Amino Acid and Nucleotide Metabolism

Introduction to Amino Acid Metabolism

  • Dr. Mark Shepherd, Reader in Microbial Biochemistry

  • Recommended textbooks:

    • Biochemistry, Garrett & Grisham – ebook

    • Biochemistry, Lehninger

Molecules Derived from Amino Acids

Protein Building Blocks

  • Amino acids serve as building blocks for proteins.

  • Additionally, they are precursors for various specialized biomolecules.

Specialized Biomolecules

  • Vitamins/Coenzymes:

    • Niacin from tryptophan (NAD+/NADP+ precursor)

  • Hormones:

    • Thyroxine derived from tyrosine

  • Pigments:

    • Haem, made from glycine (ALA precursor)

Host Defences and Cellular Functions

  • Host Defences:

    • iNOS produces Nitric oxide from Arginine

  • Cellular Redox Balance:

    • Cysteine, Glutamate, and Glycine are precursors of Glutathione

  • Energy Metabolism:

    • Arginine, Glycine, and Methionine are essential for phosphocreatine synthesis

Amino Acids as Neurotransmitter Precursors

Major Neurotransmitters

  • Glutamate:

    • Precursor for GABA (γ-aminobutyric acid)

    • GABA functions as an inhibitory neurotransmitter.

    • Underproduction linked to epileptic seizures.

    • Diazepam (Valium) enhances GABA receptor activity, reducing neuronal firing.

Histamine and Allergic Reactions

  • Histidine:

    • Converts to Histamine, a potent vasodilator.

    • Cetirizine, an antihistamine, blocks H1 receptors to reduce allergic reactions.

Phenylketonuria (PKU)

Overview of PKU

  • PKU is caused by diminished phenylalanine hydroxylase activity.

  • Can also arise from deficiencies in BH4 regeneration (tetrahydrobiopterin).

Classical PKU

  • Result of a mutation in the PAH gene (autosomal recessive).

  • Inhibits brain development due to high levels of phenylalanine.

  • Symptoms include seizures.

Detection and Diagnosis

  • Detection through serum amino acid measurement using tandem mass spectrometry (MS/MS).

Treatment Strategies for PKU

  • Dietary Management:

    • Restrict phenylalanine consumption, monitor protein intake.

  • Enzyme Infusions:

    • Infusion of Phenylalanine ammonia lyase converts phenylalanine to non-toxic cinnamic acid for easier excretion.

Nucleotide Metabolism

Nucleotide Components

  • Bases/Nucleosides/Nucleotides:

    • Adenine (Adenosine, AMP), Guanine (Guanosine, GMP), Cytosine (Cytidine, CMP), Thymine (Deoxy-thymidine, dTMP), Uracil (Uridine, UMP)

Functions of Nucleotides

  • Precursors for DNA and RNA synthesis

  • Energy carriers: ATP, GTP

  • Co-factors: FAD, NAD, CoA

  • Second messengers: cGMP

Nucleotide Synthesis and Salvage

  • De Novo Pathway:

    • Involves amino acids, ribose 5-phosphate, CO2, and NH3.

    • Enzyme: Adenine phosphoribosyltransferase.

  • Salvage Pathway:

    • Recycles free bases and nucleosides.

  • Lesch Nyhan Syndrome:

    • Defect in hypoxanthine-guanine phosphoribosyltransferase leading to high uric acid levels, mental issues, aggression, and gout.

Nucleotide Degradation and Gout

Purine Degradation

  • AMP and GMP degradation processes detailed step-by-step.

  • Excess uric acid can lead to gout, characterized by painful joints due to sodium urate crystal deposits.

  • Treatment options include Allopurinol, which inhibits xanthine oxidase.

Gout Management

  • Lifestyle modifications: reduce meat/seafood intake, increase vitamin C, manage alcohol/fructose consumption, maintain a healthy weight.

Learning Outcomes

  • Recognize the role of amino acids in synthesizing vital biomolecules.

  • Understand PKU causes, effects, and treatments.

  • Acknowledge nucleotide metabolism, its breakdown, and implications on health such as gout.