The MbtH-like protein (MLP) superfamily consists of relatively small proteins (60-80 amino acids) that are found only in eubacteria and are most commonly associated with nonribosomal peptide synthetases (NRPS). This superfamily is named after its founding member MbtH, which is a protein of unknown function in the mycobactin biosynthesis pathway in Mycobacterium tuberculosis. The common association of these proteins with NRPS systems suggested that they play some role in nonribosomal peptide production, but the prevailing view was that these proteins were not involved in the enzymology of NRPSs. Our recent data suggest this view needs to be revised since we have shown MLPs impact the solubility and function of heterologously overproduced NRPSs. Our overall goal is to understand how MPLs influence NRPS enzymology and how the MLP and NRPS interactions occur at the molecular level to provide general function and protein-protein interaction specificity. The results from this project will have a broad impact on the basic understanding of NRPS enzymology, the generation of new derivatives of nonribosomal peptides using metabolic engineering, the targeting of these enzymes for drug development, and the understanding of the role these proteins have on bacterial physiology.
Bacteria are known to produce a number of physiologically important secondary metabolites that are nonribosomal peptides. The biosynthesis of these nonribosomal peptides is of broad interest, but the function of MbtH-like protein superfamily members associated with the biosynthesis of these metabolites is unknown. This proposal aims to define the function of these proteins in nonribosomal peptide synthesis.
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