Chemistry of Fe Flashcards
Where are cytochrome P450s found?
Liver
What type of molecules are cytochrome P450s?
Oxidising molecules
What do cytochrome P450s do to aromatic rings?
Add OH
What do cytochrome P450s do to heterocycles?
Add OH to them
What do cytochrome P450s do to methyl groups?
Change to an alcohol
What do cytochrome P450s do to alkenes?
Form epoxide
How many phases is there in drug metabolism?
2
What is Phase I of drug metabolism?
Functionalisation
What phase are cytochrome P450s part of?
Phase I
What happens in Phase II of drug metabolism?
Conjugation
Describe Phase I (oxidation)
Addition of O
Cytochrome P450
Require cofactors
Whay are examples of cofactors?
NADH
NADPH
O
What is the general equation for cofactors in Phase I oxidation?
R-H + NADPH + O2 + H+ —-> R-OH + NADP+ + H2O
What are cytochrome P450s?
Heme-containing enzymes
What are similar about cytochrome P450s?
Catalytically + structurally similar
Describe iron containing porphyrin
Fe2+/3+ ion at active site
Ligated by 4 N atoms
Sharing of non-bonding e- with metal
Why is there N in iron containing porphyrin?
N holds metal ion on specific position
Metals have preferred geometry
What is the shape of iron containing porphyrin?
Planar = sp2
Describe what happens to iron containing porphyrin prodrug (clopidogrel)
Cytochrome P450 adds O
Then hydrolase adds H2O
Describe what happens to iron containing porphyrin prodrug (clopidogrel)
MORE DETAIL
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
Describe cytochrome P450 cycle
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
How do you stop the cytochrome P450 cycle?
Add substrate that has much stronger bond
eg. C-F or C-Cl
What Fe overload/toxicity do?
Damage tissue
Catalyse conversion of hydrogen peroxide to free radical ions
What can free-radicals attack?
Cellular membranes
Proteins
DNA
What Fe deficiency due to?
Reduced intake
Increased loss
Increased demand
Why is Fe deficiency not a diagnosis?
A cause needs to be identified for it
What are the 3 common structures for complex ions?
Octahedral - Mg
Tetrahedral
Square planar - Cisplatin
What can Fe be classified into?
Fe-bearing heme moiety
Non-heme containing
What is the relevance of Fe?
O transport
Metabolism
O transfer
Energy transport
What are the 2 structures of protein with metals?
Spiral
Tape
Describe spiral structure
Alpha helix form of protein
Describe tape structure
Beta pleated sheet form of protein
What is a co-factor?
Non-protein chemical compound that is bound to a protein + is required for the protein’s biological activity
What are examples of cofactors
NAPDH
What is protoporphyrin IX?
Organic compound
sp2 single planar
Bridges = linked
What are hemes?
Prosthetic groups in haemoglobin, myoglobin + cytochrome C
What is the function of haemoglobin?
Transport O
What is the function of myoglobin?
Store O + facilitate O diffusion
Where is haemoglobin found?
RBCs
Where is myoglobin found?
Muscle cells
Describe structure of myoglobin
Contains single polypeptide chain
Single prosthetic group = Fe protoporphyrin (heme)
Describe structure of heme group in myoglobin
Consists of protoporphyrin, which binds to Fe2+
Describe Fe2+ in heme of myoglobin
6 coordination positions
4 in plane of protoporphyrin + bonded to it
2 perpendicular to ring
Describe the 2 perpendicular positions of Fe2+ in heme of myoglobin
1 is bound to N
2 serves as O bindign site
What is the role of distal histidine?
Makes O bind in a bent fashion = makes it difficult for CO to bind in linear fashion
Describe haemoglobin
Tetrameric protein
Each subunit contains bound heme group
What are the 2 types of chain in adult Hb?
2 alpha
2 beta
What are the 2 states of haemoglobin?
R state = relaxed
T state = tense
O binds to BOTH BUT favours R
Which state is more stable in the absence of O?
T state
What happens when O binds to Hb in T state?
Triggers change in conformation of R state
What does O binding to Hb promote?
Flattening of porphyrin ring + shifting of helix
What would a protein (eg. myoglobin) with a high affinity do?
Bind efficiently in lungs
BUT not release much into tissues
What would a protein with low affinity do?
Release efficiently in tissues
BUT not pick up much in lungs
What does Hb do solve affinity problem?
Undergoes structural transition from low affinity T-state to high affinity R state
As more O molecules are bound
