JOANNE STUBBE: My lab works on the only cool enzyme
in the world--
ribonucleotide reductase.
It's the only way in all organisms
that you make the building blocks de novo
that are required for DNA biosynthesis and repair.
So if you inhibit this enzyme, you have no building blocks.
You can't survive.
So from a practical point of view,
it's the target of drugs they use therapeutically
in the treatment of cancer.
And I think in probably not so distant future
in the antibacterials because I think
there are sufficient differences between humans and bacteria
reductases that you could make specific inhibitors.
Why am I interested in it?
Because the chemistry is sort of unbelievable.
So I mean it was the first example where you learn,
or you hear about-- you heard from John--
radicals.
They're reactive oxygen species and nitrogen species
that you can't control.
They want to pick up an extra electron
and form a stable octet.
And if you leave them to their own demise,
they react with anything and destroy it.
Well nature has figured out how to harness
the reactivity of radicals to do really tough chemistry
with exquisite specificity.
And ribonucleotide reductases have been the paradigm
for thinking about that.
And from bioinformatics now there
are 50,000 reactions in metabolic systems
that are going to be radical mediated transformations,
yet we never talk about radicals in introductory courses.
So I think that's all going to change.
So why is it unusual?
Well, for the human ribonucleotide reductase,
the key to making this work catalytically
is the amino acid side chain tyrosine
needs to be oxidized to a tyrosyl radical.
So automatically nobody believes that.
A tyrosyl radical in solution has
a half-life of a microsecond.
In the active site of these enzymes,
the half-life of the enzyme can be on the order four days.
And this radical, which is again one electron
oxidized amino acid-- if you reduce it
with an electron and a proton, the enzyme is completely dead.
So this was the first example of-- it
would be another example of a post-translational modification
that we talked about earlier-- modifying your amino acids.
And so nature has figured out a way.
How do you do this oxidation?
She has a little metal cluster right adjacent to where
this tyrosine is.
And the function of this little metal cluster
is to put this into the oxidized state, which
is essential for the way the enzyme works.
So the other thing that's amazing about the enzyme
is the chemistry.
There are two subunits.
The chemistry all happens in this subunit,
but the tyrosyl radical is there.
And this oxidation-- normally when you do an oxidation
the two atoms are sitting within a few angstroms of each other--
the oxidation happens over 35 angstroms.
So that's unprecedented.
It involves hopping radicals which
no one has ever seen before.
And so that was another thing that
was completely fascinating from a chemical perspective
about how the system works.
The other reason that people in biology
are interested in this, besides the fact that makes a building
block for DNA, is that if you believe in an RNA world
where we have a ribosome where a catalysis of peptide bond
formation is all with the RNA, not with the protein.
How do you get from an RNA world to a DNA world?
The only enzyme that does that transformation
making these building blocks are ribonucleotide reductases.
And there are many classes of ribonucleotide reductases--
one uses this tyrosyl radical--
but they all have the same active site
and do the same chemistry, but they
have different metal cofactors depending
on where they evolved.
And the function of the metal cofactors in all cases,
even though one's cobalt, one's iron sulfur cluster,
one's manganese, one's iron--
the function in all cases is to generate a radical
in the active site and then the chemistry
is the same in all these things.