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S2 Case 3 - asthma & COPD > Chemistry of Fe > Flashcards

Chemistry of Fe Flashcards

1
Q

Where are cytochrome P450s found?

A

Liver

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2
Q

What type of molecules are cytochrome P450s?

A

Oxidising molecules

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3
Q

What do cytochrome P450s do to aromatic rings?

A

Add OH

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4
Q

What do cytochrome P450s do to heterocycles?

A

Add OH to them

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5
Q

What do cytochrome P450s do to methyl groups?

A

Change to an alcohol

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6
Q

What do cytochrome P450s do to alkenes?

A

Form epoxide

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7
Q

How many phases is there in drug metabolism?

A

2

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8
Q

What is Phase I of drug metabolism?

A

Functionalisation

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9
Q

What phase are cytochrome P450s part of?

A

Phase I

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10
Q

What happens in Phase II of drug metabolism?

A

Conjugation

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11
Q

Describe Phase I (oxidation)

A

Addition of O
Cytochrome P450
Require cofactors

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12
Q

Whay are examples of cofactors?

A

NADH
NADPH
O

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13
Q

What is the general equation for cofactors in Phase I oxidation?

A

R-H + NADPH + O2 + H+ —-> R-OH + NADP+ + H2O

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14
Q

What are cytochrome P450s?

A

Heme-containing enzymes

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15
Q

What are similar about cytochrome P450s?

A

Catalytically + structurally similar

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16
Q

Describe iron containing porphyrin

A

Fe2+/3+ ion at active site
Ligated by 4 N atoms
Sharing of non-bonding e- with metal

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17
Q

Why is there N in iron containing porphyrin?

A

N holds metal ion on specific position
Metals have preferred geometry

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18
Q

What is the shape of iron containing porphyrin?

A

Planar = sp2

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19
Q

Describe what happens to iron containing porphyrin prodrug (clopidogrel)

A

Cytochrome P450 adds O
Then hydrolase adds H2O

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20
Q

Describe what happens to iron containing porphyrin prodrug (clopidogrel)
MORE DETAIL

A

Reduced to coordinated hydroperoxide (0)
H2O relays cleavage of O-O bond
Highly oxidising intermediate formed (I)
Abstract H, radical forms
OH, transfers from II
Enzyme back to start

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21
Q

Describe cytochrome P450 cycle

A

Fe3+
Then shunting of e-
Fe2+
Addition of O = radical
Fe3+ -O-O.
Addition of e- via NADPH = no longer radical
Fe3+-O-O
2H+ remove additional O
Fe3+-O
C-H bond cleaved by adding OH
R-OH removed

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22
Q

How do you stop the cytochrome P450 cycle?

A

Add substrate that has much stronger bond
eg. C-F or C-Cl

23
Q

What Fe overload/toxicity do?

A

Damage tissue
Catalyse conversion of hydrogen peroxide to free radical ions

24
Q

What can free-radicals attack?

A

Cellular membranes
Proteins
DNA

25
Q

What Fe deficiency due to?

A

Reduced intake
Increased loss
Increased demand

26
Q

Why is Fe deficiency not a diagnosis?

A

A cause needs to be identified for it

27
Q

What are the 3 common structures for complex ions?

A

Octahedral - Mg
Tetrahedral
Square planar - Cisplatin

28
Q

What can Fe be classified into?

A

Fe-bearing heme moiety
Non-heme containing

29
Q

What is the relevance of Fe?

A

O transport
Metabolism
O transfer
Energy transport

30
Q

What are the 2 structures of protein with metals?

A

Spiral
Tape

31
Q

Describe spiral structure

A

Alpha helix form of protein

32
Q

Describe tape structure

A

Beta pleated sheet form of protein

33
Q

What is a co-factor?

A

Non-protein chemical compound that is bound to a protein + is required for the protein’s biological activity

34
Q

What are examples of cofactors

A

NAPDH

35
Q

What is protoporphyrin IX?

A

Organic compound
sp2 single planar
Bridges = linked

36
Q

What are hemes?

A

Prosthetic groups in haemoglobin, myoglobin + cytochrome C

37
Q

What is the function of haemoglobin?

A

Transport O

38
Q

What is the function of myoglobin?

A

Store O + facilitate O diffusion

39
Q

Where is haemoglobin found?

A

RBCs

40
Q

Where is myoglobin found?

A

Muscle cells

41
Q

Describe structure of myoglobin

A

Contains single polypeptide chain
Single prosthetic group = Fe protoporphyrin (heme)

42
Q

Describe structure of heme group in myoglobin

A

Consists of protoporphyrin, which binds to Fe2+

43
Q

Describe Fe2+ in heme of myoglobin

A

6 coordination positions
4 in plane of protoporphyrin + bonded to it
2 perpendicular to ring

44
Q

Describe the 2 perpendicular positions of Fe2+ in heme of myoglobin

A

1 is bound to N
2 serves as O bindign site

45
Q

What is the role of distal histidine?

A

Makes O bind in a bent fashion = makes it difficult for CO to bind in linear fashion

46
Q

Describe haemoglobin

A

Tetrameric protein
Each subunit contains bound heme group

47
Q

What are the 2 types of chain in adult Hb?

A

2 alpha
2 beta

48
Q

What are the 2 states of haemoglobin?

A

R state = relaxed
T state = tense
O binds to BOTH BUT favours R

49
Q

Which state is more stable in the absence of O?

A

T state

50
Q

What happens when O binds to Hb in T state?

A

Triggers change in conformation of R state

51
Q

What does O binding to Hb promote?

A

Flattening of porphyrin ring + shifting of helix

52
Q

What would a protein (eg. myoglobin) with a high affinity do?

A

Bind efficiently in lungs
BUT not release much into tissues

53
Q

What would a protein with low affinity do?

A

Release efficiently in tissues
BUT not pick up much in lungs

54
Q

What does Hb do solve affinity problem?

A

Undergoes structural transition from low affinity T-state to high affinity R state
As more O molecules are bound

S2 Case 3 - asthma & COPD (25 decks)

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