Control of toxic metal concentration Flashcards
Toxic metal
A metal for which cell growth drops for any concentration > 0
Mercury
Most well-studied toxic metal
Hg2+ has a high affinity for Cys residues in proteins (soft)
Why is RHg+ more toxic to cells than Hg2+?
RHg+ can interact with cell membranes better
Detoxification (removal of RHg+)
- Removal of RHg+ by organomercury lyase
RHg+ + H+ + 2RS- —> RH + Hg(SR)2
R-Hg bond difficult to cleave - lyase accelerates reaction by 1 million fold
Hg is less toxic in its elemental form - Removal of Hg(SR)2 by mercury reductase
Hg(SR)2 + H+ + NADPH —> Hg + 2RSH + NADP+
Reduction via hydride transfer from NADPH
Hg(0) can diffuse through the membrane and out of the cell
MerR
DNA-binding protein - an intracellular sensor that controls the expression of mercury detoxification genes at the transcriptional level
MerR is bound to DNA in a “repressor conformation” in the absence of Hg(II), therefore repressing the transcription of mer genes for mercury detoxification
At [Hg] = 10 nM, Hg(II) binding to one of two sites on MerR results in a conformational change to the “activating conformation”
This causes distortion of the DNA (due to the tight binding of MerR), allowing a productive interaction with DNA polymerase and transcription of mercury detoxification genes
Transcription can also be initiated by Cd, Au and Zn but at conc. > 1 mM (i.e. not as sensitive as with Hg)
Cadmium
Mimics Zn and interferes with Zn enzymes
Can also be stored in Ca2+ sites in bones
Mostly stored in metallothionines
Effectively absorbed via tobacco smoke
Acute Cd poisoning
Vomiting
Abdominal cramps
Headaches
Chronic Cd poisoning
Brittle bones
Painful deformation of the skeleton
Treatment for Cd poisoning
Chelate therapy
Intake of Zn and Ca to lessen impact
Lead
Most ubiquitous toxic metal Mimics Ca 90 % of Pb2+ stored in bones, 10 % CNS Modifies neuronal circuitry Alters cell-cell connections Affects RBCs leading to anaemia
Symptoms of Pb poisoning
Loss of appetite
Dizziness
Degradation of motor nerves
Loss of consciousness, coma, death
Treatment for Pb poisoning
Chelates e.g. Ca(EDTA)
Mineral-rich water
Thallium
Mimics K
Affects Na/K-ATPase
Treatment for Tl
High K supplementation
Aluminium
Mimics Mg2+ and Fe3+
Binds to ATP/phosphates stronger than Mg
Transported by transferrin
Increased Al levels in brains of Alzheimer’s patients
Beryllium
Most toxic non-radioactive element
Strong phosphate binding and DNA alteration (carcinogenic)
Inhibits (de)phosphorylations
Iron
Excess leads to deposists in the liver, kidneys and heart
Treatment for excess iron
Chelation therapy e.g. desferrioxamine
Plutonium
Mimics Fe(III) Often binds more strongly
Why is CN- more toxic than CO?
CN- is charged so prefers to bind to Fe(III) rather than Fe(II)
Initially binds to the Fe centre in Hb (like CO) but then transfers to the enzyme cytochrome C oxidase
Binds at haem site and is then transferred to the nearby electron transfer subunits
Blocks catalytic cycle
CN- also acts much more rapidly than CO because it blocks the electron transfer chain which blocks ATP production
Treatment for CN- poisoning
- Thiosulfate ion converts CN- to the less toxic thiocyanate in the presence of the enzyme rhodanase
CN- + S2O3^2- —> SCN- + SO3^2- - Ferrous sulfate and sodium carbonate - the basic ferrous hydroxide suspension is insoluble and forms non-toxic Fe/CN complexes
- Inhalation of nitrite - irreversibly oxidises Hb to its met Fe(III) form which binds CN- very strongly and protects cytochrome C oxidase - at the cost of some Hb
Function of cytochrome C oxidase
O2 + 8H+(inside) + 4Cytc2+ —> 2H2O + 4H+(outside) + 4Cytc3+
