Novel octaketide macrolides related to 6-deoxyerythronolide B provide evidence for iterative operation of the erythromycin polyketide synthase.
BACKGROUND
The macrolide antibiotic erythromycin A, like other complex aliphatic polyketides, is synthesised by a bacterial modular polyketide synthase (PKS). Such PKSs, in contrast to other fatty acid and polyketide synthases which work iteratively, contain a separate set or module of enzyme activities for each successive cycle of polyketide chain extension, and the number and type of modules together determine the structure of the polyketide product. Thus, the six extension modules of the erythromycin PKS (DEBS) together catalyse the production of the specific heptaketide 6-deoxyerythronolide B.


RESULTS
A mutant strain of the erythromycin producer Saccharopolyspora erythraea, which accumulates the aglycone intermediate erythronolide B, was found unexpectedly to produce two novel octaketides, both 16-membered macrolides. These compounds were detectable in fermentation broths of wild-type S. erythraea, but not in a strain from which the DEBS genes had been specifically deleted. From their structures, both of these octaketides appear to be aberrant products of DEBS in which module 4 has 'stuttered', that is, has catalysed two successive cycles of chain extension.


CONCLUSIONS
The isolation of novel DEBS-derived octaketides provides the first evidence that an extension module in a modular PKS has the potential to catalyse iterative rounds of chain elongation like other type I FAS and PKS systems. The factors governing the extent of such 'stuttering' remain to be determined.
Wilkinson
B
B
Bioprocessing Unit, Glaxo Wellcome Research and Development, Medicines Research Centre, Stevenage, SG1 2NY, UK. bw37730@glaxowellcome.co.uk
Foster
G
G
Rudd
B A
BA
Taylor
N L
NL
Blackaby
A P
AP
Sidebottom
P J
PJ
Cooper
D J
DJ
Dawson
M J
MJ
Buss
A D
AD
Gaisser
S
S
Böhm
I U
IU
Rowe
C J
CJ
Cortés
J
J
Leadlay
P F
PF
Staunton
J
J
D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry*; D004917:Erythromycin / Q000031:analogs & derivatives / Q000737:chemistry; D009097:Multienzyme Complexes / Q000235:genetics*; D005810:Multigene Family / Q000235:genetics; D009154:Mutation; D010441:Peptide Chain Elongation, Translational / Q000235:genetics; D014176:Protein Biosynthesis; D016930:Saccharopolyspora / Q000235:genetics
D000900:Anti-Bacterial Agents; D009097:Multienzyme Complexes; C034277:6-deoxyerythronolide B; D004917:Erythromycin