A PKS/NRPS/FAS hybrid gene cluster from Serratia plymuthica RVH1 encoding the biosynthesis of three broad spectrum, zeamine-related antibiotics.
Serratia plymuthica strain RVH1, initially isolated from an industrial food processing environment, displays potent antimicrobial activity towards a broad spectrum of Gram-positive and Gram-negative bacterial pathogens. Isolation and subsequent structure determination of bioactive molecules led to the identification of two polyamino antibiotics with the same molecular structure as zeamine and zeamine II as well as a third, closely related analogue, designated zeamine I. The gene cluster encoding the biosynthesis of the zeamine antibiotics was cloned and sequenced and shown to encode FAS, PKS as well as NRPS related enzymes in addition to putative tailoring and export enzymes. Interestingly, several genes show strong homology to the pfa cluster of genes involved in the biosynthesis of long chain polyunsaturated fatty acids in marine bacteria. We postulate that a mixed FAS/PKS and a hybrid NRPS/PKS assembly line each synthesize parts of the backbone that are linked together post-assembly in the case of zeamine and zeamine I. This interaction reflects a unique interplay between secondary lipid and secondary metabolite biosynthesis. Most likely, the zeamine antibiotics are produced as prodrugs that undergo activation in which a nonribosomal peptide sequence is cleaved off.
Division of Gene Technology, KU Leuven, Heverlee, Belgium.
Joleen
J
Masschelein
Wesley
W
Mattheus
Ling-Jie
LJ
Gao
Pieter
P
Moons
Rob
R
Van Houdt
Birgit
B
Uytterhoeven
Chris
C
Lamberigts
Eveline
E
Lescrinier
Jef
J
Rozenski
Piet
P
Herdewijn
Abram
A
Aertsen
Chris
C
Michiels
Rob
R
Lavigne
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D004251:DNA Transposable Elements / Q000235:genetics; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D050939:Gene Fusion; D023061:Gene Order; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry / Q000379:methods; D008969:Molecular Sequence Data; D015394:Molecular Structure; D005810:Multigene Family; D016254:Mutagenesis, Insertional; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D012705:Serratia / Q000235:genetics / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004251:DNA Transposable Elements; D018942:Macrolides; D011073:Polyamines; C547236:zeamine; D048630:Polyketide Synthases; D064429:Fatty Acid Synthases; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase