Halogenation Biochemistry in Human and Environmental Health

PROJECT SUMMARY
Biotic processes in the oceans introduce various halogenated molecules in the environment and in the human
exposome. Some of these halogenated molecules possess favorable pharmaceutical activities making them
attractive drug candidates while many of these naturally produced marine halogenated molecules are potent
toxins and pollutants. Understanding, at the organismal, molecular, and atomistic levels how these
halogenated molecules are naturally constructed in the oceans is the principal motivation of the research
program described herein.
Seaweeds and filter feeding marine benthic invertebrates such as sponges are well validated to be
exceptionally prolific producers of halogenated natural products. Contrary to prokaryotic natural product
biochemistry, our understanding of how these eukaryotes biosynthesize natural products is far less
developed due to challenges in culturing and genetically interrogating these organisms. This is the key
scientific challenge that this proposal seeks to address in order to deliver seaweed- and sponge-derived
halogenated natural products using biogenetic means.
Progress envisaged here is predicated upon two key intellectual drivers. The first of these is the sequencing
of eukaryotic transcriptomes, rather than genomes, to circumvent the eukaryotic genome complexity. The
second driver is to design natural product biosynthetic schemes based on intermediates that are mined from
untargeted metabolomic datasets and then use these rationalized schemes to guide the mining of eukaryotic
transcriptomes for biosynthetic enzyme discovery. Specifically, halogenated intermediates and halogenating
enzymes are used as diagnostic signatures in this workflow.
Interdisciplinary competence in genomics, biochemistry, synthetic biology, and metabolomics allows the
program participants to not only interrogate biogenetic pathways for the production of marine eukaryote-
derived halogenated pharmacophores and pollutants, but to also use the genetic dark matter locked away in
marine holobiont metagenomes to produce new-to-nature halogenated molecules with favorable
pharmaceutical bioactivities. The program design also embraces opportunities to discover and characterize
new halogenation enzymology and adapt halogenases as general purpose biocatalysts. Research described
here is both molecule focused, in that, it will lead to the understanding of how key halogenated molecules of
interest are constructed in marine sponge biomes, while concomitantly embracing method-development and
engineering opportunities.

Grant Number: 5R35GM142882-05
NIH Institute/Center: NIH
Principal Investigator: Vinayak Agarwal