Chronic Disease - Metal Toxicity and Homeostasis Notes

Chronic Disease - Metal Toxicity and Homeostasis

Metal Toxicity

  • Cells require mechanisms to ensure correct metal delivery to the appropriate protein.
  • Dehydratases contain a [4Fe−4S][4Fe-4S] cluster at the active site (e.g., aconitase, fumarase).
  • Fumarase catalyzes the hydration of fumarate to malate in the citric acid cycle.
  • Increasing copper concentration leads to iron loss from fumarate.
  • Human pathogenic fungi (soil, trees) produce spores.
  • Macrophages deal with fungal spores; immunocompromised patients may experience growth issues.
  • Example: Brain session with yeast infection.
  • Blood-brain barrier (BBB) penetration is dependent on urease activity.
  • Cobalt (Co) can displace nickel (Ni) due to larger concentrations outcompeting metals higher in the Irving Williams series.
  • Ferrochelatase catalyzes the insertion of iron into protoporphyrin IX.
  • Zinc protoporphyrin forms in patients with anemia, leading to loss of activity/function.
  • Cryptococcal Urease - loss of function.

Metal Homeostasis

  • Mechanisms are needed for each biological metal to:
    • Sense the amount in the cell and the amount needed.
    • Distribute the metal to the correct location.
    • Store, export, or prevent the uptake of excess metal.
  • Aim: Ensure metal needs are met and any free cellular metal does not cause oxidative stress or inhibit protein function.
  • Many microbial metal-sensing transcription factors exist.
  • Metal binding causes an allosteric change.
  • Binding sensitivity increases up the Irving Williams series, making transcription factors more sensitive (bacterial copper sensitivity to one atom).
  • Transcription factors act as sensors.
  • Aft1 and Aft2 transcription factors (Saccharomyces cerevisiae) regulate iron homeostasis.
  • In iron-replete conditions:
    • Grx3/4 binds to Aft1/2, keeping the Aft1/2 regulon off.
    • mRNA turnover occurs.
  • In iron-deplete conditions:
    • Aft1/2 translocates to the nucleus, activating the iron regulon.
  • Regulation of copper import (Saccharomyces cerevisiae):
    • Copper binding inactivates Mac1.
    • CTR1 is a copper transporter.
    • Yeast needs copper to survive DNA damage.
    • MethylMethaneSulfonate (MMS) is a DNA damaging agent that methylates the N7-guanine residue.
  • MTF1 transcription factor (Human):
    • MTF1 is a main example of a human metal-responsive transcription factor.
    • Metallothionine (MT) protects against Cadmium.
    • Cadmium displaces Zinc on MT and sequesters it away.
    • Zinc then binds to MTF1, activating the transcription of Metallothionine (MT).
  • Transporter degradation (Human):
    • ZIP transporters in the presence of high concentrations of iron in the cytosol are degraded, while at low concentrations of zinc, the protein is endocytosed and cleaved, returning to the membrane.
    • Hepcidin regulates Ferroportin (FPN) release and regulates iron in the cell, internalizing the transporter.
  • Metal Chaperones:
    • Chaperones are involved in delivering the right metal to the protein (e.g., Urease).
    • Binding of Ni to the protein blocks binding of Ni to other proteins.
  • Compartmentalization:
    • [Fe−S][Fe-S] clusters are directed to the mitochondria.
    • Copper is directed to the Golgi instead of the cytosol.
    • Storage occurs in the vacuole (plants and fungi).
    • Cyanobacteria contain two enzymes, MncA and CucA, that are structurally identical but contain different metals.
    • Both proteins are active in the periplasm.
    • There is no free copper in the cytosol but in the periplasm.