MOLYBDOPTERIN
and
the
COFACTOR
OF THE OXOMOLYBDOENZYMES
Oxomolybdoenzymes
- contain molybdenum
- molybdenum is the only second
row transition metal with a biological function
- are involved in oxidation/reduction processes
which amount to an oxygen atom transfer
- The oxomolybdoenzymes are
found throughout the entire range of organisms in the biosphere
- have a cofactor which is common to
all (with small variations)
Examples of
oxomolybdoenzymes include
nitrate reductase 
dimethylsulfoxide
reductase 
xanthine oxidase
What is known
about the mechanism of action of the enzymes ?
- the molybdenum is the site
at which the oxygen atom transfer takes place
- molybdenum changes from oxidation
state VI to oxidation state IV during turnover
- there are two types of oxomolybdoenzymes:
enzymes which add oxygen
to a heteroatom
(e.g. DMSO reductase)
have two oxo ligands
X + H2O Æ XO + 2H+ + 2e-
enzymes which insert
oxygen into a C-H bond
(e.g. xanthine oxidase) have
one oxo and one sulfido ligand
XH
+ H2O Æ XOH + 2H+ + 2e-
The cofactors of
ALL oxomolybdoenzymes have one or two
organic
PROSTHETIC GROUPS
which are common
to all
(with small variations
in a side-chain)
Tungsten-containing
enzymes (thermophilic anaerobes) utilise the same cofactors
but with molybdenum replaced by tungsten
Early work, mainly
by Rajagopalan et al. (Duke University, North Carolina,
U.S.A.) identified pteridines
in minute quantities as oxidative degradation products from denatured
samples of the enzyme.
Oxidative
degradation products of the molybdenum cofactor
Natural
metabolite of molybdenum cofactor
The whole enzymes do
not have the very characteristic fluorescence associated with
a fully aromatic pteridine suggesting that the enzyme cofactor
contains a (partially) reduced pteridine.
This was confirmed
by crystal structure determinations for five whole enzymes, four
molybdenum enzymes and one tungsten enzyme.
All
contained the same pterin unit - MPT
The prosthetic group
of was originally christened molybdopterin, abbreviated MPT. Now
that it is known that the same unit occurs in tungsten-containing
enzymes, 'molybdopterin' is no longer appropriate; the abbreviation
MPT has been retained but is now taken to stand for
Metal-binding Pteridine
diThiolate.
We asked ourselves:
Why would Nature go
to the trouble of incorporating a complex pterin into these enzymes
cofactor if it would not have any function ?
Could it be involved
in the redox/oxygen transfer processes ?
One can, for example,
propose involvement of the pteridine moiety in the mechanism of
action of dimethylsulfide oxidase.
In order to address
questions concerning the role of MPT in the mode of action of
the oxomolybdoenzymes, we have devised a synthetic
route to MPT. This will now allow us to synthesise non-natural
analogues for study, in vitro and in vivo, to seek
answers to questions concerning the rôle of the pterin in
enzyme turnover.