Amino Acids

Stereochemistry and Chirality

Summary

Chirality in amino acids arises from the tetrahedral α-carbon bearing four different substituents. All proteinogenic amino acids (except glycine) are L-enantiomers, a choice that pervades all of biochemistry and determines protein structure, enzyme specificity, and drug-receptor interactions.

Key Points

  • 1Chirality arises from four different groups on α-carbon
  • 2All proteinogenic amino acids are L-enantiomers (except achiral glycine)
  • 3Homochirality enables consistent protein secondary and tertiary structure
  • 4D-amino acids occur in bacteria, antibiotics, and as signaling molecules

Stereochemistry is fundamental to understanding why life uses specific molecular forms and how proteins achieve their exquisite selectivity.

Fundamentals of Chirality

The Chiral Center

A carbon atom is chiral (asymmetric) when bonded to four different groups:

- For amino acids, this is the α-carbon (Cα)

  • Substituents: amino group, carboxyl group, hydrogen, R group

    • - Glycine exception: R = H, so only three different groups (achiral)

    Enantiomers

    Chiral molecules exist as non-superimposable mirror images:

    - L-amino acids: The biological form

    - D-amino acids: Mirror images of L-amino acids

  • Same physical properties (melting point, solubility)
  • Differ in interaction with other chiral molecules

    • Nomenclature Systems

    D/L System (Fischer Convention)

    Based on comparison to glyceraldehyde:

    - L-amino acids: Amino group on LEFT in Fischer projection

    - D-amino acids: Amino group on RIGHT

  • Named after Latin: *laevus* (left), *dexter* (right)

    • R/S System (Cahn-Ingold-Prelog)

    Absolute configuration based on priority rules:

    - Most L-amino acids are (S) configuration

    - Exception: L-cysteine is (R) due to sulfur's high priority

  • More rigorous but less intuitive for amino acids

    • The Homochirality of Life

    L-Amino Acids Dominate

    All ribosomally synthesized proteins use exclusively L-amino acids:

  • Encoded by the genetic code
  • Recognized by aminoacyl-tRNA synthetases
  • Essential for proper protein folding

    • Origin of Homochirality

    One of biology's great mysteries:

    - Chance: Initial random selection, then amplification

    - Asymmetric catalysis: Chiral minerals or light

    - Extraterrestrial origin: Meteorites show L-excess

    - Parity violation: Weak nuclear force slightly favors L

    Consequences for Protein Structure

    Backbone Conformation

    L-configuration restricts allowed backbone angles:

    - Ramachandran plot: Reflects L-amino acid geometry

  • D-amino acids would have inverted allowed regions
  • Mixing L and D would disrupt regular secondary structures

    • Secondary Structure

    All common secondary structures assume L-amino acids:

    - Right-handed α-helix: Favored for L-amino acids

    - Left-handed α-helix: Would require D-amino acids

    - β-sheets: Geometry depends on L-configuration

    Tertiary Structure

    Protein folds are stereospecific:

  • Chiral active sites recognize substrate chirality
  • Enzyme-substrate "lock and key" requires matching
  • D-amino acid substitution typically inactivates proteins

    • D-Amino Acids in Biology

    Non-Ribosomal Sources

    D-amino acids do occur naturally:

    - Bacterial cell walls: D-Ala, D-Glu in peptidoglycan

    - Antibiotics: Many contain D-amino acids (vancomycin, gramicidin)

    - Venoms: D-amino acids in cone snail toxins

    - Aged tissues: Spontaneous racemization over time

    Racemases

    Enzymes that interconvert L and D forms:

  • Alanine racemase (essential for bacteria)
  • Serine racemase (produces D-serine in brain)
  • Drug targets: Inhibiting racemases kills bacteria

    • D-Serine and D-Aspartate

    Important signaling molecules:

    - D-Serine: Co-agonist at NMDA receptors

    - D-Aspartate: Neuroendocrine signaling

  • Challenges the "L-only" paradigm

    • Pharmaceutical Implications

    Chiral Drugs

    Many drugs are chiral, with different enantiomer activities:

    - Thalidomide tragedy: One enantiomer therapeutic, other teratogenic

  • Modern drugs often sold as pure enantiomers
  • FDA requires evaluation of both forms

    • Proteolytic Stability

    D-amino acids confer protease resistance:

  • Proteases evolved to cleave L-amino acid bonds
  • D-substituted peptides have longer half-lives
  • Strategy for peptide drug design

    • Mirror-Image Proteins

    D-proteins (made from D-amino acids) are:

  • Resistant to all natural proteases
  • Invisible to the immune system
  • Potentially useful therapeutics ("mirror-image phage display")
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