Comparative genomic and transcriptomic analysis guides to further
enhance the biosynthesis of erythromycin by an overproducer
Abstract
Omics approaches have been applied to understand the boosted
productivity of natural products by industrial high-producing
microorganisms. Here, with the updated genome sequence and
transcriptomic profiles derived from high-throughput sequencing, we
exploited comparative omics analysis to further enhance the biosynthesis
of erythromycin in an industrial overproducer, Saccharopolyspora
erythraea HL3168 E3. By comparing the genome of E3 with the wild type
NRRL23338, we identified fragment deletions inside 56 coding sequences
and 255 single nucleotide polymorphisms over the genome of E3.
Substantial numbers of genomic variations were observed in genes
responsible for pathways which were interconnected to the biosynthesis
of erythromycin by supplying precursors/cofactors or by signal
transduction. Through comparative transcriptomic analysis,
L-glutamine/L-glutamate and 2-oxoglutarate were identified as reporter
metabolites. Around the node of 2-oxoglutarate, genomic mutations were
also observed. Furthermore, the transcriptomic data suggested that genes
involved in the biosynthesis of erythromycin were significantly
up-regulated constantly, whereas some genes in biosynthesis clusters of
other secondary metabolites contained nonsense mutations and were
expressed at extremely low levels. Based on the omics association
analysis, readily available strategies were proposed to engineer E3 by
simultaneously overexpressing sucB (coding for 2-oxoglutarate
dehydrogenase E2 component) and sucA (coding for 2-oxoglutarate
dehydrogenase E1 component), which increased the erythromycin titer by
71% compared to E3 in batch culture. This work provides more promising
molecular targets to engineer for enhanced production of erythromycin by
the overproducer.