Lecture 7- Bioinorganic Flashcards
How does zinc occur under physiological conditions?
- as Dicationic Zn(II)
- closed shell d10 configuration
- diamagnetic and colourless complexes
What are the important chemical characteristics of Zn(II)?
- Strong Lewis acid.
- NOT redox active.
- Ready formation of low coordinate binding sites (> acidity)
- Accessible coordination numbers of 4, 5, 6.
- Easily deformed coordination geometry.
- Easily undergoes mono-ligand substitution chemistry
What are the three possible reactions of a water molecule with mononuclear zinc sites?
- Ionisation
- Polarization
- displacement
Lower Zn coordination numbers increase the acidity of the bound water molecule
How are Zn(II) mechanisms discovered?
- Using Co(II) due to Zn ‘transparency’
- similar size and reactivity and can be substituted without perturbing protein structure
- UV can be used to monitor coordination geometry due to the d7 electronic structure of Co(II)
What is carbonic anhydride II?
- found in red blood cells
- catalyses the reversible hydration of CO2
- makes CO2 more soluble and therefore easier to remove from metabolising sites such as muscles
What is the general mechanism of carbonic anhydride II?
1) Hydrophobic pocket next to Zn 2+ captures CO2
2) Nucleophilic attack on carbon of CO2
3) Conformational rearrangement at Zn centre
4) product displacement by substitution with water
5) His-64 acts as a proton acceptor via a chain of hydrogen bonded water molecules (RDS)
The peptide chain environment around the active site is important for catalytic activity as it orients the molecules correctly
CPA (Carboxypeptidase A)
- where is it found?
- what is the main reaction its used for?
- how is it specific?
- digestive enzyme found in the pancreas
- catalyses the cleavage of peptide links in a polypeptide chain and helps organisms break down ingested proteins
- cleavage is specific to C-terminal amino acids, and is selective to amino acids with large aliphatic or Ph substituents
CPA structure
- molecular weight of approx 34500 kDA
- one zinc Atom in a cavity
- 307 amino acids
- Zn2+ with one bidentate Glu and 2 His ligands
- coordinate sphere completed by water molecule
- vital for the mechanism are a guanidium ion of Arg-127 and the carboxylate group og Glu-270
Proposed CPA mechanism
1) Peptide that will be cleaved is manoeuvred into position using hydrophobic and H- bonding interactions
2) Arg-127 polarises the carbonyl group, activating it towards nucleophilic attack by the Zn bound ‘activated’ H20
3) Cleavage of the CN bond facilitated by Glu-270
4) Proton transfer and peptide and the new amino acid leaves
What is required for a platinum drug (PtL2X2) anti-caner activity requires
1) Cis leaving groups
2) Neutral complex with Pt(II) or Pt(IV) centre
3) Leaving groups are moderately strong bound, usually anionically. Too strongly and the drug isn’t active enough, too weakly and the drug is toxic
4) non leaving groups are also crucial, amine groups with at least one NH
What are the stages of clinical trails?
- in vitro in mouse lukemia cells
- animals
- several stages of clinical trails
- only 1 in 10000 screened drugs make it to clinical use
What is the active complex of cis platin? Describe its chemistry.
- Monoaqua complex is the active species
- the positive charge on the complex means it is attracted to the negative surface of DNA
- the complex is slow to form due to the CFSE of cis platin causing a high activation energy
- this means there is a 2-3 hour delay in sensitisation when the drug is administered
Biological targets of cis-platin
- diseases where DNA repair processes are deficient are hypersensitive to cis-platin
- correlation between Pt-DNA adducts in peripheral blood cells and disease response in cis-platin patients
Pt binding to mononucleotides
- G(N7) to be the most electron rich centre, binding most strongly to Pt. This bond can only be broken by a strong nucleophile such as CN or thiourea
- G(N7)>A(N7)>A(N1)>C(N3)
- adduct ca be readily detected using 1H NMR with a shift from 7.8 to 8.8 and introduction of Pt satellites
