2. Amino Acids and Peptides

Amino Acids and Peptides

• There are 20 amino acids used for protein synthesis.
• Amino acids are building blocks of peptides and proteins.
  • Peptides are shorter polymers of amino acids.
  • Proteins are longer polymers of amino acids.

Amino Acid Structure

• Monomer Structure:
  • Acetic or carboxy group.
  • Amino group on the alpha carbon.
  • Side chains (R groups) that differ among amino acids.

Peptide Structure

• Polymers consist of multiple amino acids linked together.
• Example: A polymer with four amino acids is a peptide.

Chirality

• Amino acids are chiral around the alpha carbon.
• Asymmetric molecules have L and D isomers (mirror images).
• Proteins contain amino acids in the L configuration.

Acid-Base Properties

• Amino acids have weak acidic and basic groups.
• Carboxyl group:
  • Deprotonates (loses a proton) at pH > 2.
• Amino group:
  • Protonates (gains a proton) at pH < 9.
• At intermediate pH levels (including neutral pH of 7):
  • Both groups are ionized.
  • Amino acid has both positive and negative charges.
• Zwitterions:
  • Molecules with two opposite charges.

Peptide Bond Formation

• Formed by covalent linkage of:
  • Carboxyl group of one amino acid.
  • Amino group of a second amino acid.
• Amide bonds:
  • General term for carboxyl-amino linkage.
• Peptide bonds:
  • Specifically refer to linkages of amino acids.
• Formation involves the loss of a water molecule (H_2O).

Polypeptide Characteristics

• Defined by:
  • Number of amino acids.
  • Specific sequence of amino acids.
• R represents the rest of the amino acid molecule.

Polypeptide as Zwitterion

• N-terminal amino group: positively charged.
• C-terminal carboxy group: negatively charged.

Protein/Peptide Length

• Most proteins: 50 to 200 amino acid residues.
• Shorter chains: peptides or oligopeptides.
• Peptides as hormones: Some peptides can act as hormones.

Side Chain Importance

• Side chains provide unique properties to the polypeptide or protein.

Leu-Enkephalin Example

• Pentapeptide (five amino acids).
• Opioid peptide modulates pain perception.
• Sequence: tyrosine, glycine, glycine, phenylalanine, leucine.
• Tyrosine and phenylalanine: aromatic side chains.
• Glycine: hydrogen side chain.
• Leucine: branched side chain.

Directionality

• Importance of directionality: Reversing the sequence changes the molecule's effect.
• Example: reversing leu-enkephalin sequence eliminates opioid effect.

Amino Acid Repertoire

• Proteins are synthesized from 20 amino acids.
• All are alpha amino acids (amino group on carbon adjacent to carboxyl carbon).
• All have the L stereochemical structure.

Side Chain Properties

• Nonpolar side chains (approximately half).
• Polar but uncharged side chains.
• Positively or negatively charged side chains.

Amino Acid Codes

• Three-letter code (straightforward).
• One-letter abbreviation (used by molecular biologists).
• Example: Tryptophan is TRP (three-letter) and W (one-letter).

Nonpolar Amino Acids

• Glycine and alanine: simplest.
  • Glycine: hydrogen side chain.
  • Alanine: methyl group side chain.
• Valine, leucine, and isoleucine: longer hydrocarbon groups, branched chains.

More Nonpolar Amino Acids

• Proline: side chain forms a ring structure with the nitrogen on the alpha carbon (technically an amino acid).
• Methionine and cysteine: contain sulfur.
  • Cysteine: sulfur is present as a sulfhydryl group, which can react with other sulfhydryl groups.
  • Methionine: sulfur atom is methylated.

Aromatic Amino Acids

• Phenylalanine, tyrosine, and tryptophan: aromatic rings.
• Aromatic: hydrocarbon ring with alternating single and double bonds.
• Phenylalanine and tryptophan: nonpolar and hydrophobic.
• Tyrosine: similar to phenylalanine, but has a hydroxyl group (more polar).
• Tryptophan: complex structure with two fused rings.

Charged Amino Acids

• Side chains contain groups that are ionized at physiological pH.
• Acidic amino acids: aspartate and glutamate.
  • Additional carboxyl group with a negative charge.
• Basic amino acids: lysine and arginine.
  • Additional nitrogen groups and a net positive charge.
  • Lysine: Second amino group.
  • Arginine: Three nitrogens covalently bonded to the same carbon.

Histidine

• Ring structure with two nitrogen and three carbon atoms (not aromatic).
• At pH slightly below 7, accepts an additional hydrogen ion and acquires a positive charge.
• pKa is near 6, so both charged and non-charged forms are present at neutral pH.
• Often found in the active site of enzymes.
• Ability to bind and release protons contributes to catalysis.

Polar But Non-Ionized Amino Acids

• Serine and threonine: hydroxyl groups.
• Tyrosine: aromatic and polar amino acid.
• Asparagine and glutamine: derived from aspartate and glutamate.
  • Amino group in amide linkage on the side chain carboxyl group.
  • Highly polar hydrophilic side chain, but cannot ionize at physiological pH.

Leu-Enkephalin Reexamined

• Contains two large aromatic side chains (phenylalanine and tyrosine).
• One branched chain amino acid (leucine).
• Two small nonpolar glycines.

Importance of Side Chains

• Provide unique properties of the molecule.
• Determine specificity for interacting with other molecules.
• Determine overall structure of larger proteins and polypeptides.
• In enzymes, determine substrate specificity and are key components of the catalytic mechanism.

Cystine and Disulfide Bonds

• Sulfhydryl group of cysteine plays a major role in stabilizing protein structure.
• Oxidation of two sulfhydryl groups results in the formation of a disulfide bridge linking two cysteine side chains together.
• Removal of two hydrogen atoms from the molecule (removal of two electrons and two accompanying protons or hydrogen ions).

Vasopressin Example

• Small peptide hormone that stimulates the kidney to reabsorb water.
• Contains nine amino acids with a disulfide bridge between the two cysteine residues.
• Net charge of zero with one positively charged side chain (arginine) and one negatively charged side chain (glutamate).
• Arginine is shown in more detail because this figure is part of a discussion of the use of a synthetic peptide analog as a drug for people who do not synthesize sufficient hormone.

Insulin Example

• Hormone secreted by the beta cells of the pancreas to regulate blood sugar levels.
• Two peptide chains (21 and 30 amino acids long) with different amino acid sequences.
• Chains are attached by two disulfide bridges.
• A chain also contains a disulfide bridge that forms a loop within the A chain.