title: Dedicated ent-kaurene and ent-atiserene synthases for platensimycin and platencin biosynthesis.
abstract: Platensimycin (PTM) and platencin (PTN) are potent and selective inhibitors of bacterial and mammalian fatty acid synthases and have emerged as promising drug leads for both antibacterial and antidiabetic therapies. Comparative analysis of the PTM and PTN biosynthetic machineries in Streptomyces platensis MA7327 and MA7339 revealed that the divergence of PTM and PTN biosynthesis is controlled by dedicated ent-kaurene and ent-atiserene synthases, the latter of which represents a new pathway for diterpenoid biosynthesis. The PTM and PTN biosynthetic machineries provide a rare glimpse at how secondary metabolic pathway evolution increases natural product structural diversity and support the wisdom of applying combinatorial biosynthesis methods for the generation of novel PTM and/or PTN analogues, thereby facilitating drug development efforts based on these privileged natural product scaffolds.
authors.affiliation: Microbiology Doctoral Training Program, University of Wisconsin, Madison, WI 53705, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Smanski
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Yu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Casper
authors.forename: Shuangjun
authors.initials: S
authors.lastname: Lin
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Peterson
authors.forename: Yihua
authors.initials: Y
authors.lastname: Chen
authors.forename: Evelyn
authors.initials: E
authors.lastname: Wendt-Pienkowski
authors.forename: Scott R
authors.initials: SR
authors.lastname: Rajski
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
mesh_terms: D000218:Adamantane / Q000138:chemical synthesis* / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D062365:Aminobenzoates / Q000138:chemical synthesis* / Q000378:metabolism; D000627:Aminophenols / Q000138:chemical synthesis* / Q000378:metabolism; D000813:Anilides / Q000138:chemical synthesis* / Q000378:metabolism; D000900:Anti-Bacterial Agents; D007004:Hypoglycemic Agents; D053858:Metabolic Networks and Pathways; D008969:Molecular Sequence Data; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D013302:Streptomyces / Q000201:enzymology* / Q000378:metabolism
chemical_list: D062365:Aminobenzoates; D000627:Aminophenols; D000813:Anilides; D000900:Anti-Bacterial Agents; D007004:Hypoglycemic Agents; D011083:Polycyclic Compounds; D019883:Alkyl and Aryl Transferases; C105712:ent-kaurene synthetase B; D000218:Adamantane; C510909:platensimycin; C520340:platencin