Human biochem lecture 9

Lecture 7: Proteins – Primary Structure

• Date: February 11th, 2025

• Reading Material: Biochemistry: Concepts and Connections, Chapter 5, Pages 109-125

Lecture Overview

• Topic: Phenylketonuria (PKU)

  • Definition: An amino acid disease due to genetic abnormality affecting metabolism.

• Focus Areas:

  • General structure of amino acids

  • Categorization of amino acids into five general categories

  • Biological roles of amino acids

  • Formation of amino acids in primary structure

  • Construction of polypeptide from genome codons

Test 1 Results

• Overall performance was good with an average score of 75%.

Phenylketonuria (PKU)

• Autosomal recessive disorder and metabolic disorder

• Key Characteristics:

  • Impaired conversion of phenylalanine into metabolic products due to a disabled/mutated gene for phenylalanine hydroxylase.

  • Prevalence: Roughly 1 in 12,000 individuals.

  • Symptoms: Untreated individuals may present a musty odor in urine due to phenylacetate.

Pathology of PKU

• Effects Due to Toxic Build-Up:

  • Excess phenylalanine leads to damage and improper folding of the enzyme, reducing its effectiveness.

  • Missense mutations may cause reduced expression of the protein.

• Downstream Effects:

  • Tyrosine and dopamine deficiencies, and lowered tryptophan levels leading to significant neurological and behavioral effects if not promptly treated.

  • Long-term effects: Decreased mental acuity and increased aggressive behaviors.

Brain Function Impairment

• Mechanisms of damage:

  • Reduction of myelin, potentially caused by excess phenylalanine.

  • Decreased neurotransmitter levels, important for brain function, specifically dopamine and norepinephrine.

  • Impairment of large neutral amino acid uptake into the brain, further hindering neurotransmitter synthesis.

Classification of Amino Acids

• Nonpolar Aromatic Amino Acids:

  • Examples: Phenylalanine (Phe; F), Tyrosine (Tyr; Y), Tryptophan (Trp; W)

Phenylalanine Degradation

• Conversion of Phenylalanine to Tyrosine via phenylalanine hydroxylase.

Untreated PKU Pathology

• Issues arise due to:

  • Toxic phenylalanine accumulation

  • Deficiencies in tyrosine and other amino acids.

  • Albinism (light pigmentation) due to decreased melanin production.

Consequences of PKU

• Symptoms from untreated PKU include:

  • Developmental delays

  • Hyperactivity

  • Seizures

  • Aesthetic traits: fair skin, blue eyes, and blonde hair.

Treatment for PKU

• Best method: Eliminate phenylalanine from the diet, crucially during pregnancy.

  • Options include:

    • Tetrahydrobiopterin (alternative breakdown method)

    • Large neutral amino acids (LNAA) to reduce phenylalanine transport to the brain.

    • Glycomacropeptides (low in phenylalanine, derived from cheese whey).

    • Potential for gene therapy.

• Importance of early screening for effective treatment.

Larger Screening Programs

• Summary of disorders screened with focus on metabolic diseases:

  • Incidence rates and implications including various metabolic disorders requiring dietary management to prevent severe symptoms.

Amino Acids Overview

• All proteins consist of alpha amino acids, defined by both amino and acidic (carboxylic) groups.

• Classification of Amino Acids:

  • 20 main amino acids categorized into five groups based on polarity, charge, etc.

Nonpolar Aliphatic Amino Acids

• Key Examples: Glycine, Alanine, Valine, Leucine, Isoleucine, Proline, Methionine.

  • Functions: Typically located within the protein's interior due to hydrophobic properties.

Nonpolar Aromatic Amino Acids

• Key Examples: Phenylalanine, Tyrosine, Tryptophan.

  • Function: Essential in the production of signaling molecules, particularly neurotransmitters.

Polar Amino Acids

• Key Examples: Serine, Cysteine, Threonine, Asparagine, Glutamine.

  • Role: Involved in structural modifications and inter-chain bonds in proteins.

Charged Amino Acids

• Positively Charged: Histidine, Lysine, Arginine

  • Generally found on protein surfaces, playing roles in enzyme active sites.

• Negatively Charged: Aspartic acid, Glutamic acid

  • Often function at protein surfaces and involved in neural signaling as glutamate.

Essential vs. Non-Essential Amino Acids

• Definition and importance in human biochemistry.

  • Essential: Cannot be synthesized by the body and must be obtained from diet (9 essential).

  • Non-essential: Synthesized by the body from other compounds (11 non-essential).

  • Some non-essentials may be conditionally essential under specific circumstances.

Peptide Bond Formation

• Peptide bond formed in the ribosome by ribosomal RNA enzyme peptidyl transferase.

• Process requires energy input from ATP and results in the formation of an amino acid residue.

Polypeptide Structure

• Primary structure includes N-terminus and C-terminus.

• Reading direction goes from N-terminus to C-terminus.

Genetic Code and Protein Synthesis

• Codons in mRNA specify which amino acid is added to the polypeptide during translation.

• Genetic code includes redundancy, with 64 codon combinations representing around 20 amino acids.

Mutations and Protein Structure

• Mutations in the genetic code can be silent, conservative, or non-conservative.

• Non-conservative changes affect protein function by altering shape and activity.

Post-Translational Modifications

• Involves modifications leading to secondary and tertiary structures critical for protein functionality.

• Examples: Cleaving and rearranging of polypeptide chains, formation of secondary structural elements like alpha helices and beta sheets.

Example: Preproinsulin to Insulin

• Preproinsulin undergoes folding and cleavage to form the mature insulin molecule, illustrating processing and functional maturation of proteins.