Biomedical Engineering Reference
In-Depth Information
according to the correlation existing between cephalosporin production
and differentiation (Bartoshevich et al. 1990). Type 1 corresponds to the
transition from the vegetative cell stage into a reproductive one with the
formation of conidia (usually not formed by high-producing strains of
A. chrysogenum
) and with a lowered cephalosporin production. In the
late stages of development, Type 2 cells correspond to the formation of
arthrospores and a lowered production of cephalosporin C. During Type 3
differentiation the mycelial cells transform into swollen fragments (yeast-
like cells) capable of periodical polycyclic development. This alternating
mycelial and yeast-like organization is most pronounced under conditions
of high cephalosporin production (Bartoshevich et al. 1990).
Arthrospores and conidiospores are structures that regularly occur
during the asexual cycle of many fi lamentous fungi. Arthrospores are not
authentic resistance forms, unlike conidiospores, which show signifi cant
resistance to heat and UV radiation. The molecular mechanisms controlling
hyphal fragmentation and arthrospore formation remain mostly undefi ned.
In
A. chrysogenum
, early publications reported that hyphal differentiation
is coincident with the maximum rate of cephalosporin C biosynthesis
and arthrospore formation is correlated with high-yield cephalosporin C
production (Nash and Huber 1971, Bartoshevich et al. 1990). A correlation
also exists between the cephalosporin enhancing effect of the microbody
protein CefM and the formation of arthrospores (Teijeira et al. 2009). It is
also well established that D-methionine is an inducer of cephalosporin
biosynthesis (Martín and Demain 2002). Exogenous D-(or DL-) methionine
increases the transcription of
pcbAB
,
pcbC
and
cefEF
genes (Velasco et al.
1994). D-methionine (but not L-methionine) induces IPN synthase and
deacetylcephalosporin-C acetyltransferase and also stimulates arthrospore
formation (Velasco et al. 1994).
Morphological differentiation in several fungi is controlled by the G
α
subunit of the heterotrimeric G protein. In
A. nidulans
, a signaling pathway
including a G
α
subunit (encoded by the
fadA
gene) and its regulatory GTPase
activating protein negatively regulate secondary metabolite production and
conidiation at least in part via a cAMP-dependent protein kinase catalytic
subunit (PkaA) (Hicks et al. 1997, Shimizu and Keller 2001). In addition,
the dominant activating
fadA
allele encoding a “constitutive” G
α
subunit
has a positive effect on the transcription of
ipnA
(the second penicillin
biosynthetic gene of
A. nidulans
), leading to an increase in penicillin
production (Tag et al. 2000). In the penicillin producer fungus
P. chrysogenum
the dominant activating
pga1
(G42R) allele for the heterotrimeric G
α
protein
Pga1, upregulates the biosynthesis of the secondary metabolites penicillin
(increases the expression of the penicillin biosynthesis genes
pcbC
and
penDE
), chrysogenin and roquefortine (García-Rico et al. 2008a). In this
