Chronic Disease and Metals

Chronic Disease

Dr. Jon Sellars, Newcastle University, jon.sellars@newcastle.ac.uk

Learning Outcomes

At the end of this lecture series, students will:

• Understand the general principles of metallobiology, with emphasis on metal types and their incorporation in biological systems, leading to downstream effects.
• Understand the relationship between metals and disease, focusing on Wilson’s disease (copper overload), Menkes disease (copper deficiency), and Haemochromatosis (iron overload).

Metals

Nearly 50% of proteins require a metal for function, including alkali metals (Group 1), alkaline earth metals (Group 2), and transition metals (d-block). (N. Robinson, Nature, 2009, 460, 823)

Metal Choice: Oxidation States

Energy

Special cases: Chromium and copper

• Chromium and copper have $4s^1$ instead of $4s^2$.

Metal Choice: Oxidation States

• Forming an ionic compound depends on energetic processes; the compound formed will release the most energy.
• The more energy released, the more stable the compound. Key energy terms to consider:
  • Amount of energy to ionize the metal
  • Amount of energy released when the compound forms, as lattice energy (solids) or hydration enthalpy (solutions)
• Consider Calcium: $Ca [Ar] 4s^2$. It forms $CaCl_2$ because forming $Ca^+$ is slightly exothermic; however, making $Ca^{2+}$ requires more energy, but the lattice energy released while forming the compound is high, making the process very exothermic.
• Why not $CaCl_3$? Removing a 3p electron requires a lot more energy, while there is not enough lattice energy to compensate, making the process endothermic and impossible.
• For Iron, there's a different story with the ability to utilize 3d electrons of very similar energy. Considering the ionization energy below, it is not a huge jump to ionize Fe from +2 to +3.

• The increase in ionization energy for Fe is less than for Ca and is compensated for by either the lattice or hydration enthalpy, allowing Fe to be either +2 or +3.

Metal Choice: Metal Centre Geometry

• Proteins' primary and secondary coordination sphere tune the properties of the metal to aid reactivity and selection.
• Heme

Metals Function

Metal Ions are Vital For Processes That Include

• Transcription and translation: e.g., zinc fingers, metal sensors
• Human proteome - Zinc finger (3%) & Ring finger (1%)
• Structural function - no catalytic function. Zinc fingers attached to DNA and RNA.

Metal Ions are Vital For Processes That Include

• Aconitase - responsible for the stereospecific isomerization of citrate to isocitrate.
• Solvent exposed iron with overall cluster oxidation of +2
• Catalytic function

Metal Ions are Vital For Processes That Include

• Structural and Catalytic function
• Copper-zinc superoxide dismutase
  • Superoxide dismutase (SOD) - the disproportionation of superoxide
  • Copper and Zinc are the most common in eukaryotes and present in the cytosol
  • Zinc is structural, and copper is the catalytically active metal

Metallobiology

Why are there organism differences in metal content?

• Prokaryotes - Fe-S, Cobalt and Nickel
• Eukaryotes - Zinc, Haem
• SOD 2 Mn containing species
• Delete SOD1 in WT yeast and add SODB from E. coli, and you get a fully functioning SOD.

Metallobiology

Metal availability changes with the environment.

• Copper mine - USA
  • High levels of metal
• Ocean
  • Metals limited
• Evolutionary pressure forces the choice of metals.

Metallobiology

Metal availability changes with the environment.

• Early Earth environment - lots of metals in the ocean
• Oxygenation and moving away from a reducing environment
• Banded iron formation - $Fe^{2+}$ soluble in reducing (early oceanic environment); however, through oxygenation, converted to $Fe^{3+}$, which is insoluble
• Underwater volcanic vent
• Cyanobacteria evolution producing oxygen
• Banded iron formation - layers of iron and silica

Metallobiology

Evolutionary mechanism for acquiring Iron

• Reduction strategy - cell surface reductases
• Chelation - siderophore molecules chelate Iron and import this.

Metallobiology

Evolutionary mechanism involves changing the metal used

• Helicobacter pylori - bacterial infection of the stomach, causes ulcer, cancer, and other diseases
  • Urease (Ni containing enzyme) breaks down urea to ammonia, raising local pH for survival. Ni comes from the plants we eat.
• Helicobacter mustelae - same problem but meat-only diet limits Ni content.
  • Urease here has the Ni form but also an Fe-containing form, rich in meaty food.

Metallobiology

Evolutionary mechanism involves changing the metal used or not

• Can use two different metals
  • Carbonic anhydrase - hydration of carbon dioxide, most use zinc
  • Cambialistic - flexible loop allows the use of zinc or cadmium.
• Algae (Thalassiosira weissflogii)
• Methanogen
• Nickel is a relic, limiting growth due to lack of availability. Enzymes affected:
  • NiFe hydrogenases
  • Carbon monoxide dehydrogenase
  • Acetyl CoA synthase
  • Methyl-coenzyme M reductase

Metal Homeostasis

How cells maintain relative concentrations of metals for function

• To regulate this, there must be a way for the cell to sense these levels and switch on or off accordingly.
• Sufficient, Insufficient, Metal toxicity
• Non-biological metals - cadmium, lead, mercury, silver
  • Two mechanisms are involved:
    • Bind to protein and inhibit function
    • Displace metal from binding
  • Mercury - Minamata disease
  • Lead poisoning
• Biological metals in excess or misdirected - copper and iron
  • Two mechanisms are involved:
    • Bind to protein and inhibit function
    • Displace metal from binding
  • Copper - Wilson and Menkes disease
  • Iron - Haemochromatosis

Metal Toxicity

• Minamata disease - a coastal city in Japan ravaged by mercury poisoning.
• American photojournalist Eugene Smith