Novel features in a combined polyketide synthase/non-ribosomal peptide synthetase: the myxalamid biosynthetic gene cluster of the myxobacterium Stigmatella aurantiaca Sga15
B. Silakowski et al., Novel features in a combined polyketide synthase/non-ribosomal peptide synthetase: the myxalamid biosynthetic gene cluster of the myxobacterium Stigmatella aurantiaca Sga15, CHEM BIOL, 8(1), 2001, pp. 59-69
Background: Myxobacteria have been well established as a potent sourer: for
natural products with biological activity. They produce a considerable var
iety of compounds which represent typical polyketide structures with incorp
orated amino acids (e.g. the epothilons. the myxothiazols and the myxalamid
s). Several of these secondary metabolites are effective inhibitors of the
electron transport via the respiratory chain and have been widely used. Mol
ecular cloning and characterization of the genes governing the biosynthesis
of these structures is of considerable interest, because such information
adds to the limited knowledge as to how polyketide synthases (PKSs) and non
-ribosomal peptide synthetases (NRPSs) interact and how they might be manip
ulated in order to form novel antibiotics.
Results: A DNA region of approximately 50 000 base pairs from Stigmatella a
urantiaca Sga15 was sequenced and shown by gene disruption to be involved i
n myxalamid biosynthesis. Sequence analysis reveals that the myxalamids are
formed by a combined PKS/NRPS system. The terminal NRPS MxaA extends the a
ssembled polyketide chain of the myxalamids with alanine. MxaA contains an
N-terminal domain with homology to NAD binding proteins, which is responsib
le during the biogenesis for a novel type of reductive chain release giving
rise to the 2-aminopropanol moiety of the myxalamids. The last module of t
he PKS reveals an unprecedented genetic organization: it is encoded on two
genes (mxaB1 and mxaB2). subdividing the domains of one module from each ot
her. A sequence comparison of myxobacterial acyl-transferase domains with k
nown systems from streptomycetes and bacilli reveals that consensus sequenc
es proposed to be specific for methylmalonyl-CoA and malonyl-CoA are not al
ways reliable.
Conclusions: The complete biosynthetic gene cluster of the myxalamid-type e
lectron transport inhibitor From S, aurantiaca Sga15 has been cloned and an
alyzed. It represents one of the few examples of combined PKS/NRPS systems.
the analysis and manipulation of which has the potential to generate novel
hybrid structures via combinatorial biosynthesis (e.g. via module-swapping
techniques). Additionally, a neu type of reductive release from PKS/NRPS s
ystems is described. (C) 2001 Elsevier Science Ltd. All rights reserved.