Chemistry of Fe

Question 1

Where are cytochrome P450s found?

Answer 1

Liver

Question 2

What type of molecules are cytochrome P450s?

Answer 2

Oxidising molecules

Question 3

What do cytochrome P450s do to aromatic rings?

Answer 3

Add OH

Question 4

What do cytochrome P450s do to heterocycles?

Answer 4

Add OH to them

Question 5

What do cytochrome P450s do to methyl groups?

Answer 5

Change to an alcohol

Question 6

What do cytochrome P450s do to alkenes?

Answer 6

Form epoxide

Question 7

How many phases is there in drug metabolism?

Answer 7

2

Question 8

What is Phase I of drug metabolism?

Answer 8

Functionalisation

Question 9

What phase are cytochrome P450s part of?

Answer 9

Phase I

Question 10

What happens in Phase II of drug metabolism?

Answer 10

Conjugation

Question 11

Describe Phase I (oxidation)

Answer 11

Addition of O
Cytochrome P450
Require cofactors

Question 12

Whay are examples of cofactors?

Answer 12

NADH
NADPH
O

Question 13

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

Answer 13

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

Question 14

What are cytochrome P450s?

Answer 14

Heme-containing enzymes

Question 15

What are similar about cytochrome P450s?

Answer 15

Catalytically + structurally similar

Question 16

Describe iron containing porphyrin

Answer 16

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

Question 17

Why is there N in iron containing porphyrin?

Answer 17

N holds metal ion on specific position
Metals have preferred geometry

Question 18

What is the shape of iron containing porphyrin?

Answer 18

Planar = sp2

Question 19

Describe what happens to iron containing porphyrin prodrug (clopidogrel)

Answer 19

Cytochrome P450 adds O
Then hydrolase adds H2O

Question 20

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

Answer 20

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

Question 21

Describe cytochrome P450 cycle

Answer 21

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

Question 22

How do you stop the cytochrome P450 cycle?

Answer 22

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

Question 23

What Fe overload/toxicity do?

Answer 23

Damage tissue
Catalyse conversion of hydrogen peroxide to free radical ions

Question 24

What can free-radicals attack?

Answer 24

Cellular membranes
Proteins
DNA

Question 25

What Fe deficiency due to?

Answer 25

Reduced intake Increased loss Increased demand

Question 26

Why is Fe deficiency not a diagnosis?

Answer 26

A cause needs to be identified for it

Question 27

What are the 3 common structures for complex ions?

Answer 27

Octahedral - Mg Tetrahedral Square planar - Cisplatin

Question 28

What can Fe be classified into?

Answer 28

Fe-bearing heme moiety Non-heme containing

Question 29

What is the relevance of Fe?

Answer 29

O transport Metabolism O transfer Energy transport

Question 30

What are the 2 structures of protein with metals?

Answer 30

Spiral Tape

Question 31

Describe spiral structure

Answer 31

Alpha helix form of protein

Question 32

Describe tape structure

Answer 32

Beta pleated sheet form of protein

Question 33

What is a co-factor?

Answer 33

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

Question 34

What are examples of cofactors

Answer 34

NAPDH

Question 35

What is protoporphyrin IX?

Answer 35

Organic compound sp2 single planar Bridges = linked

Question 36

What are hemes?

Answer 36

Prosthetic groups in haemoglobin, myoglobin + cytochrome C

Question 37

What is the function of haemoglobin?

Answer 37

Transport O

Question 38

What is the function of myoglobin?

Answer 38

Store O + facilitate O diffusion

Question 39

Where is haemoglobin found?

Answer 39

RBCs

Question 40

Where is myoglobin found?

Answer 40

Muscle cells

Question 41

Describe structure of myoglobin

Answer 41

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

Question 42

Describe structure of heme group in myoglobin

Answer 42

Consists of protoporphyrin, which binds to Fe2+

Question 43

Describe Fe2+ in heme of myoglobin

Answer 43

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

Question 44

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

Answer 44

1 is bound to N 2 serves as O bindign site

Question 45

What is the role of distal histidine?

Answer 45

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

Question 46

Describe haemoglobin

Answer 46

Tetrameric protein Each subunit contains bound heme group

Question 47

What are the 2 types of chain in adult Hb?

Answer 47

2 alpha 2 beta

Question 48

What are the 2 states of haemoglobin?

Answer 48

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

Question 49

Which state is more stable in the absence of O?

Answer 49

T state

Question 50

What happens when O binds to Hb in T state?

Answer 50

Triggers change in conformation of R state

Question 51

What does O binding to Hb promote?

Answer 51

Flattening of porphyrin ring + shifting of helix

Question 52

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

Answer 52

Bind efficiently in lungs BUT not release much into tissues

Question 53

What would a protein with low affinity do?

Answer 53

Release efficiently in tissues BUT not pick up much in lungs

Question 54

What does Hb do solve affinity problem?

Answer 54

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