Control of toxic metal concentration

Question 1

Toxic metal

Answer 1

A metal for which cell growth drops for any concentration > 0

Question 2

Mercury

Answer 2

Most well-studied toxic metal

Hg2+ has a high affinity for Cys residues in proteins (soft)

Question 3

Why is RHg+ more toxic to cells than Hg2+?

Answer 3

RHg+ can interact with cell membranes better

Question 4

Detoxification (removal of RHg+)

Answer 4

1. 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
2. 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

Question 5

MerR

Answer 5

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)

Question 6

Cadmium

Answer 6

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

Question 7

Acute Cd poisoning

Answer 7

Vomiting
Abdominal cramps
Headaches

Question 8

Chronic Cd poisoning

Answer 8

Brittle bones

Painful deformation of the skeleton

Question 9

Treatment for Cd poisoning

Answer 9

Chelate therapy

Intake of Zn and Ca to lessen impact

Question 10

Lead

Answer 10

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

Question 11

Symptoms of Pb poisoning

Answer 11

Loss of appetite
Dizziness
Degradation of motor nerves
Loss of consciousness, coma, death

Question 12

Treatment for Pb poisoning

Answer 12

Chelates e.g. Ca(EDTA)

Mineral-rich water

Question 13

Thallium

Answer 13

Mimics K

Affects Na/K-ATPase

Question 14

Treatment for Tl

Answer 14

High K supplementation

Question 15

Aluminium

Answer 15

Mimics Mg2+ and Fe3+
Binds to ATP/phosphates stronger than Mg
Transported by transferrin
Increased Al levels in brains of Alzheimer’s patients

Question 16

Beryllium

Answer 16

Most toxic non-radioactive element
Strong phosphate binding and DNA alteration (carcinogenic)
Inhibits (de)phosphorylations

Question 17

Iron

Answer 17

Excess leads to deposists in the liver, kidneys and heart

Question 18

Treatment for excess iron

Answer 18

Chelation therapy e.g. desferrioxamine

Question 19

Plutonium

Answer 19

Mimics Fe(III)
Often binds more strongly

Question 20

Why is CN- more toxic than CO?

Answer 20

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

Question 21

Treatment for CN- poisoning

Answer 21

1. Thiosulfate ion converts CN- to the less toxic thiocyanate in the presence of the enzyme rhodanase
   CN- + S2O3^2- —> SCN- + SO3^2-
2. Ferrous sulfate and sodium carbonate - the basic ferrous hydroxide suspension is insoluble and forms non-toxic Fe/CN complexes
3. 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

Question 22

Function of cytochrome C oxidase

Answer 22

O2 + 8H+(inside) + 4Cytc2+ —> 2H2O + 4H+(outside) + 4Cytc3+