Source: http://www.asmscience.org/content/book/10.1128/9781555816827.ch27
Timestamp: 2019-04-26 06:27:32+00:00

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The term combinatorial biosynthesis embraces a broad set of methodologies—including genetic engineering, the use of mutants blocked in specific biosynthetic steps, and the exploitation of natural variations in substrates and feeding unnatural substrates—to expand the numbers of compounds generated beyond what can be achieved by genetic engineering alone. For relatively small antibiotic gene clusters, it is possible to isolate complete biosynthetic gene clusters on individual cosmids. Another approach is to clone antibiotic gene clusters in bacterial artificial chromosome (BAC) vectors, which can accommodate DNA inserts of >100 kb. The methods discussed in this chapter include some that are specific to nonribosomal peptide synthetases (NRPSs) engineering, including (i) splicing at intermodule or interpeptide linker sites; (ii) recognizing and exploiting the correct type of C domain when coupling fatty acids to L-amino acids (FCL), D-amino acids to L-amino acids (DCL), or L-amino acids to L-amino acids (LCL); and (iii) maintaining the integrity of T-TE didomains when engineering terminal modules. The chapter points out that both S. roseosporus and S. fradiae can be readily manipulated by the genetic engineering methods described. As such, they may be useful hosts for the expression and engineering of other secondary metabolic pathways, particularly other NRPS pathways. For example, the A54145 gene cluster was expressed successfully in an S. roseosporus strain deleted for daptomycin biosynthetic genes.
Structures of lipopeptide antibiotics and of NRPS subunits. (Top) A21978C factors naturally produced by S. roseosporus A21978.6 and A21978.65 ( Table 1 ), and daptomycin, which is produced by feeding decanoic acid during fermentation. (Bottom) A54145 factors naturally produced by S. fradiae A54145.
Functional organization of NRPS. The condensation domains designated as C (or LCL), CII (or DCL), and CIII (or FCL) normally couple l-amino acids, d-amino acids, and long-chain fatty acids to l-amino acids, respectively. The shaded modules show CATE structures followed by CII (DCL) condensation domains. A, adenylation domain; E, epimerase domain; M, methyltransfer-ase domain; T, thiolation domain; TE, thioesterase domain. Figure modified from reference 6 .
Ectopic trans-complementation systems for S. roseosporus and S. fradiae. (Top) The dpt genes on BAC pCV1 are shown in black. S. roseosporus strains deleted for different dpt genes (dotted lines) and plasmids containing different sets of dpt genes (pDA300, pLT02, pKN24, and pRB04), cdaPS3 (pMF23), and lptD (pMF30) are also shown (see Table 1 for plasmid details). (Bottom) The lpt genes on BACpCB01 are shown in black, and S. fradiae deletion mutants and plasmids for trans-complementation are shown below.
λ Red-mediated recombination in E. coli. (A) BAC pCB01 containing the complete lpt gene cluster is engineered to delete lptC by λ Red-mediated insertion of an Amr-oriT cassette. The recombinant BAC can be transferred to Streptomyces by conjugation via oriT, and recombinants can be selected for Amr. Other manipulations include (B) the insertion of a terminator cassette, (C) deletion and insertion of a promoter, and (D) insertion of a conjugation/integration cassette.
λ Red-mediated recombination to generate a C-A-T tridomain exchange and gene fusion in lptB and lptC.
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