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Titolo:
Molecular characterization and analysis of the biosynthetic gene cluster for the antitumor antibiotic mitomycin C from Streptomyces lavendulae NRRL 2564
Autore:
Mao, YQ; Varoglu, M; Sherman, DH;
Indirizzi:
Univ Minnesota, Dept Microbiol, Biol Proc Technol Inst, Minneapolis, MN 55455 USA Univ Minnesota Minneapolis MN USA 55455 l Inst, Minneapolis, MN 55455 USA
Titolo Testata:
CHEMISTRY & BIOLOGY
fascicolo: 4, volume: 6, anno: 1999,
pagine: 251 - 263
SICI:
1074-5521(199904)6:4<251:MCAAOT>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
COMPLETE GENOME SEQUENCE; ADENOSYLMETHIONINE-DEPENDENT METHYLTRANSFERASES; ESCHERICHIA-COLI K-12; ACYL CARRIER PROTEIN; NUCLEOTIDE-SEQUENCE; METHANOBACTERIUM-THERMOAUTOTROPHICUM; 3-AMINO-5-HYDROXYBENZOIC ACID; TRANSCRIPTIONAL ANALYSIS; TETRACENOMYCIN-C; SACCHAROPOLYSPORA-ERYTHRAEA;
Keywords:
antibiotic biosynthesis; antibiotic resistance; gene disruption; mitosane; shikimate pathway;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
106
Recensione:
Indirizzi per estratti:
Indirizzo: Sherman, DH Univ Minnesota, Dept Microbiol, Biol Proc Technol Inst, 1460 Mayo Mem Bldg,Box 196 UFHC,420 Delaware St S, Minneapolis, MN 55455 USA UnivMinnesota 1460 Mayo Mem Bldg,Box 196 UFHC,420 Delaware St S Minneapolis MNUSA 55455
Citazione:
Y.Q. Mao et al., "Molecular characterization and analysis of the biosynthetic gene cluster for the antitumor antibiotic mitomycin C from Streptomyces lavendulae NRRL 2564", CHEM BIOL, 6(4), 1999, pp. 251-263

Abstract

Background: The mitomycins are natural products that contain a variety of functional groups, including aminobenzoquinone- and aziridine-ring systems. Mitomycin C (MC) was the first recognized bioreductive alkylating agent,and has been widely used clinically for antitumor therapy. Precursor-feeding studies showed that MC is derived from 3-amino-5-hydroxybenzoic acid (AHBA), D-glucosamine, L-methionine and carbamoyl phosphate. A genetically linkedAHBA biosynthetic gene and MC resistance genes were identified previously in the MC producer Streptomyces lavendulae NRRL 2564, We set out to identify other genes involved in MC biosynthesis. Results: A cluster of 47 genes spanning 55 kilobases of S. lavendulae DNA governs MC biosynthesis. Fourteen of 22 disruption mutants did not express or overexpressed MC, Seven gene products probably assemble the AHBA intermediate through a variant of the shikimate pathway, The gene encoding the first presumed enzyme in AHBA biosynthesis is not, however, linked within the MC cluster. Candidate genes for mitosane nucleus formation and functionalization were identified. A putative MC translocase was identified that comprises a novel drug-binding and export system, which confers cellular self-protection on S. lavendulae. Two regulatory genes were also identified. Conclusions: The overall architecture of the MC biosynthetic gene cluster in S. lavendulae has been determined. Targeted manipulation of a putative MC pathway regulator led to a substantial increase in drug production. The cloned genes should help elucidate the molecular basis for creation of the mitosane ring system, as well efforts to engineer the biosynthesis of novel natural products.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 03/12/20 alle ore 06:12:28