Nematodes are the most species-rich animal on the planet, either as free-living organisms or parasites. In order to survive in different environments, nematodes need to rely on their ability to process complex chemical signals, hormones, or pheromones, essentially at all times. We work on a model of nematodes, Caenorhabditis elegans, and many classes of signaling molecules are known in it. Considering the similarity between C. elegans and parasitic nematodes, the signaling molecules discovered from C. elegans can potentially be used for developing novel compounds to control the life cycle of parasitic nematodes. One of these molecules, nemamide is a pentapeptide consisting of a polyketide side-chain moiety and a non-ribosomal cyclic peptide part. It has been found that nemamide is important for the survival during starvation-induced larval arrest. Nemamide is biosynthesized by a hybrid polyketide synthase-nonribosomal peptide synthetase (PKS-1) and nonribosomal synthetase (NRPS-1) in an assembly line manner. However, the specific biosynthetic mechanism of nemamide in C. elegans remains to be studied. Study on the enzymatic steps of nemamide biosynthesis will elucidate how polyketides and nonribosomal peptides are synthesized in an animal system and how nemamide biosynthesis is regulated. Our group found that, as an acyl-CoA synthetase, polyketide AMP ligase (PKAL-1) possesses unique roles in the production of the nemamide by trafficking biosynthetic intermediates like polyketide side-chain between PKS-1 and NRPS-1. We found that PKAL-1 can activate fatty acids as AMP-esters, and then loads fatty acyl AMP-esters onto NRPS-1 ACP7. In order to assess the ability of PKAL-1 to activate and load substrates, synthesized β-amino fatty acids as nemamide side-chain analogs were tested under the treatment of PKAL-1. The preliminary result shows that PKAL-1 likely cannot load the racemic C-9 and C-11 β-amino acid onto ACP7 of NRPS-1. Future work will be synthesizing stereospecific β-amino acids with a longer chain to detect the enzymatic activities for PKAL-1 further.

Synthesis and biological activity of nemamide polyketide side-chain analogs

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