polar, neutral at all physiological pH

• Important in rapidly dividing cells (including cancer)

• Used in protein synthesis

• Enhances fuel metabolism (provides TCA cycle components)

• Provides nitrogens for nucleotide synthesis (RNA/DNA)

• Similar to Glu but uncharged (amide vs carboxyl)

Aspartate

• Polar, charged, HYDROPHILIC

• Negatively charged (at pH 7.4)

  • R-group: -CH₂-COO⁻ (carboxylic acid - shorter than Glu)

  • Ionizable side chain: pKa ~3.9

  • At pH 7.4: negatively charged (pH > pKa → deprotonated)

  • Forms salt bridges with Lys, Arg, His

  • Maintains charge balance in proteins

  • Enables electrostatic interactions

  • Central to metabolic pathways (amino acid metabolism)

  • Hydrophilic - found on protein surfaces

Glutamate

• Polar, charged, HYDROPHILIC

• Negatively charged (at pH 7.4)

  • R-group: -CH₂-CH₂-COO⁻ (carboxylic acid - one more CH₂ than Asp)

  • Ionizable side chain: pKa ~4.3

  • At pH 7.4: negatively charged (pH > pKa → deprotonated)

  • Forms salt bridges with Lys, Arg, His

  • Key player in amino acid metabolism

  • Neurotransmitter (excitatory in CNS)

  • Monosodium glutamate (MSG) enhances umami flavor

  • Umami = one of five basic tastes (sweet, sour, bitter, salty, umami)

  • Japanese word for "deliciousness" - savory taste in soy sauce, cheese, meats

  • Sickle cell anemia: Glu → Val mutation at position 6 of hemoglobin β-chain

Lysine

• Polar, charged, HYDROPHILIC

• R-group: -(CH₂)₄-NH₃⁺ (long chain ending in amino group)

• Essential amino acid (must come from diet)

• Ionizable side chain: pKa ~10.5

• At pH 7.4: positively charged (pH < pKa → protonated)

• Interacts with negatively charged molecules (DNA, phosphates)

• Forms salt bridges with Asp and Glu

• Deficiency linked to increased stress and anxiety

• Important for physical and mental health

Arginine

• Polar, charged, HYDROPHILIC

• Positively charged (at pH 7.4)

  • R-group: Guanidinium group (very basic)

  • Ionizable side chain: pKa ~12.5 (highest pKa of all amino acids)

  • At pH 7.4: very positively charged (pH < pKa → protonated)

  • More basic and more positively charged than lysine

  • Effective at binding negatively charged molecules/ions

  • Forms salt bridges with Asp and Glu

  • Precursor for nitric oxide (NO) - vascular health, immune function

  • Remains charged across nearly all physiological pH ranges

Histidine

• Polar, charged, HYDROPHILIC

• R-group: Imidazole ring (aromatic)

• Ionizable side chain: pKa ~6.0 ⭐ MOST IMPORTANT

• Uniquely close to physiological pH (7.4)

• At pH 7.4: can be charged (+) or neutral depending on microenvironment

• "The exam question amino acid"

• "Swiss Army knife of catalysis"

• Why Histidine is Special:

  • Lives on the edge of protonation at physiological pH

  • Tiny environmental shifts change its charge state

  • Can both donate AND accept protons (amphoteric)

  • Workhorse for general acid/base catalysis

  • Pivot point that shuttles protons around

• Used in hemoglobin (Bohr effect - adjusts protonation to tune O₂ affinity)

• Ideal for metal binding (Zn²⁺, Cu²⁺ coordination spheres)

• Found in active sites of many enzymes

• Precursor for histamine (immune response, allergies)

• Occasionally used in phosphorylation pathways

• Ideal pKa for catalytic residue: Around physiological pH (~6-7) - Histidine is perfect

How pH Affects Amino Acid Side-Chain Ionization

• pH determines the protonation state of ionizable side chains

• Ionizable amino acids: D, E, R, K, H, C, Y, S, T

• Each ionizable group has a pKa

  • pH < pKa → protonated

  • pH > pKa → deprotonated

Key Concepts:

• Titration curve shows stepwise loss of protons as pH increases

• Plateaus = buffering regions (near pKa values)

• Isoelectric point (pI):

  • pH where net charge = 0

  • Occurs between pKa values surrounding the neutral species

Charge Trends:

• Acidic side chains (D, E):

  • Low pH → neutral

  • High pH → negative

• Basic side chains (K, R, H):

  • Low pH → positive

  • High pH → neutral

Exam Tip 🧠:

Compare pH to pKa to predict charge — don’t memorize charge blindly

SUMMARY TABLE - ALL IONIZABLE GROUPS

Amino Acid	Side Chain	Side Chain pKa	Charge at pH 7.4	Category
Asp (D)	β-Carboxyl	3.65	Negative (-)	Acidic
Glu (E)	γ-Carboxyl	4.25	Negative (-)	Acidic
His (H)	Imidazole	6.00 ⭐	+/Neutral (toggles)	Basic
Cys (C)	Thiol	8.00-8.30	Neutral (mostly)	Weakly acidic
Tyr (Y)	Phenol	10.07	Neutral	Weakly acidic
Lys (K)	ε-Amino	10.53	Positive (+)	Basic
Arg (R)	Guanidinium	12.48	Positive (+)	Basic
Ser (S)	Hydroxyl	~13-14	Neutral (no ionization)	NOT ionizable*
Thr (T)	Hydroxyl	~13-14	Neutral (no ionization)	NOT ionizable*

*Ser and Thr hydroxyls have pKas so high (~13-14) that they do NOT ionize at any physiologically relevant pH

Essential amino acids VS Non essential amino acid

Essential amino acids cannot be produced by the body and must be obtained through diet, while nonessential amino acids are produced internally. The 9 essential amino acids are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Nonessential amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine. 

Essential Amino Acids (Must be consumed):

• Histidine

• Isoleucine

• Leucine

• Lysine

• Methionine

• Phenylalanine

• Threonine

• Tryptophan

• Valine 

Nonessential Amino Acids (Produced by the body):

• Alanine

• Asparagine

• Aspartic acid

• Glutamic acid

• Serine 

Conditionally Essential Amino Acids:
These are typically nonessential, but become necessary during illness, stress, or intense training: 

• Arginine

• Cysteine

• Glutamine

• Tyrosine

• Glycine

• Proline

• Ornithine