Chemistry Reference
In-Depth Information
Based on its high sequence homology to CoA ligases, NonL was identified as
a CoA ligase catalyzing the transformation of (
±
)-nonactic acid into (
±
)-nonactyl
CoA. The sequence of reactions for the biosynthesis of nonactin and the other
macrotetrolides in
S. griseus
is shown in Fig. 8.3g.
S. griseus
is likely to be protected from nonactin by two mechanisms. The
first mechanism seems to involve pumping excess antibiotic from the cell. Two
genes, orf5 and orf6, which are clustered with the rest of the nonactin biosynthe-
sis genes, show homology with ABC transporter genes. The second mechanism
is the enzyme catalyzed hydrolysis of nonactin and homologues by NonR, which
is homologous to serine protease and esterase enzymes and confers tetranactin
resistance to
S. lividans
TK24. Overexpressed NonR has been shown to stere-
ospecifically catalyze the breakage of the macrotetrolide ring into homochiral
nonactate dimers
37
(Fig. 8.3f) in a two-step process (23). The macrotetrolides are
converted initially into their seco-tetramer species and subsequently hydrolyzed
to the dimer; in both cases, it is the bond between the alcohol of the (
+
)-nonactate
and the carboxylate of (
−
)-nonactate that is cleaved. No trimer or monomers were
detected.
8.2.4 Marine Polyether Ladders
All marine polyether ladders thus far characterized (e.g., maitotoxin
16
(Fig. 8.4a), the brevetoxins
12
and
13
and hemibrevetoxin B, the yessotoxins
14
(and the truncated adriatoxin), the Pacific and Caribbean ciguatoxins, the
gambieric acids
15
and gamberiol (the gymnocins and brevenal) can be grouped
into 14 backbone structures (3).
Retrobiosynthetic analysis of these structures has led to the development of a
model for the biosynthesis of these complex structures from the cyclization of
a polyepoxide precursor (3). The model accounts for the conserved stereochem-
istry of the numerous ring junctions in these polyethers, which are
syn/trans
(Fig. 8.4b). The required configuration of the rings can be derived from stereo-
chemically identical all (
R,R
)- or (
S,S
)-
trans
epoxides, which are derived from
the appropriate polyene (which may contain over 20 double bonds). Epoxidation
of the polyene precursor takes place from the same face, and consequently, it is
possible for a single monooygenase with broad specificity to produce all
trans
epoxides. Ring closure requires an
endo
-selective opening of each epoxide.
Independently, Prasad and Shimizu (24) as well as Lee et al. (25) proposed that
brevetoxin A is biosynthesized from the cyclization of a polyepoxide precursor in
a series of S
N
2(
R,R
)-
trans
epoxide openings (Fig. 8.4c). Gallimore and Spencer
(3) argue that the nine disfavored
endo
-tet closures required for this mechanism
makes it mechanistically unlikely and point out that an alternative cascade of
S
N
2
epoxide openings in the opposite direction from all (
S,S
)-
trans
epoxides yields
the same structure.
Although it can be envisaged that a
trans
-polyene is converted by a monooxy-
genase to a polyepoxide intermediate, which is processed by an epoxide hydrolase
