Expanding the potential of mutasynthetic approaches for pseudomonic acids

Alsammarraie, Yusra (2016). Expanding the potential of mutasynthetic approaches for pseudomonic acids. University of Birmingham. Ph.D.

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Abstract

Natural products, particularly polyketides are among the most important sources of antimicrobial compounds. 20% of the top selling drugs are polyketide based. In recent years genetic engineering has played a critical role in modifying biosynthetic pathways of different polyketide compounds as a way to create novel structures with improved clinical properties. Further investigation and understanding of these giant multi-enzyme complexes is necessary to achieve efficient synthetic engineering.

In many PKS systems including the mupirocin biosynthesis pathway, the thioesterase (TE) is normally considered as the end of the assembly line. However, expressing the CoA-ligase tmlU from the thiomarinol pathway in the mupirocin producer strain (Pseudomonas fluorescens NCIMB10586) revealed that TmlU could only release truncated pseudomonic acid when a TE domain was present. This finding led to the hypothesis that perhaps the TE domain could act as a tether for TmlU, in order for the latter to be able to capture the growing chain and perhaps load it onto the post TE pathway. This study also presents the first evidence of MmpB being involved in producing the 9-hydroxynonanoic acid in the mupirocin biosynthesis pathway.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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