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variable amino acids at the different positions and variable degree of meth-
ylation (
Welker & von Dohren, 2006
). Positions 2 and 4 show the highest
variability, and the most common form is microcystin-LR (leucine in posi-
tion 2 and arginine in position 4,
Fig. 6.1
). Microcystins are hepatotox-
ins and their primary targets are eukaryotic protein phosphatases of types
1 or 2A (
Dawson, 1998
;
MacKintosh, Beattie, Klumpp, Cohen, & Codd,
1990
). Interestingly, the dehydroalanyl residue (position 7) of microcystin
reacts specifically with an active site cysteine residue of protein phospha-
tase 1 (
MacKintosh et al., 1990
;
Maynes et al., 2006
;
Meissner, Dittmann,
& Borner, 1996
). The unusual structure of microcystins suggested that
they were products of NRPSs, thus facilitating the identification of the
biosynthetic genes. A 2-kb DNA sequence coding for an NRPS was first
identified in the genome of the strain
Microcystis aeruginosa
PCC 7806, a
microcystin producer (
Meissner et al., 1996
), and genetic inactivation of
this gene confirmed that it coded for an NRPS involved in microcystin
biosynthesis (
Dittmann, Neilan, Erhard, von Dohren, & Borner, 1997
).
The complete cluster was then sequenced in to two
M. aeruginosa
strains,
and several gene-inactivation experiments confirmed the implication of
this cluster in the biosynthesis of microcystin (
Nishizawa, Asayama, Fujii,
Harada, & Shirai, 1999
,
Nishizawa, Asayama, & Shirai, 2000
;
Tillett et al.,
2000
). The
mcy
cluster was later sequenced in
P. agardhii
NIVA-CYA 126/8
(
Christiansen, Fastner, Erhard, Borner, & Dittmann, 2003
), and
P. rubescens
NIVA-CYA 98 (
Rounge, Rohrlack, Nederbragt, Kristensen, & Jakobsen,
2009
), and
Anabaena
sp. 90 (
Rouhiainen et al., 2004
). The 55-kb
mcy
cluster
of
M. aeruginosa
PCC 7806 comprises 10 genes (
mcyA-J
,
Fig. 6.2
) arranged
in two divergently transcribed operons, consisting of
mcyA-C
and
mcyD-J
.
However, other promoters were identified upstream of
mcyE
,
mcyF
,
mcyG
,
mcyH
,
mcyI
and
mcyJ
(
Kaebernick, Dittmann, Borner, & Neilan, 2002
;
Tillett
et al., 2000
). In the two other
mcy
gene clusters so far sequenced (
Fig. 6.2
),
the genes
mcyA
,
mcyB
, and
mcyC
are similarly arranged, while some differ-
ences are observed for the other
mcy
genes. This has been interpreted as
the consequence of probable horizontal gene transfers, supported by the
presence of transposase genes close to the
mcy
clusters in
M. aeruginosa
and
Anabaena
strains (
Rantala et al., 2004
). Recombination events as well as
point mutations and insertions or deletions, within the
mcy
cluster, have also
been proposed to explain the variations observed (
Pearson, Moffitt, Ginn,
& Neilan, 2008
).
Not much is known concerning the regulation of the production of
microcystins either at the transcriptional level or at the metabolic level.
