Biomedical Engineering Reference
In-Depth Information
numbers leads to higher statin titers (Abe et al. 2002c, Baba et al. 2009). In
order to make the semi-synthetic chemical conversion of lovastatin into
pravastatin more cost-effective two approaches are reported. Xie et al.
(2006) expressed the
A. terreus lovD
gene in
Escherichia coli
and used the
isolated enzyme to convert monacolin J effi ciently into various derivates,
including simvastatin. A whole cell bioconversion was shown to be even
more effective (Xie and Tang 2007). Recently, the enzyme was improved
11-fold by directed evolution (Gao et al. 2009) and the process is currently
tested at 50,000 liter scale (Y. Tang, personal communication). Another
approach followed is the reengineering of
A. terreus
, with or without feeding
dimethyl-butyrate as precursor, in order to directly synthesize simvastatin
(reviewed by Barrios-González and Miranda 2010). Single fermentation
biosynthesis of pravastatin has also been reported, however this involves
the expression of a bacterial gene in compactin producing fungi (van den
Berg and Meijrink 2007).
Mycophenolate
Yet another secondary metabolite produced by different species of the
Penicillium
genus is mycophenolate, currently applied as an effective
immunosuppressant quite often in combination therapies with for
example tacrolimus and cyclosporine. Already discovered at the end of
the 19th as an inhibitor of
Bacillus anthracis
, it has been applied to treat
many different diseases (reviewed by Bentley 2000).
P. brevicompactum
is
used for the industrial production of mycophenolate which is via
chemical esterification converted in the prodrug mycophenolate
mofetil (MMF, brand names CellCept and Myfortic, respectively of
Roche and Novartis) and widely applied with kidney, heart and liver
transplantation.
Only very recently, more insight in the biosynthesis has been obtained
via cloning of the responsible polyketide synthase (PKS) gen,
mpaC
,
residing in a 25-kb gene cluster in the genome (Requeira et al. 2011) and
functionally expressing the same gene in
A. nidulans
(Hansen et al. 2011)
creating an opportunity for synthesizing new variants of mycophenolate.
Intriguingly, the cluster contains a gene encoding IMP dehydrogenase
(IMPDH), its target gene in human application. Apparently, the presence
of this gene, in addition to the gene elsewhere in the genome, prevents that
the product targets the production host. This is similar as with the statins,
which is a known anti-fungal and thus also targets the fungal production
host. Therefore the statin biosynthetic clusters have a gene encoding for an
additional HMG CoA reductase; the enzyme level was shown to control
the statin titer (Van den Berg and Hans 2009).
