Lecture 7: Proteins – Primary Structure

Lecture 7: Proteins – Primary Structure

Date: February 24, 2026
Reading Material: Biochemistry: Concepts and Connections, Chapter 5, Pages 109-125

Lecture Overview

  • Phenylketonuria (PKU)

    • Described as a metabolic disorder caused by a genetic abnormality affecting amino acid metabolism.

    • Introduction to amino acids, focusing on their structure, categorization, biological roles, and formation into primary structures.

- Discussion on the transition from gene sequences to protein synthesis via polypeptides.

Phenylketonuria (PKU)

Definition and Background

  • PKU is an autosomal recessive disorder characterized by a metabolic dysfunction.

  • It results from the inability to convert phenylalanine into its usual metabolic products.

  • This inability is due to a mutation or disablement of the gene responsible for the protein phenylalanine hydroxylase.

  • Incidence rate is approximately 1 in 12,000 live births.

  • Characteristic symptom: Untreated patients may exhibit a musty odor in their urine due to the accumulation of phenylacetate, a breakdown product of phenylalanine.

Mechanism of Pathology

  • Toxic Accumulation: Excess phenylalanine and its breakdown products lead to neurological issues.

    • The protein's catalytic domain folds improperly, reducing enzyme effectiveness.

    • A missense mutation in the gene may lead to diminished expression of phenylalanine hydroxylase.

Downstream Effects

  • Implications of toxic buildup include:

    • Tyrosine deficiency, impacting dopamine production.

    • Altered levels of tryptophan, leading to further neurotransmitter imbalances.

  • Key neurological and behavioral effects resulting from improper metabolic processing can cause:

    • Decreased mental acuity.

    • Increased aggressive behaviors if not managed properly.

Pathophysiological Process

  • Reduced myelin (white matter) impacts brain connectivity and function, potentially due to excess phenylalanine.

  • Lower availability of critical neurotransmitters, notably dopamine and norepinephrine, results from insufficient tyrosine due to phenylalanine accumulation.

  • Additionally, high phenylalanine levels hinder the intake of other large neutral amino acids into the brain, negatively impacting overall neurological function.

Metabolic Consequences

  • Untreated PKU leads to:

    • Albinism: Reduced production of melanin due to decreased tyrosine, affecting hair and eye pigmentation.

    • Toxic buildup similarly leads to:

    • Developmental delays.

    • Hyperactivity.

- Seizures.

Treatment of PKU

  • Main Treatment: Lifelong dietary restriction of phenylalanine (first introduced in 1953).

    • Especially critical during pregnancy due to fetal development concerns.

  • Alternative Treatments:

    • Tetrahydrobiopterin: Facilitates phenylalanine breakdown through alternative pathways.

    • Large neutral amino acids (LNAA): Help reduce phenylalanine transportation to the brain.

    • Glycomacropeptides (GMP): Derived from cheese whey, low in phenylalanine.

    • Potential future avenues include gene therapy.

- Early detection via newborn screening enhances treatment efficacy and quality of life but cannot fully restore normal function.

Screening for PKU and Other Disorders

  • Screening incidences:

    • Maple Syrup Urine Disease (MSUD): 1 in 200,000 births.

    • PKU: 1 in 12,000 births.

  • Metabolic Disorders Summary:

- Each disorder leads to specific health consequences, highlighting the importance of early detection and dietary management.

Introduction to Amino Acids

  • All proteins are comprised of alpha (α) amino acids.

    • The term "amino acid" derives from the presence of an amine group and a carboxylic acid group in their structure.

  • Technically, there are 22 amino acids, including selenocysteine and pyrrolysine, but focus will remain on the 20 standard amino acids.

Categories of Amino Acids

  • The 20 amino acids are categorized into five groups:

    1. Nonpolar aliphatic.

    2. Nonpolar aromatic.

    3. Polar.

    4. Positively charged.

    5. Negatively charged.

Differentiating Knowledge Expectations

  • Be able to:

    1. Identify specific amino acids and their distinguishing features.

    2. Categorize amino acids based on polarity and charge.

3. understand the metabolic significance of various amino acids, including implications evident in PKU patients.

Nonpolar Aliphatic and Aromatic Amino Acids

  • Nonpolar Aliphatic Amino Acids: Include glycine, alanine, valine, leucine, isoleucine, proline, and methionine.

    • Characteristics: Found primarily within protein interiors due to their hydrophobic nature.

    • Roles:

    • Methionine: Initiates protein synthesis.

    • Leucine, isoleucine, and valine are essential amino acids (EAAs).

    • Glycine and alanine are deemed non-essential as the body can synthesize them.

  • Nonpolar Aromatic Amino Acids: This group encompasses phenylalanine, tyrosine, and tryptophan.

- Vital for generating signaling molecules, particularly phenylalanine, which is a precursor for numerous neurotransmitters.

Polar Amino Acids and Charged Amino Acids

  • Polar Amino Acids: Include serine, cysteine, threonine, asparagine, and glutamine.

    • Cysteine is notable for forming disulfide bonds, which are critical for protein structure.

  • Positively Charged Amino Acids: Consist of histidine, lysine, and arginine.

    • Commonly located on protein surfaces; play essential roles within enzyme active sites.

  • Negatively Charged Amino Acids: Comprised of aspartic acid and glutamic acid.

- These are also typically found on protein surfaces; glutamic acid transforms to glutamate, a significant excitatory neurotransmitter.

Essential vs. Non-Essential Amino Acids

Essential Amino Acids

  • Definition: Amino acids that cannot be synthesized in sufficient quantities by the body and must be obtained through dietary sources.

  • Total: 10 essential amino acids include:

    • Isoleucine, leucine, valine, lysine, methionine, threonine, phenylalanine, tryptophan, histidine, and arginine.

  • Deficiencies in essential amino acids can lead to muscle repair issues, especially in BCAAs.

Non-Essential Amino Acids

  • Definition: Amino acids that can be synthesized by the body and are often by-products of metabolism.

  • Examples:

    • Phenylalanine converts to tyrosine.

- Typically synthesized through biological processes linked to the citric acid cycle.

Peptide Bonds and Their Formation

  • Peptide bonds form within the ribosome.

  • The peptidyl transferase enzyme in the ribosomal large subunit facilitates the bond formation between the carboxylic acid of one amino acid and the amine group of another, resulting in a peptide bond and releasing a water molecule.

    • The process requires energy, supplied by ATP.

Key Definitions

  • Amide/Peptide Bond: Formed between amino acids, crucial for maintaining protein structure post-formation.

- Metastable: Describes polypeptides; the bonds can hydrolyze under normal conditions but do so slowly without catalysts.

Structure of Polypeptides

  • Primary structure features an N-terminus and C-terminus:

    • Example of representation: MGAK or Met-Gly-Ala-Lys denotes amino acids sequenced from N- to C- terminus.

Genetic Code and Translation Process

  • The genetic code dictates the amino acid sequence through codons (triplet bases).

    • Codon redundancy exists, with 64 possible codons for 20 amino acids with some indicating STOP signals.

Mutation Impact

  • Mutations in the genetic code can be classified as:

    • Conservative Changes: Mutations that do not significantly alter protein function or structure.

- Non-Conservative Changes: Mutations that affect the protein's activity or appearance, potentially leading to dysfunctional proteins.

Post-Translational Processing

  • Following polypeptide synthesis, significant transformations occur, including:

    • Development of secondary (alpha helices and beta sheets) and tertiary structures (overall three-dimensional configuration).

    • Cleavage and reorganization of polypeptide may occur, especially in signaling peptides.

Example: Preproinsulin to Insulin

  1. Preproinsulin synthesized as a random coil on ribosomes.

  2. After transport, the leader sequence is cleaved; proinsulin folds into a stable form.

3. Disulfide bonds form, and the connecting sequence is cleaved to produce mature insulin.

Conclusion

  • A complex interplay of genetic information, amino acid properties, and biochemical processes create the functional structures necessary for life.

  • Understanding amino acids, their metabolism, and the resultant effects of disorders like PKU is crucial for advancements in treatment and care.