Mettalobiology Flashcards
What are the main functions of metals in the body?
Structural - e.g. zinc finger (zn2+ binds 2 cysteine and 2 histadine residues) - structural motif that can bind proteins/DNA - found in TFs
Catalytic - e.g. 4 iron/4sulphur in aconitase (converts citrate to isocitrate) - iron binds citrate and causes conformational change which activates catalysis
REDOX activity - Fe/Cu in cytochrome C oxidase - final enzyme in respiratory chain
What are the reasons for evolution favouring different metals?
Characteristics -
Metal - Size, charge - coordination geometry (how many ligands it can bind)
Enzyme - Coordination sphere (decided by primary and secondary AA sequences which determine metal binding domain)
Metal availability - at time of evolution - H.pylori (nickel)/ H.mustalae (iron) example
What is metal homeostasis?
Maintenance of a replete system, with the right of amount of metals for enzymes to function, but not too many for toxicity to occur
What are the two classes of metals that can lead to toxicity?
Non-biological - not useful for the body - mainly heavy metals such as mercury (minamata disease) and lead. Light metals (such as lithium) can also cause toxicity in excess. Often treated by metal chelation therapy.
Biological metals - useful for the body - e.g. iron, copper - excess amounts or misdirected. Also, chromium (III) is useful for the body as part of insulin sensitivity, however when in the wrong oxidation state - chromium (VI) is a carcinogen.
How do excess metals cause toxicity?
Bind enzyme and inhibit function (cysteine residues)
Displace metal bound to enzyme
What determines a metals affinity?
Irving Williams Series (IWS)
What metals are highest on the IWS?
Zn, Cu, Ni
What metals are lowest on the IWS?
Mg, Ca, Mn
How do metals cause damage via oxidative stress?
Certain metals (Fe, Cu, Ni) can react with H2O2 to form Hydroxyl radical which can damage Lipids (lipid peroxidation), DNA, proteins
What happens when we have too little metal?
Affects function of enzymes - e.g. Zinc Protoporhyrin (ZPP) when iron levels low ferrochelatase inserts Zinc instead of Iron as Haem group - Anaemia
What must our body do in order to maintain homeostasis?
Sense available metals
Sense cells need for metals
Direct metals to correct location
How can the body sense availability?
1) - TFs - bind metals and either bind DNA or jump off DNA
e. g. in bacteria - TF for Cu has very high affinity - only requires 1 Cu atom in the cell to be active - results in activation of transporter to pump Cu out of cell - ensures no free Cu in cell (Cu has very affinity and as a result may bind other enzymes or TFs and cause dysfunction)
In humans…MTF1 - Zn and Cd - when Cd levels rise - displace Zn from MT and Zn binds MTF1 - increases transcription of MT to sequester Cd
2) mRNA regulation - e.g IRP in Iron - regulate mRNA for storage when low levels of iron (vice versa for high levels)
What is the main methods of metal homeostasis in humans?
Transporter localisation - Copper
Transporter degradation - Iron (FPN) - hepcidin - Liver
What are chaperones?
Bind metals and take them out of solution and deliver to target proteins - ensures they dont react with other proteins or TFs
E.g. urease - UrE dimer binds Nickel (chaperone) and delivers to ApoUrease (inactive) to activate it
No chaperone for Zinc - highest affinity metal
What is an example of compartmentalization?
In bacteria there are two enzymes, MnCA, CuCA - identical except they bind different metals. In order to get MnCA to bind, it is folded in the cytosol (where Cu levels are low due to TF) and then exported by transported (Tat) which only exports folded proteins. Unfolded MnCA is transported using Sec transported and can then be displaced by Cu in the periplasm.
