Lecture notes
Lecture Notes
- Module
- Metabolic Pathways
- Institution
- Queen Mary, University Of London (QMUL)
Lecture notes of 6 pages for the course Metabolic Pathways at QMUL
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Ribonucleotide reductaseLearning objectives:
1. To see the evolution within ribonucleotide reductase
2. Focus on class 1 ribonucleotide reductase
3. Understand their structure in relation to their function
4. To relate the known biochemistry and features of class 1 enzymes to their mechanism
5. Understand the mechanism of class 1 ribonucleotides reductase
6. The intricate steps required in controlling ribonucleotide reduction
Background
Don’t make the deoxyribonucleotides, dN (monomer of DNA: phosphate group, deoxyribose sugar & nitrogenous
base) from de novo, make it from ribonucleotides ( phosphate group, ribose sugar & nitrogenous base)
- Shown by 14C labelled cytidine in rats
Cytidine = a nucleoside composed of cytosine linked to ribose, obtained from RNA by hydrolysis.
Ribonucleotide reductase
- Converts NDP (nucleoside-diphosphate) to dNDP (deoxy nucleoside-diphosphate)
There are 3 classes of ribonucleotide reductase (RNR)
- Classified by:
Metal ion
Cofactor requirement
Common features:
- Similar reactions
- All use a free radical mechanism
- All replace 2’-OH with 2’-H
Individual features
- Class 1
An aerobic RNR
Found in all higher classes of eukaryotes
Found in many prokaryotes
Uses tyrosyl as free radical and a binuclear Fe (III)
- Class II
Both an aerobic (oxygenated environment) and anaerobic (non-oxygenated environment) RNR
Only found in prokaryotes
Uses coenzyme B12 or vitamin B12 as free radical
- Class III
An anaerobic RNR
Only found in prokaryotes
Uses iron-sulphur complex as free radical
o [3Fe – 4S]
o Possible also [4Fe – 4S]
, LO1. TO SEE THE EVOLUTION WITHIN RIBONUCLOETIDE REDUCTASE
Sequences:
- Same primary function
- Primary structure not very similar
- But key conserved areas do suggests common ancestor
- Most likely class III is the most distant common ancestor
LO2. FOCUS ON CLASS 1 RNR
LO3. UNDERSTAND CLASS I RNR STRUTURE IN RELATION TO FUNCTION
Humans have 2 types of RNR
Structure from E.coli RNR
- A dimmer of dimmers
2 R1 subunits & 2 R2 subunits
R1 is an α subunit
R2 is a β- subunit
Therefore, α2β2 tetramer
If create 2 homodimers (α2) and (β2) that are separate = enzyme catalytically inactive
For the enzyme to be active need to be an α 2β2 tetramer, which means that the alpha and beta
subunits are interacting
The active site is in the α-subunit
Tyrosyl radical is held in the β-subunit
The tyrosyl radical needs to be able to move to the active site in the α-subunit (hence there needs
to be interaction between the α & β subunits)
- Similar structure for mammalian RNR
R1 (α) subunit
- Contains substrate binding site
- And 2 separate effector sites
1. Specificity site
These are allosteric sites
2. Activity site
Involve triphosphates both RN’s and dN’s
- Overall there are 3 sites: active site, specificity site, activity site
R2 (β) subunit
- Tyrosyl radical needs to be stabilised in the beta subunits
- Tyrosyl radical uses an octahedral coordinated Fe (III) group with various ligands to be stabilised
- Ligands:
Bridged by O2- ion (µ-oxo bridge)
Carboxyl of Gln115
Carboxyls Asp 84, Gln 204, Gln 238
Nẟ of His118 & His241
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