The biosynthetic genes for disorazoles, potent cytotoxic compounds that disrupt microtubule formation.
Disorazoles are polyketides produced by the myxobacterium Sorangium cellulosum So ce12. Their mode of action is to inhibit tubulin polymerization and destabilize microtubules. Using transposon mutagenesis, two mutant strains were identified that produced no disorazoles. Sequencing the DNA flanking the insertions revealed a polyketide synthase gene cluster that would encode three polypeptides, DszA, DszB, and DszC, with DszC containing both nonribosomal peptide synthetase and polyketide synthase modules. The disorazole polyketide synthase modules lack an acyltransferase domain. Instead, a separate gene, dszD, encodes an AT protein, thus revealing that the disorazole gene cluster falls into the trans-AT Type I family of PKS enzymes.
Carvalho
Ruby
R
Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, CA 94545, USA.
Reid
Ralph
R
Viswanathan
Nina
N
Gramajo
Hugo
H
Julien
Bryan
B
D000595:Amino Acid Sequence; D020134:Catalytic Domain / Q000235:genetics; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D019281:Dimerization; D023061:Gene Order; D008870:Microtubules / Q000378:metabolism*; D008956:Models, Chemical; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D009231:Myxococcales / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D048630:Polyketide Synthases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014404:Tubulin / Q000096:biosynthesis
D004269:DNA, Bacterial; D010080:Oxazoles; D014404:Tubulin; C092171:disorazol A; D048630:Polyketide Synthases