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Biocoordination Flashcards

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1
Q

What are siderophores?

A

Siderophores are molecules which chelate Fe(III) extremely strongly:

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2
Q

How are siderophores used?

A

excreted by organism to strip Fe(III) from minerals and form soluble complexes which are absorbed
by organism.

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3
Q

The strongest known binders of Fe(III); based on tris-catecholateor tris-hydroxamate ligands which give octahedral Fe(III) complexes. How do they work?

A

Both give stable 5-membered chelate rings

with ‘hard’ O-donor set and –ve charges

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4
Q

How can stronger binding of Fe(III) be achieved in siderophores?

A

Combining three bidentate chelating sites in one molecule

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5
Q

What is Enterobactin?

A

Cyclic triester core with three pendant catecholate arms which forms an octahedral complex with Fe(III)

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6
Q

why does Enterobactine have a high affinity for Fe(III) than other siderophore?

A

Improved chelate effect from one hexadentate ligand instead of three bidentate ligands
• Preorganisation of ligand (all three arms directed to same face of ring to give predefined cavity) minimises cost of conformational change and increases binding affinity

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7
Q

what does Tris-hydroxamate siderophores: ferrichrome consist of?

A

Cyclic hexapeptide
• Three chelating arms pendant from cyclic core
• Partly preorganised octahedral cavity for Fe(III)

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8
Q

what is the structure of the siderophore desferrioxamine?

A

a linear tris-hydroxamate from bacteria which folds up around Fe(III) centre to act as hexadentate ligand

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9
Q

what is desferrioxamine used for?

A

used medically to bind excess iron in cases of iron overload

from either poisoning (too many iron tablets!) or disease

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10
Q

What are two types of metalloproteins in the body?

A

Enzymes: catalyse chemical transformations involving bond formation / breaking
Non-enzymes: other functions (electron transfer; oxygen transport; iron storage)

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11
Q

what is the role of the metal and protein in a metalloprotein?

A

Metal ion = ACTIVITY
Provides basic action and reactivity of metalloprotein eg (low ox - soft ligand)
Protein (ligand) = SELECTIVITY
Provides fine tuning so that reactivity is only applied where needed

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12
Q

how do metal ions bind to proteins?

A

Directly through side chains

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13
Q

How is Zn(II) bonded?

A

Sits within folded proteins strands directly coordinated to a protein at a point where three ligating side chains converge. There is cleft present

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14
Q

How is porphyrin organised?

A

Fe bind to porphyrin ring and the whole Fe/porphyrin rinf unit binds at an axial Fe site

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15
Q

where does heme bind oxygen?

A

At an axial site

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16
Q

describe the coordination of oxygen to heme unit?

A
  1. Deoxygenated form: square pyramidal Fe(II) high spin and Fe moves away from porphryin ring towards histidine ligand.
  2. Oxygen binds at an open face. Fe moves into porphryin plane. oxygen forms H bonds with distal histidine.
    the oxygenated form: Fe is low spin (III) and has a smaller radius that HS spin Fe(III)
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17
Q

what are the components to bonding between oxygen and Fe?

A

1 sigma donation and 2 back bonding components (draw orbital diagrams)

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18
Q

both low spin Fe(III) and anionic superoxide are paramagnetic but oxyHb is diamagnetic, why?

A

antiferromagnetic coupling - unpaired electrons couple over a distance due to orbital overlap and interaction

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19
Q

what is the evidence of how Oxygen in bonded in oxyHb?

A

Transfer of e density into ∏* orbital results in lengthening of O-O bond and reduced stretching frequency in vibrational spectra (1105 cm-1 - consistent with bond order of 1.5)

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20
Q

why is CO not lethal in small quantities?

A

Steric clash with distal histidine when CO binds which results in a bend of 20 - 30 degrees. This means binding of CO is not completely linear and therefore binding not optimised and weaker CO binding.

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21
Q

true or false: Distal histidine stabilised CO but not Oxygen

A

False- Oxygen binding is stabilised by H bonding with distal histidine

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22
Q

how do simple Fe- porphryin complexes bind to Oxygen

A

They react irreversibly with Oxygen to give a v stable Fe(III) - O - Fe(III) dimer

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23
Q

how is dimerization prevented?

A

steric protection, use bulky groups on one side of porphryin ring. Allows O2 to bind in a cavity but prevent face to face approach of two rings

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24
Q

what are the structural evidence for the structure of hemocyanin?

A
  1. a peak in raman spec at 750 cm-1, consistent with o-o single
  2. isotopic labelling: 1 peak observed, suggest that bonding is symmetrical and two atoms are equivalent
  3. strong absorption at 580 nm (blue colour), LMCT
  4. hemocyanin is diamagnetic so suggest antiferromagnetic coupling via a single Cu - x - Cu bridge.
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25
Q

why are HEMES - CYTOCHROME P450 important?

A

They can oxidise of inert/unreactive organic substrates
which is essential for oxidising endogenous products as part of metabolism and also for the oxidation of foreign products as part of destruction

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26
Q

describe the active site of HEMES - CYTOCHROME P450?

A

Fe(III) stabilised by 2 negative charge of porphryin and a negative cysteine thiolate. Fe(III) is LS and can fir into the p ring

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27
Q

give the mechanism for the oxidation of simple substrate RH to ROH?

A
  1. substrate binds in a hydrophobic cavity
  2. water dissociates as RH binds which generates high spin Fe(III) which moves out of ring plane. Fe reduced to generate HS Fe(II) ready for O2 binding
  3. Oxygen binds generating a low spin Fe(III) superoxide
  4. 2nd reduction generates Fe(III) peroxide which is v reactive and short lived
  5. Reaction of two H+ liberates H20 and cleaving the o-o bond leaving Fe(IV)/O•– unit (this is the key reactive species that oxidises substrate
  6. Transfer of mono oxygen to substrate. CH bond undergoes catalytic cleavage and O atom is inserted. product dissociates.
28
Q

what evidence is there to suggest that Fe(III) porp reacting with PhIO generates a species whose properties are consistent with formulation (P•–)FeIV=O?

A
  1. perfoms the same type of oxidation as P456
  2. short Fe-O distance consistent with Fe=O
  3. HNMR shifts up to 70 ppm - indicates paramagnetic P unit
  4. magnetic behaviour is consistent with Fe4+ and P`- radical
29
Q

what is the evidence for the final oxygen transfer in the P450 oxidation (steps F-A)

A
  1. chiral substrates partially racemise, suggesting non chiral intermediate
  2. large kinetic isotope effect, much slower with CD suggesting that RDS involves CH cleavage
30
Q

describe the basic properties of Cu(I) and Cu(II) complexes?

A

Cu(I) prefers soft ligands and low coordination numbers to prevent build up of negative charge
d(10) so no CFSE preference
Cu(II) prefers hard donor ligands and high coordination numbers to balance charge and is d9 so geometry controlled by jhan teller effect
Low redox potentials - Cu(II) preferred
high redox potentials - Cu(I) preferred

31
Q

how to favour Cu(I)?

A

soft donor set and tetrahedral geometry - need strong oxidising agent to generate higher one

32
Q

How to favour Cu(II)?

A

Hard donor set and square planar geometry

33
Q

how does changing the R groups and donor sets effect the Cu(I)/Cu(II) redox potential?

A

small R - favour square planar, larger R introduces steric effects which impose a tetrahedral twist.
changing hard to soft will stabilise Cu(I)

34
Q

describe the geometry of the plastocyanin unit

A

(draw) trigonal NNS array of two histidine donors and cysteine thiolate. weaker axial interaction to thioether s donor so overall trigonal pyramidal

35
Q

why is electron transfer between Cu(I) and Cu(II) v fast?

A

the proteins impose a nearly identical geometry on blue cu proteins. blue Cu proteins are constrained to be structurally identical. Rigid protein does nor permit structural rearrangement so ET rate is fast.

36
Q

what 2 problems are there associated with making models for blue copper proteins?

A
  1. difficult to isolate Cu(II) thiolate complexes due to oxidation to disulphides
  2. hard to impose distorted geometry on metal using simple ligands
37
Q

why was the first MODEL FOR BLUE COPPER PROTEIN ACTIVE SITES?

A
  1. Cu - S distances are too long

2. Red as LMCT is too high in energy

38
Q

is Bulky tris(pyrazolyl)borate a good model for blue copper proteins? `

A

bulky groups provide a cavity to protect thiolate and prevent dimerization
approx. tetrahedral and is blue as it has an LCMT at 609 cm-1 BUT redox potential is too low.

39
Q

why is the C6F6S- anologue a good model for blue copper proteins?

A

distorted tetrahedral towards trigonal pyramidal with N2S donors in basal plane.

40
Q

why does Zn(II) make a good lewis acid?

A

it is small and high charge +2

41
Q

how does Zn make water a better nucleophile?

A

Coordinates to water making deprotonation easier as OH- is stabilized by the Zn ion

42
Q

what does CAH catalyses?

A

reversible hydration of carbon dioxide to make it water soluble

43
Q

how does CAH work?

A

It accelerates the reaction of HO- with carbon dioxide

so that it becomes diffusion controlled.

44
Q

describe the bonding in CAH active site

A

Zn is in a deep cleft, tetrahedrally coodinated to 3x histidine and one water molecule. The +2 charge is not neutralised. The pi acceptor character of histidine ligands removes e density from the metal ion making it more positive: it has the highest residual charge of any metalprotein

45
Q

CAH is a combination of both lewis acid mechanisms.what are these.

A
  1. facilitates the deprotonation of water molecules
  2. polarises CO2 making it more electrophillic
  3. OH- and CO2 held close together
  4. ordered H bonded chain of water molecules acts as a shuttle
46
Q

what is the mechanism of CAH?

A
  1. deprotonation of bound water via imidazole at the end of the proton shuttle
  2. Diffusion of CO2 to active site. Weak interaction between Oxygen and Zn anchors CO2. This increases the inductive charge on C.
  3. bound hydroxide attack on CO2 to give bound biocarbonate at 5 coordinate metal centre
  4. bidentate carbonate anion is displaced by water.
47
Q

what is the push pull mechanism?

A

Involves CAH. Water made more nucleophillic and carbon dioxide made more electrophillic.

48
Q

how does hydrogen bonding aid the CO2 binding at active site?

A

threonine residue (Thr-199) provides alcohol group to stabilise OH– ion, and NH proton to help anchor
far end of CO2.
Two hydrogen bonds retained in product when HCO3
– is coordinated: may weaken Zn–O bonds and assist in rapid displacement of product by water

49
Q

what do isotopic labelling experiments show?

A

that attack on CO2 is from bound hydroxide ion as 17O incorporated into CO”

50
Q

what does the inability of water to displace HCO3- show?

A

when reduce steric crowding you get a stable 5 coordinate Zn(II) complex in water shows that alone water cant displace carbonate so other factors must assist eg steric crowding and H bonding

51
Q

why is the dimerisation of Zn(II) in CAH not possible?

A

sterically not possible as Zn(II) is buried deep in the cleft which prevents face to face dimerization

52
Q

why is the uncatalysed hydrolysis of amines slow?

A

The electronegative behaviour of N reduces δ+ on the carbonyl. hydrolysis requires strong acid or base to make water more nucleophillic or amide a better electrophile

53
Q

describe the active site of CAH?

A

Zn(II) buried in a deep cleft in which substrates can diffuse to. 5 coordinate Zn complex, with water and three amino acid residues (1 x glu and 2 x histidine donors)

54
Q

how is the substrate anchored in carboxypeptidase?

A
  1. Carboxylate end groups form H bonds with arginine - 145 .
  2. hydrophobic R groups stabilised by hydrophobic pocket
  3. carbonyl to be attacked h bonds to arg - 127 making it more electrophilic
55
Q

what is the mechanism of Carboxypeptidase?

A

developing negative charge on O is stabilised by H bonding to Glu - 270 and by interaction to Zn ion
leaving group is protonated from glu - 270 so it becomes a better leaving group
glu - 270 acts a base and pulls off 2nd proton off Zn- OH
amine terminus of leaving amino acid protonates again and products dissociate

56
Q

what are the roles of the amino acid residues in Carboxypeptidase?

A

Glu-270 in acting twice as a base (removing protons from Zn-bound water) and as an acid (donating protons to leaving amine group)

roles of Arg-145 and Arg-127

(i)   Binding substrate (both)
(ii)   Activating carbonyl group of substrate by partial protonation (Arg-127)
(iii)   Stabilising anionic intermediate (Arg-127)

57
Q

from the two models for Carboxypeptidase, which one reacts faster?

A

Model B as intramolecular reaction dominates. The proximity of E and Nu more important than activation of CO group.

58
Q

why is the hydrolysis of Amide accelerated at pH 7 by presence of Zn(II) ions?

A
  1. activation of water coordinated to Zn generates bound OH
  2. HO- ion held closely to Carbonyl
  3. activation of CO to nucleophillic attack by coordination to Zn(II).
59
Q

how is Fe transported in mammals?

A

Transferrin’s

60
Q

how is Fe(III) binding favoured in transferrins?

A

hard donor set to prevent precipitation

synergistic binding with carbonate anion which enhances binding.

61
Q

how does the carbonate anion specifically enhance Fe(III) binding in transferrins?

A

organises the binding pocket by H bonding to amino acid side chains to give an octahedral conformation for Fe(III) binding to occur.

62
Q

how does Fe(III) / transferrin move across the lipid bilayer?

A
  1. Apo transferrin binds to Fe(III) and whole complex binds to membrane receptors.
  2. fold in membrane as vesicle starts to form
  3. lipid based endosomes forms which protect Fe/transferrin is protected from the cytoplasm
  4. Influx of protons reduces the pH of
  5. protonation of tyrosine and aspartate to neutral reduces affinity for Fe(III) which moves into cell through special channel in membrane.
63
Q

what is the key to controlling the uptake and release of Fe(III)?

A

pH swing. phenolate and carboxylate bind strongly to Fe(III) when deprotonated

64
Q

what does ferritin consist of?

A

core of hydrated ferric oxide inside a protein overcoat protein coat - 24 proteins roughly in a spherical array with cavities In the faces to allow access od ions to central cavity

65
Q

describe the interior of Ferritin?

A

Inside the core the iron crystallises with OH - ions and dihydrogen phosphate ions. The terminating groups on the surface anchor the protein overcoat to the ferric oxide core.

66
Q

What is the Structure of ferrihydrite?

A

close-packed array of oxide / hydroxide ions with Fe

(III) ions in octahedral cavities. Nonstoichiometric mix of three phases.

67
Q

how is Fe extracted from complex after its been assimilated?

A

Decomposition of siderophore ligand: e.g. enterobactin contains a trimester ringwhich is easily hydrolysable and can be broken down by
organism
(ii)  Protonation of ligand (OH much poorer ligand than O–), cf. transferrin
(iii) Reduction of Fe(III) to Fe(II), which makes metal ‘softer’ and reduces its affinity for the hard binding site → more labile, less stable complex

Chemistry (22 decks)

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