Integrating transcriptional and metabolite profiles to direct the engineering of lovastatin-producing fungal strains.
We describe a method to decipher the complex inter-relationships between metabolite production trends and gene expression events, and show how information gleaned from such studies can be applied to yield improved production strains. Genomic fragment microarrays were constructed for the Aspergillus terreus genome, and transcriptional profiles were generated from strains engineered to produce varying amounts of the medically significant natural product lovastatin. Metabolite detection methods were employed to quantify the polyketide-derived secondary metabolites lovastatin and (+)-geodin in broths from fermentations of the same strains. Association analysis of the resulting transcriptional and metabolic data sets provides mechanistic insight into the genetic and physiological control of lovastatin and (+)-geodin biosynthesis, and identifies novel components involved in the production of (+)-geodin, as well as other secondary metabolites. Furthermore, this analysis identifies specific tools, including promoters for reporter-based selection systems, that we employed to improve lovastatin production by A. terreus.
Askenazi
Manor
M
Microbia, Inc., 320 Bent Street, Cambridge, MA 02141, USA.
Driggers
Edward M
EM
Holtzman
Douglas A
DA
Norman
Thea C
TC
Iverson
Sara
S
Zimmer
Daniel P
DP
Boers
Mary-Ellen
ME
Blomquist
Paul R
PR
Martinez
Eduardo J
EJ
Monreal
Alex W
AW
Feibelman
Toby P
TP
Mayorga
Maria E
ME
Maxon
Mary E
ME
Sykes
Kristie
K
Tobin
Jenny Vittum
JV
Cordero
Etchell
E
Salama
Sofie R
SR
Trueheart
Joshua
J
Royer
John C
JC
Madden
Kevin T
KT
D001230:Aspergillus / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D001572:Benzofurans / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D015966:Gene Expression Regulation, Fungal; D005818:Genetic Engineering / Q000379:methods; D008148:Lovastatin / Q000096:biosynthesis* / Q000235:genetics; D025341:Principal Component Analysis; D016415:Sequence Alignment / Q000379:methods; D017422:Sequence Analysis, DNA / Q000379:methods; D013045:Species Specificity; D013223:Statistics as Topic; D014158:Transcription, Genetic / Q000235:genetics
D001572:Benzofurans; C052047:geodin; D008148:Lovastatin