Biomedical Engineering Reference
In-Depth Information
Fungins
Fungins are cyclic semi-synthetic lipopeptide antibiotics (see
Fig. 3
for general structure), derived from fungal secondary metabolites as
echinocandinB, pneumocandinB0 and FR901379 (produced by
A. nidulans
,
Glarea lozoyensis
and
Coleophoma empetri
, respectively) via acylation by
a bacterial acylase (see for example Hormigo et al. 2010). Although the
yearly production is low (only several hundred of kilo's per year) it is one
of the major selling fungal derived pharmaceuticals with fi nished dosages
selling at several million dollars per kilo.
Fungal Biocatalysts for Pharmaceuticals
It is clearly established that enantiomers of racemic pharmaceutical drug
mixtures can have different pharmacokinetic properties due to a better
bioavailability higher, a higher binding affi nity or a more advantageous
side-effect profi le. The versatility of fungal enzymes and the relative
easy fermentation processes make fungi very attractive for whole cell
bioconversions or isolation of the enzymes as effi cient biocatalysts in
order to produce the correct enantiomer of an active pharmaceutical
ingredient (API).
The natural lovastatin producer
A. terreus
was able to produce the more
bioactive simvastatin when fed with 2,2-dimethylbutyrate (van den Berg
et al. 2007). In fact, as described above, one of the lovastatin biosynthetic
enzymes, the acyltransferase encoded by
lovD
, was shown to attach
the 2,2-dimethylbutyrate side chain onto the statin core molecule in stead
of the natural methylbutyrate (Xie et al. 2006). The enzyme was further
improved via directed evolution identifying seven amino acid changes
leading to an 11-fold increase in simvastatin synthesis rate at a 30 g/l titer
(Gao et al. 2009).
Fungal conversions were often identifi ed as part of a screen, starting
with a bioactive compound fed to a variety of cells in order to identify
new, more active, compounds (for example for mycophenolic acid, Jones
et al. 1970), or alternative, more effi cient, processing steps. An example
of the latter
P. decumbens
, capable of epoxidizing cis-propenylphosphonic
acid to produce the antibiotic fosfomycin (Watanabe et al. 1999), applied
as a very effective broad-spectrum antibiotic, in nature also produced by
several Streptomycetes.
Most industrially applied fungal bioconversions for pharmaceutical
applications fall into three classes:
(1)
lipases
;stableenzymes, easy to handle and do not require cofactors.
Particularly useful due to their enantioselectively, either in water
