About

Emily Balskus is the Thomas Dudley Cabot Professor of Chemistry at Harvard University and an Investigator at the Howard Hughes Medical Institute. She joined the faculty of the Department of Chemistry and Chemical Biology in 2011. Her research group focuses on discovering, understanding, and manipulating microbial metabolism, emphasizing the importance of microbial metabolic functions in shaping the environment, influencing human health, and providing medicinally and industrially useful molecules. Her work involves uncovering new metabolic pathways and enzymes through microbial genome sequencing data, with particular attention to enzymes that perform novel chemistry and the biochemical functions of genes linked to biological activities, especially within the human microbiome. Prof. Balskus's research integrates microbiology, biochemical logic, and organic chemistry to develop strategies for combining synthetic organic chemistry with microbial metabolism. This includes developing biocompatible, non-enzymatic chemical transformations capable of modifying cellular metabolites. She is also involved in elucidating biochemical functions of genes and enzymes, focusing on their roles in microbial communities and human health. Her contributions to biomedical research have been recognized through awards such as the 2011 Smith Family Award for Excellence in Biomedical Research, the 2012 NIH Director’s New Innovator Award, and the 2012 Searle Scholar. She is also an Associate Member of the Broad Institute of Harvard and MIT and a Faculty Associate of the Microbial Sciences Initiative at Harvard.

Research topics

• Biology
• Microbiology
• Genetics
• Biochemistry
• Chemistry
• Ecology
• Computational biology
• Internal medicine
• Cell biology
• Evolutionary biology
• Food science
• Stereochemistry
• Bioinformatics
• Immunology

Selected publications

• Chemical capture of diazo metabolites reveals biosynthetic hydrazone oxidation

  Nature · 2026-02-04 · 3 citations

  articleOpen accessSenior author

  Abstract Chemically reactive microbial natural products have enabled therapeutic development 1 via their well-established anticancer, antibiotic and antioxidant activities. However, discovery of reactive metabolites is particularly challenging because they may not tolerate traditional bioactivity-guided isolation workflows 2 . Diazo-containing natural products are a subset of highly reactive microbial metabolites that display potent bioactivity 3 and enable powerful biosynthetic transformations 4,5 ; however, instability of the diazo group to light 6 , heat 7 , mild acid 8 and mechanical shock 9 has precluded their efficient discovery and application. Here we develop a reactivity-based screening approach to capture diazo-containing metabolites and facilitate their discovery by mass spectrometry. This workflow revealed two novel diazo-containing natural products, 4-diazo-3-oxobutanoic acid ( 1 ) and diazoacetone ( 2 ), from the human lung pathogen Nocardia ninae . Biosynthetic investigations revealed a distinct enzymatic logic for diazo formation involving hydrazone oxidation catalysed by the metalloenzyme Dob3, and its biochemical characterization suggests promising future applications in biocatalysis. Overall, our work highlights the power of reactivity-guided strategies for identifying reactive metabolites and facilitating the discovery of unique enzymatic transformations.

  PublisherOA PDFDOI

• Flavoaffinins, Elusive Cellulose-Binding Natural Products from an Anaerobic Bacterium

  Journal of the American Chemical Society · 2026-01-15

  articleOpen accessSenior authorCorresponding

  Cellulose is the most abundant polymer on Earth. Many anaerobic cellulose-degrading bacteria produce uncharacterized yellow-orange, cellulose-binding pigments known as yellow affinity substances (here referred to as flavoaffinins) that are associated with cellulose degradation. Here, we isolate and structurally characterize the flavoaffinins from Clostridium (Hungateiclostridium) thermocellum, a key workhorse for the industrial conversion of cellulosic feedstocks to ethanol. Flavoaffinins represent an unprecedented structural juxtaposition of an aryl polyene chain with a hydroxy-diene γ-lactone. We also shed light on their biosynthesis using stable-isotope feeding experiments. This effort lays the groundwork for understanding the biological function(s) of the flavoaffinins and expands the limited number of natural products isolated from obligately anaerobic microbes.

  PublisherOA PDFDOI

• Active Site Structure and Mechanism of a Molybdenum Catechol Dehydroxylase

  Journal of the American Chemical Society · 2026-03-31

  articleOpen accessCorresponding

  The dehydroxylation of catechols represents an important chemical transformation facilitated by gut bacteria in mammals. This reaction is catalyzed by pyranopterin molybdenum enzymes that belong to the DMSO reductase family. Despite their chemical and biological significance, the structure and mechanisms of catechol dehydroxylases remain uncharacterized. In this manuscript, we interrogated the active site structure of hydrocaffeic acid dehydroxylase from the gut bacterium Gordonibacter urolithinfaciens (Gu Hcdh) using Mo K-edge X-ray absorption near-edge structure (XANES) spectroscopy and extended X-ray absorption fine structure (EXAFS) analyses. In the oxidized state, the Mo(VI) ion is coordinated by a terminal oxo atom, a cysteine thiolate, and four sulfur atoms from the two bidentate pyranopterin dithiolene (PDT) ligands. Upon reduction to the Mo(IV) state, the active site remains hexacoordinate with a similar first coordination sphere; however, the terminal oxo ligand present in the Mo(VI) state has been protonated to yield a coordinated hydroxyl ligand. The EXAFS-derived coordination geometries for the Mo(VI) and Mo(IV) sites are consistent with the results of bond valence sum (BVS) analyses. Reaction coordinate computations suggest the likely role of an active site carboxylate in facilitating substrate dearomatization and product formation. Protein sequence analysis and site-directed mutagenesis experiments reveal that Cys157 is ligated to the Mo ion, and Asp210 serves as a catalytically essential active site acid–base. Together, these analyses enrich our understanding of an emerging pyranopterin molybdenum enzyme family from the human gut microbiota.

  PublisherOA PDFDOI

• A previously unappreciated class of metal-dependent bile salt hydrolases from the human gut microbiome

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-06

  articleOpen accessSenior author

  Abstract Bile salt hydrolases (BSHs) are gut microbial enzymes that catalyze the deconjugation of glycine-or taurine-conjugated bile acids (BAs), a key step in shaping the BA pool in the human gastrointestinal tract and modulating host-gut microbiome interactions. 1–3 All known BSHs are members of the N-terminal nucleophile (Ntn) hydrolase superfamily and share a conserved architecture and mechanism involving a nucleophilic active site cysteine. 4,5 This knowledge has guided predictions and study of BSH activity in the gut microbiome 6,7 as well as the development of BSH inhibitors 8 . Here, we report the discovery and characterization of a previously unknown BSH from the human gut bacterium Bilophila wadsworthia that belongs to the metal-dependent amidohydrolase superfamily and exhibits robust and specific activity toward taurine-conjugated bile salts. We show this secreted enzyme, metalloBSH, utilizes a metallocofactor for BA deconjugation, a mechanism distinct from that of canonical Ntn-type BSHs. MetalloBSHs are conserved in B. wadsworthia and present in many other Desulfovibrionaceae found in vertebrate gut microbiomes. Analysis of multi-omic datasets indicates metalloBSHs are expressed in vivo and correlate with BA metabolism. Overall, our findings reshape our understanding of BSH activity in the gut microbiome and highlight the promise of activity guided discovery in revealing previously overlooked gut microbial enzymes.

  PublisherDOI

• Inhibitors of gut bacterial L-dopa decarboxylation with reduced susceptibility to host metabolism

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-09

  articleOpen accessSenior author

  Abstract Microorganisms in the human gut influence the efficacy and metabolism of host-targeted small molecule therapeutics, including the frontline Parkinson’s disease drug levodopa (L-dopa). Previous work has identified a mechanism-based inhibitor of gut bacterial decarboxylases that degrade L-dopa, α-fluoromethyltyrosine (AFMT). However, early experiments with AFMT in rodent models suggested undesirable in vivo metabolism by host tyrosine hydroxylase, producing a metabolite likely to worsen Parkinson’s phenotypes and prevent application as an L-dopa co-treatment. Here, we demonstrate oxidation of AFMT in vitro by recombinant human tyrosine hydroxylase. We then develop AFMT analogs that retain activity against bacterial decarboxylases but have reduced susceptibility to host hydroxylation. Suitable arenes for inhibitor design were identified using assays with commercially available noncanonical amino acids, which revealed aryl difluorination as a promising modification. Difluoroaryl AFMT derivatives are less prone to degradation by tyrosine hydroxylase in vitro yet still inhibit L-dopa metabolism by bacterial decarboxylases. This work exemplifies how substrate reactivity can streamline design of mechanism-based enzyme inhibitors, as well as how constraints posed by the host can be incorporated during development of microbiome-targeted therapeutics. The compounds reported here are promising starting points for future studies in animal models and further exploration of gut bacterial effects on L-dopa treatment efficacy.

  PublisherDOI

• Chemiluminescent probes allow for the rapid identification of colibactin-producing bacteria

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-02

  articleOpen accessSenior authorCorresponding

  ABSTRACT The pks (or clb ) gene cluster, which produces the genotoxic natural product colibactin, is encoded by human gut Enterobacteriaceae , including many commensal strains of E. coli . Colibactin crosslinks DNA and is implicated in colorectal cancer development, highlighting the importance of identifying colibactin-producing gut bacteria within biological samples. In this study, we develop phenoxy-dioxetane chemiluminescent probes that selectively react with a critical colibactin biosynthetic enzyme, the serine peptidase ClbP. We show that these chemiluminescent probes have superior sensitivity, speed, and detection capabilities compared to previously reported fluorescent ClbP probes. Furthermore, we employ these chemiluminescent probes to detect pks + E. coli directly in complex stool suspensions. These probes will enable multiple applications requiring detection of colibactin-producing bacteria, including the identification of ClbP inhibitors and the screening of clinical samples.

  PublisherOA PDFDOI

• Phenotypic high-throughput screening identifies modulators of gut microbial choline metabolism

  mBio · 2026-02-23

  articleOpen accessSenior author

  ABSTRACT Anaerobic metabolism of dietary choline to trimethylamine (TMA) by the human gut microbiome is a disease-associated pathway. The host’s impaired ability to oxidize TMA to trimethylamine- N -oxide (TMAO) results in trimethylaminuria (TMAU), while elevated serum TMAO levels have been positively correlated with cardiometabolic disease. Small molecule inhibition of gut bacterial choline metabolism attenuates the development of disease in mice, highlighting the therapeutic potential of modulating this metabolism. Inhibitors previously developed to target this pathway are often designed to mimic choline, the substrate of the key TMA-generating enzyme choline trimethylamine-lyase (CutC). Here, we use a growth-based phenotypic high-throughput screen and medicinal chemistry to identify distinct chemical scaffolds that can modulate anaerobic microbial choline metabolism and lower TMAO levels in vivo . These results illustrate the potential of using phenotypic screening to rapidly discover new inhibitors of gut microbial metabolic activities. IMPORTANCE Gut microbial metabolic activities play important roles in human health, prompting interest in the discovery of gut microbiome-targeted small molecule inhibitors as potential therapeutics. Anaerobic choline metabolism by the gut microbiome generates trimethylamine and its downstream metabolite trimethylamine- N -oxide (TMAO), which cause trimethylaminuria and are correlated with cardiometabolic diseases, respectively. Current strategies for modulating microbial metabolism with small molecule inhibitors typically require having a target enzyme. Here, we show that a growth-based phenotypic screen can identify inhibitors of choline metabolism with chemical scaffolds that are structurally distinct from choline and existing inhibitors. The resulting optimized compounds lower serum TMAO in gnotobiotic mice without significantly perturbing gut microbiome composition. This work highlights the potential of using phenotypic screening to rapidly discover additional inhibitors of microbial metabolic activities, which would accelerate mechanistic studies of the microbiome and deepen our understanding of disease biology from correlation to causation.

  PublisherDOI

• Chemiluminescent Probes Allow for the Rapid Identification of Colibactin-Producing Bacteria

  JACS Au · 2026-04-06

  articleOpen accessSenior authorCorresponding

  The pks (or clb) gene cluster, which produces the genotoxic natural product colibactin, is encoded by human gut Enterobacteriaceae, including many commensal strains of E. coli. Colibactin cross-links DNA and is implicated in colorectal cancer development, highlighting the importance of identifying colibactin-producing gut bacteria within biological samples. In this study, we develop phenoxy-dioxetane chemiluminescent probes that selectively react with a critical colibactin biosynthetic enzyme, the serine peptidase ClbP. We show that these chemiluminescent probes have superior sensitivity, speed, and detection capabilities compared with previously reported fluorescent ClbP probes. Furthermore, we employ these chemiluminescent probes to detect pks+ E. coli directly in complex stool suspensions. These probes will enable multiple applications requiring the detection of colibactin-producing bacteria, including the identification of ClbP inhibitors and the screening of clinical samples.

  PublisherDOI

• Chemical capture of diazo metabolites reveals biosynthetic hydrazone oxidation

  Figshare · 2026-01-01

  datasetOpen accessSenior author

  Source data for figures in the main text, extended data, and supporting information.

  PublisherDOI

• Discovery of the Metalloenzyme IsmB Revises a Pathway for Coprostanol Formation by the Human Gut Microbiome

  SSRN Electronic Journal · 2026-01-01

  preprintOpen access
  PublisherDOI

Recent grants

• Understanding the Formation and Utilization of Halogenated Metabolites in Natural Product Biosynthesis

  NSF · $435k · 2020–2023

• NIH Grant DP2GM105434

  NIH · $2.5M · 2017

• The biosynthesis of N-N bond-containing natural products

  NIH · $348k · 2020–2024

• NIH Grant F32GM084625

  NIH · $143k · 2011

• CAREER: Chemically-Enabled Strategies for the Discovery and Characterization of Novel Enzymatic Function

  NSF · $676k · 2015–2020

Frequent coauthors

• Pedro N. Leão

  Universidade do Porto

  38 shared

• William H. Gerwick

  Scripps Institution of Oceanography

  35 shared

• Vı́tor Vasconcelos

  Centro Interdisciplinar de Investigação Marinha e Ambiental

  33 shared

• Peter J. Turnbaugh

  University of California, San Francisco

  31 shared

• Curtis Huttenhower

  Harvard University

  27 shared

• Catherine L. Drennan

  Massachusetts Institute of Technology

  23 shared

• Andrew T. Chan

  Brigham and Women's Hospital

  18 shared

• Jay D. Keasling

  Joint BioEnergy Institute

  18 shared

Labs

• Balskus GroupPI

Education

• Ph.D., Chemistry

  Harvard University

  2007

• B.S., Chemistry

  University of California, Berkeley

  2002

Awards & honors

• 2011 Smith Family Award for Excellence in Biomedical Researc…
• 2012 NIH Director’s New Innovator Award
• 2012 Searle Scholar