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.