Victoria University

Functional analysis of Hypoxylon pulicicidum genes required for heterologous biosynthesis of nodulisporic acids

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dc.contributor.advisor Parker, Emily en_NZ
dc.contributor.advisor Nicholson, Matthew en_NZ Van de Bittner, Kyle Cornelius en_NZ 2018-09-03T22:59:10Z 2021-03-03T22:50:48Z 2018-09-03T22:59:10Z 2021-03-03T22:50:48Z 2018 2021
dc.identifier.uri en_NZ
dc.description.abstract Nature holds some of the greatest secrets in drug design and development and the ability to access these trade secrets has been revolutionised by modern bioengineering technologies. In order to exploit these technologies it is essential to understand what genes are involved in compound production and the enzymatic steps that limit flux to the desired product. This thesis describes the discovery of four secondary-metabolic enzymatic steps involved in the biosynthesis of a group of valuable natural products known as nodulisporic acids. Nodulisporic acids are known for their potent insecticidal activities; however, biosynthesis of these compounds by the natural fungal producer, Hypoxylon pulicicidum (Nodulisporium sp.), is exceptionally difficult and has prevented the commercial development of novel nodulisporic acid-containing veterinary medicines and crop protects. To discover how nodulisporic acids are biosynthesized: 1. the H. pulicicidum genome was sequenced 2. a gene cluster responsible for nodulisporic acid production was predicted 3. genes in the cluster were functionally characterised by pathway reconstitution in a common, fast growing mould, Penicillium paxilli In turn, four genes involved in the biosynthesis of the nodulisporic acid core compound, nodulisporic acid F, have been functionally characterised. The four genes encode a geranylgeranyl transferase (NodC), a flavin adenine dinucleotide-dependent oxygenase (NodM), an indole diterpene cyclase (NodB) and a cytochrome P450 oxygenase (NodW). Two of the gene products (NodM and NodW) catalyse two previously unreported reactions that provide the enzymatic basis of the biosynthetic branch point unique to nodulisporic acid biosynthesis. From here, future efforts will explore how these genes can be engineered to overcome flux bottlenecks and enable production of significantly increased, and even industrially relevant, product titres. en_NZ
dc.language.iso en_NZ
dc.publisher Victoria University of Wellington en_NZ
dc.subject Biosynthesis en_NZ
dc.subject Indole diterpene en_NZ
dc.subject Indole diterpenes en_NZ
dc.subject Nodulisporic acid en_NZ
dc.subject Nodulisporic acids en_NZ
dc.subject Synthetic biology en_NZ
dc.subject Heterologous expression en_NZ
dc.title Functional analysis of Hypoxylon pulicicidum genes required for heterologous biosynthesis of nodulisporic acids en_NZ
dc.type Text en_NZ
vuwschema.contributor.unit School of Chemical and Physical Sciences en_NZ
vuwschema.type.vuw Awarded Doctoral Thesis en_NZ Biology en_NZ Biotechnology en_NZ Chemistry en_NZ Biochemistry en_NZ Victoria University of Wellington en_NZ Doctoral en_NZ Doctor of Philosophy en_NZ
dc.rights.license Author Retains Copyright en_NZ
vuwschema.subject.anzsrcfor 100306 Industrial Molecular Engineering of Nucleic Acids and Proteins en_NZ
vuwschema.subject.anzsrcseo 860903 Veterinary Pharmaceutical Treatments (e.g. Antibiotics) en_NZ
vuwschema.subject.anzsrcseo 970110 Expanding Knowledge in Technology en_NZ
vuwschema.subject.anzsrctoa 3 Applied Research en_NZ

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