Biochemical and genetic insights into asukamycin biosynthesis.
Asukamycin, a member of the manumycin family metabolites, is an antimicrobial and potential antitumor agent isolated from Streptomyces nodosus subsp. asukaensis. The entire asukamycin biosynthetic gene cluster was cloned, assembled, and expressed heterologously in Streptomyces lividans. Bioinformatic analysis and mutagenesis studies elucidated the biosynthetic pathway at the genetic and biochemical level. Four gene sets, asuA-D, govern the formation and assembly of the asukamycin building blocks: a 3-amino-4-hydroxybenzoic acid core component, a cyclohexane ring, two triene polyketide chains, and a 2-amino-3-hydroxycyclopent-2-enone moiety to form the intermediate protoasukamycin. AsuE1 and AsuE2 catalyze the conversion of protoasukamycin to 4-hydroxyprotoasukamycin, which is epoxidized at C5-C6 by AsuE3 to the final product, asukamycin. Branched acyl CoA starter units, derived from Val, Leu, and Ile, can be incorporated by the actions of the polyketide synthase III (KSIII) AsuC3/C4 as well as the cellular fatty acid synthase FabH to produce the asukamycin congeners A2-A7. In addition, the type II thioesterase AsuC15 limits the cellular level of omega-cyclohexyl fatty acids and likely maintains homeostasis of the cellular membrane.
Department of Biological Science, Louisiana State University, Baton Rouge, Louisiana 70803, USA.
Zhe
Z
Rui
Katerina
K
Petrícková
Frantisek
F
Skanta
Stanislav
S
Pospísil
Yanling
Y
Yang
Chung-Yung
CY
Chen
Shih-Feng
SF
Tsai
Heinz G
HG
Floss
Miroslav
M
Petrícek
Tin-Wein
TW
Yu
D000970:Antineoplastic Agents / Q000494:pharmacology; D002384:Catalysis; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003001:Cloning, Molecular; D015195:Drug Design; D064429:Fatty Acid Synthases / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008957:Models, Genetic; D005810:Multigene Family; D016366:Open Reading Frames; D011090:Polyenes / Q000737:chemistry; D011995:Recombination, Genetic; D013302:Streptomyces / Q000201:enzymology / Q000378:metabolism*
D000970:Antineoplastic Agents; D005227:Fatty Acids; D011090:Polyenes; C013404:asukamycin; D064429:Fatty Acid Synthases