Lecture 9: Proteins – Primary Structure

Lecture Overview on Proteins – Primary Structure

• Phenylketonuria (PKU)
  • A hereditary metabolic disorder caused by the inability to convert phenylalanine to tyrosine due to a lack of functional phenylalanine hydroxylase.
  • Incidence: Approximately 1 in 12,000 live births.
  • Symptoms: Untreated patients may exhibit a musty odor in urine due to phenylacetate.

General Structure of Amino Acids

• Basic Structure:

  • Amino acids possess:
  • An amino group (-NH2)
  • A carboxylic acid group (-COOH)
  • A side chain (R group) that determines the properties of the amino acid.

• Categories of Amino Acids:

  • Nonpolar Aliphatic: Glycine, Alanine, Valine, Leucine, Isoleucine, Proline, Methionine.
  • Nonpolar Aromatic: Phenylalanine, Tyrosine, Tryptophan.
  • Polar: Serine, Cysteine, Threonine, Asparagine, Glutamine.
  • Positively Charged: Histidine, Lysine, Arginine.
  • Negatively Charged: Aspartic Acid, Glutamic Acid.

Biological Roles of Amino Acids

• General Functions:
  • Amino acids are the building blocks of proteins, forming when linked via peptide bonds.
  • Essential amino acids must be obtained through diet (e.g., Isoleucine, Leucine, Valine).
  • Non-essential amino acids can be synthesized by the body (e.g., Tyrosine from Phenylalanine).

Formation of Peptide Bonds

• Peptide Bond Formation:
  • Occurs in the ribosome through the action of peptidyl transferase.
  • Energy from ATP is required for this process.
  • Removed water molecule facilitates bond formation between amino acids, resulting in peptide linkage.

Primary Structure of Proteins

• Overview of Polypeptides:

  • Contains N-terminus (amino end) and C-terminus (carboxyl end).
  • Sequence notation: Initially, polypeptides can be denoted in three-letter or one-letter formats (e.g., Met-Gly-Ala-Lys).

• Reading Polypeptide Sequences:

  • Sequences are read from the N-terminus to the C-terminus, analogous to reading nucleic acid sequences.

Genetic Code

• Codon to Amino Acid:

  • mRNA codons are triplet codes that correspond to amino acids.
  • There are 64 possible codons but only ~20 amino acids, leading to redundancy in the genetic code.

• Types of Mutations:

  • Conservative Changes: Mutations that have no significant impact on protein function.
  • Non-conservative Changes: Mutations that alter protein structure and potentially function.

Post-Translational Processing

• Protein Modifications:
  • Secondary Structure: Formation of alpha helices and beta sheets for structural integrity and functional roles.
  • Tertiary Structure: Three-dimensional conformation critical for protein function.
  • Example – Preproinsulin to Insulin:
  1. Preproinsulin is synthesized and undergoes cleavage to form proinsulin.
  2. Proinsulin folds and forms disulfide bonds, resulting in the active insulin molecule.

Implications of PKU

• Pathology of PKU:
  • Lack of tyrosine due to phenylalanine accumulation can lead to neurological issues, including loss of white matter, decreased neurotransmitters, and developmental delays.
• Treatment Strategies:
  • Lifelong dietary restriction of phenylalanine, particularly critical during pregnancy.
  • Alternative treatments such as Tetrahydrobiopterin and supplements of large neutral amino acids or Glycomacropeptides.

Summary of Disorders Screened

• Selected Disorders:
  • Phenylketonuria (PKU): Early detection allows for management and prevention of severe symptoms.
  • Maple Syrup Urine Disease (MSUD): Affects branched-chain amino acid metabolism and requires dietary management.
  • Commonalities: All these disorders highlight the importance of early screening and intervention in managing metabolic disorders effectively.