Lecture 5 Flashcards
Cisplatin has what metal in it
Auranofin has what
And cardiolyte has what
Slide one structures of cisplatin and auranofin and cardiolyte
Pt
gold (au)
Tc
Know structures
Why does gadolinium work well for contrast in MRI imaging
It is pheromagmetic
What is the difference in cisplatin vs carboplatin
Cisplatin has more side effect because it’s less selective for cancer cells
Carboplatin more selective (but works the same)
What is the activation mechanism of cisplatin
Outside the cell (in blood) where [cl] is high, the cisplatin is inactive
Through passive diffusion it goes into cell low cl concentration
it gets hydrated and one of its cl is replaced by water
When both the cl are gone that’s the active form of cisplatin
What is required for cisplatin to react with DNA
Two adjacent Guanine groups (to line up their guanidines)
ex. C-G
C-G
That way it can form a bend in the dna by interacting with the G groups
What does cisplatin do to the DNA
it forms a bend in the dna by interacting with the G groups
That way it interferes with dna transcription and replication
What distinguishes between hard and soft metals
The oxidation state
What are the hard metal and what do they bind to
Fe3+, ca2+
Na+, K+, Mg2+
Bind to oxygen
What are the borderline/intermediate metal and what do they bind to
Fe2+, ni2+, zn2+, Co2+, Cu2+
Bind to nitrogen’s
What is special about imidzole in terms of metal binding
Binds tightly to. The 2+ forms of Ni Zn Co
What are the soft metal and what do they bind to
Cu+
cd2+, pt2+, pb2+, hg2+
Bind sulfur (usually cysteine)
Sometimes bind nitrogen
What can side chains of protiens do in terms of metals
They can act as ligands for the metals
What are the types of metal side chain interactions
That cysteine , histidine, and aspartate can make
Monovalent (ex. S of cysteine binds one metal)
Divalent ( S binds two metals)
Eta nitrogen (one metal binds the eta N of his)
Delta nitrogen (one metal binds to the delta N of his)
Monodentate: (one metal bound to one oxygen of asp)
Bidentate: (one metal bound to two oxygen of asp)
Bidentate bridging: two metals bound to one each oxygen of asp
What is an example of a protien that binds soft metals
What does it do
Metallothionein
Binds zinc tightly outside the cell (in blood,)
Dextoxifies heavy metals like cd pb, mercury
Involved in zinc and copper metabolism
What are hard hard bonds
What special about calcium in these bonds
Ex. Calcium to oxygen
Calcium has a wide range of distances if can form interactions with compared to other metals
Has both bidentate and mono dentate binding
What are shared ligands in hard hard bonds
When one hard metal is bound to one oxygen in a side chain and another metal is bound to the other
This sharing causes bidentate bridging
What effect does the size (ionic radius) have on the # of interactions a metal can make
Why
Large radius, more interactions
Larger radius, the easier for water to be stripped off but the smaller metal keeps water on more strongly (water needs to be stopped of the metal before the metal can bind to a protein)
How many interactions can Mg, Ca, Al and Ga make
6, 7.3, 5.3, 4.6
coordination numbers 3,4,5,6,7 line up with which geometry and give examples of the metals that make these geometry’s
3: trigonal planar, pyramidal, T-Shaped
4: square planar (cisplatin-pt2+, ni2+, cu2+ albumin)
tetrahedral (zn2+)
5: square pyramidal (Cu2+ prion), trigonal bipyramidal
6: octahedral (fe3+,mg2+)
7: pentagonal bipyramidal (ca2+)
pentagonal bipyramidal (ca2+) interaction is
Planar
What is the pentagonal bipyramidal structure that the ca2+ binds to
The EF hand protien
What is the EF hand protien
How many positions are there and what is in each position
It’s a structural and sequential motif
Has a EF hand binding loop with 12 potitions
In positions 1,3,5,7,12: there are oxygens from asp or glu
In position 6: gly
In position 9: water
Ca binds to the oxygens and water
What is transferrin (Tf)
It’s a protien that transports fe3+ through the body
Binds tightly to fe3+ but not fe2+
What happens to transferrin if fe3+ gets reduced to fe2+
The affinity of Tf for the fe ion is decreased since transferrin only binds fe3+
What type of binding does transferrin do to fe3+
Octahedral (because it has a coordination number of 6)
Binds it’s carbonate group to fe through bidentate (hard metal)
What is different in the binding of ca2+ and fe3+
Fe3+ has restricted distances in its octahedral binding
But ca2+ is a promiscuous binder (binds with large distances)
What are the factors that make a metal ion know to bind to a specific protien and not another
If it’s hard soft or intermediate (does it like the ligands in the protein)
The size of the metal cation (is its ion is radius too big or too small to fit in the binding site?)
The preffered coordination chemistry (tetrahedral vs square planar) pt4+ is tetrahedral but 2+ is square planar
The rate and energetics of dehydration
The availability of the metal (ex. Ca not toxic, so as ca gets higher, muscles contract and proteins react and get active so they bind ca in concentration dependent manner)
Where is fe3+ and where is fe 2+, what does this mean for binding
Outside the cell
Inside the cell
This means that the availability of both forms is different depending on the location, which changes which proteins bind
Where is fe3+ and where is fe 2+, what does this mean for binding
Outside the cell
Inside the cell
This means that the availability of both forms is different depending if the location which changes which proteins bind
If fe is more abundant than ca, why did evolution choose ca for most processes?
Because fe ionic radius is lower and has less coordination sites
Whereas ca2+ is a promiscuous binder and has higher ionic radius
