Biomedical Engineering Reference
In-Depth Information
processing and morphogenesis (Burgering and Kops 2002, Carlsson and
Mahlapuu 2002, Morillon et al. 2003). AcFKH1 shows two conserved
domains (Schmitt et al. 2004c). The fi rst one is the N-terminal forkhead-
associated domain (FHA), which has been suggested to participate in
phospho-protein interactions. The second domain is the C-terminal DNA-
binding domain (FKH) of the winged helix/forkhead type. It has been
shown that the C-terminus of this protein associates with the full-length
CPCR1 protein. AcFKH1 regulates the cephalosporin C biosynthesis
through the recognition of two forkhead consensus binding sites inside the
pcbAB-pcbC
intergenic region of
A. chrysogenum
(Schmitt et al. 2004c) (Fig.
3).
This factor, however, is not directly involved in the fragmentation of
hyphae, but its presence seems to be necessary for the function of CPCR1
in
A. chrysogenum
morphogenesis. This was confi rmed by the fact that
overexpression of
cpcR1
in a strain lacking the
Acfkh1
gene had no effect
on arthrospore formation. In addition, strains lacking
Acfkh1
exhibited
defects in cell separation, suggesting the role of the forkhead transcription
factor in mycelial growth of
A. chrysogenum
(Hoff et al. 2005). The existing
data suggested that CPCR1, which is associated with AcFKH1 likely in
the form of a heterodimer, represents a molecular link between secondary
metabolism and fungal arthrospore formation (Hoff et al. 2005). Therefore,
these two factors are very important in the control of fungal growth during
the cephalosporin production process.
The Velvet Transcription Factor
Another regulator that controls cephalosporin biosynthesis and
arthrospore formation in
A. chrysogenum
is the velvet gene (
veA
) (Dreyer
et al. 2007). The protein encoded by this gene is localized inside the
nucleus and controls the expression of the cephalosporin genes
pcbAB
,
pcbC
,
cefD1
,
cefD2
,
cefEF
and
cefG
(specially the
cefEF
gene encoding the
DAOC synthetase/hydroxylase) (Dreyer et al. 2007). As a consequence of
this regulatory effect,
A.
chrysogenum
mutants disrupted in the
veA
gene
showed an 80% reduction in the production of cephalosporin C. This
regulator seems to be also involved in hyphal morphology and in the
developmentally dependent hyphal fragmentation to form arthrospores
(Dreyer et al. 2007).
Modifi cation of
Acremonium
and
Penicillium
for
The Production of Other Cephalosporins
Semisynthetic cephalosporins are made from 7-aminodeacet-
oxycephalosporanic acid (7-ADCA) or 7-aminocephalosporanic acid
