About

April Lukowski, Ph.D., is an Assistant Professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego. Her research focuses on understanding and harnessing the unique chemistry of marine life through the discovery of novel biosynthetic enzymes and exploring their potential in biocatalysis. She employs techniques in enzymology, chemical analysis, and bioinformatics to identify and characterize new biocatalysts and enzyme families, aiming to generate new natural product-derived therapeutics. Dr. Lukowski's academic background includes a B.S. in Biochemistry from Saginaw Valley State University, obtained in 2015, and a Ph.D. in Chemical Biology from the University of Michigan in 2020. She completed postdoctoral studies at the Scripps Institution of Oceanography from 2020 to 2023. Her key contributions include discovering and characterizing a new family of flavin-dependent halogenases capable of halogenating alkynes and elucidating biosynthetic pathways for marine toxins impacting human and animal health. Her work has been recognized with awards such as the NIH NRSA Postdoctoral Fellowship and the NIH NRSA Predoctoral Fellowship.

Research topics

• Chemistry
• Combinatorial chemistry
• Stereochemistry
• Biochemistry
• Biology

Selected publications

• Computational pipeline reveals nature's untapped reservoir of halogenating enzymes

  Zenodo (CERN European Organization for Nuclear Research) · 2026-01-26

  otherOpen access
  PublisherDOI

• A searchable metadata network graph for microbiome metabolomics

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-05 · 2 citations

  articleOpen access

  Abstract Establishing the biological context of microbial metabolites remains a major challenge. We present microbiomeMASST, a metadata-driven network graph that maps metabolites across 467 available datasets with 144,424 mass spectrometry files from humans, animals, and microbial culture systems. MicrobiomeMASST integrates monocultures, synthetic communities, and host-associated samples across multiple body sites and plants. MS/MS spectra can be queried to trace occurrence across hosts, experimental conditions, and interventions, enabling cross-study integration. We demonstrate this framework by contextualizing microbial-conjugated bile acids and interrogating microbiome-mediated drug metabolism. Screening gut bacteria revealed deprolylation of the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril. Using microbiomeMASST, we traced this metabolite across human cohorts, microbial isolates, environmental samples, and in Gorilla gorilla . Structural modeling and enzymatic assays showed that microbial deprolylation abolishes ACE inhibition, thereby inactivating its therapeutic effect. Together, microbiomeMASST links MS/MS spectra to biological context, converting isolated observations into an interpretable microbiome map for cross-study analysis.

  PublisherOA PDFDOI

• Computational pipeline reveals nature's untapped reservoir of halogenating enzymes

  Zenodo (CERN European Organization for Nuclear Research) · 2026-01-26

  otherOpen access
  PublisherDOI

• Computational pipeline reveals nature’s untapped reservoir of halogenating enzymes

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-22

  articleOpen access

  ABSTRACT Microbial halogenated natural products (hNPs) hold ecological, agricultural, and biomedical relevance. The hNP-producing potential of the organism can be assessed by the precise prediction of biosynthetic enzymes, yet the detailed annotations of halogenases are often missing from genomic and metagenomic data. We created a manually curated database ( https://halogenases.secondarymetabolites.org/ ) containing information on the halide-specificity, role, and position of verified catalytic residues and results of the mutagenesis studies of more than 120 experimentally validated or in silico inferred halogenases. The collection of experimental data supports a computational pipeline that allows the family-, substrate-, and halide-scope-level annotation of halogenating enzymes by relying on catalytic residues, conserved motifs, and profile Hidden Markov Models (pHMMs). Our analysis with sequence similarity networks (SSNs) highlighted several underexplored clusters in the UniRef50 database. Such finding was a halogenase from Rhodopirellula baltica ( Rhoba VHPO) previously labelled as a hypothetical chloroperoxidase, which clustered apart from the known chloroperoxidases and bromoperoxidases, but accepted chloride and preferred bromide. Our database and workflow provide extensive and scalable solutions for the systematic and precise annotation of halogenating enzymes in genomic and metagenomic data. The in-depth categorization of halogenases will improve the chemical structure prediction of microbial hNPs, supporting ecological assessments and natural product discovery. Abstract Figure

  PublisherOA PDFDOI

• Promiscuity in Nature Extends to Central Protein Biosynthetic Machinery

  ACS Central Science · 2025-03-10

  articleOpen access1st authorCorresponding

  Thioesters, rather than oxo-esters, can be tolerated and processed during translation to incorporate unnatural monomers.

  PublisherOA PDFDOI

• 31: METATRANSCRIPTOMICS REVEALS BACTERIAL TRANSGENES CONFERRING THE BENEFICIAL METABOLIC EFFECTS OF TIMERESTRICTED FEEDING

  Gastroenterology · 2025-05-01

  article
  PublisherDOI

• Metagenomic Identification of Brominated Indole Biosynthetic Machinery from Cyanobacteria

  Journal of Natural Products · 2025-07-10 · 1 citations

  articleOpen accessSenior authorCorresponding

  Halogenated indole natural products have been isolated from a variety of organisms, including plants, marine algae, marine invertebrates, and bacteria. Aquatic cyanobacteria, in particular, are rich producers of brominated indoles, but their cognate biosynthetic enzymes have only been successfully linked in a limited number of natural products, such as the eagle-killing toxin aetokthonotoxin (AETX). The biosynthetic pathway for AETX involves five enzymes, two of which were previously undescribed due to incomplete annotations as hypothetical proteins. Our recent elucidation of AETX biosynthesis established functions of the two previously unknown proteins as enzymes responsible for tryptophan halogenation (AetF) and nitrile synthesis (AetD). Given their sequence novelty, we queried metagenomic data sets for these two enzymes and identified two new cyanobacterial haloindole biosynthetic gene clusters (BGCs) from marine sediment in Moorea, French Polynesia, and soil-derived samples in Maunawili Falls, Hawaii. We characterized the recovered BGCs by biochemically validating a new AetF homologue that exclusively halogenates free indole, rather than tryptophan as observed in AETX biosynthesis, and a new AetD homologue that harbors distinct substrate preferences, expanding the scope of nitrile biosynthesis. Additional characterization of core and accessory enzymes within these AETX-like BGCs highlights the breadth and diversity of haloindole biosynthetic machinery in cyanobacteria.

  PublisherOA PDFDOI

• Metatranscriptomics uncovers diurnal functional shifts in bacterial transgenes with profound metabolic effects

  Cell Host & Microbe · 2025-06-18 · 13 citations

  article
  PublisherDOI

• Unlocking the catalytic precision of ligand-controlled enzymatic halogenation

  Proceedings of the National Academy of Sciences · 2024-12-30 · 7 citations

  articleOpen access

  A single-component flavin-dependent halogenase, AetF, has emerged as an attractive biocatalyst for catalyzing halogenation. However, its flavin chemistry remains unexplored and cannot be predicted due to its uniqueness in sequence and structure compared to other flavin-dependent monooxygenases. Here, we investigated the flavin reactions of AetF using transient kinetics. Our data revealed that NADP + binding is required for formation of C4a-hydroperoxy flavin adenine dinucleotide (FAD) (FAD C4aOOH ), a key flavin-oxygen adduct required for generating a halogenating species. In the presence of NaBr without L-tryptophan, the flavin oxygen adduct intermediates [possibly FAD C4aOOH and C4a-hydroxy FAD (FAD C4aOH )] are highly stabilized (>4,000 s) before returning to the oxidized FAD state. In the presence of L-tryptophan, the rate of FAD C4aOH dehydration to form oxidized FAD increased by ~825-fold. These data suggest that the presence of all substrates is required for speeding up AetF’s catalytic cycle. Our findings underscore the adeptness of AetF in managing its reactivity through ligand control. Structural and tunnel analyses revealed that the binding of NADP + and L-tryptophan induces changes in protein tunnels which may potentially link to the ligand-controlled mechanisms. Leveraging these catalytic insights, we employed light-induced flavin reduction and NADP + stimulation to enable AetF halogenation of various compounds. Our findings demonstrate the mechanisms of precise control over flavin chemistry by AetF. These mechanistic insights may be useful for the biocatalytic development of single-component flavin-dependent halogenases.

  PublisherDOI

• A single diiron enzyme catalyses the oxidative rearrangement of tryptophan to indole nitrile

  Nature Chemistry · 2024-09-16 · 25 citations

  articleOpen access

  Nitriles are uncommon in nature and are typically constructed from oximes through the oxidative decarboxylation of amino acid substrates or from the derivatization of carboxylic acids. Here we report a third nitrile biosynthesis strategy featuring the cyanobacterial nitrile synthase AetD. During the biosynthesis of the eagle-killing neurotoxin, aetokthonotoxin, AetD transforms the 2-aminopropionate portion of 5,7-dibromo-L-tryptophan to a nitrile. Employing a combination of structural, biochemical and biophysical techniques, we characterized AetD as a non-haem diiron enzyme that belongs to the emerging haem-oxygenase-like dimetal oxidase superfamily. High-resolution crystal structures of AetD together with the identification of catalytically relevant products provide mechanistic insights into how AetD affords this unique transformation, which we propose proceeds via an aziridine intermediate. Our work presents a unique template for nitrile biogenesis and portrays a substrate binding and metallocofactor assembly mechanism that may be shared among other haem-oxygenase-like dimetal oxidase enzymes.

  PublisherOA PDFDOI

Recent grants

• Biocatalytic approaches to antiepileptic drug targets

  NIH · $12k · 2019–2020

Frequent coauthors

• Alison R. H. Narayan

  University of Michigan–Ann Arbor

  21 shared

• Bradley S. Moore

  University of California, San Diego

  16 shared

• Sanjoy Adak

  College Station Medical Center

  9 shared

• Rebecca J. B. Schäfer

  University of California, San Diego

  9 shared

• Meagan E. Hinze

  University of Michigan–Ann Arbor

  8 shared

• Catherine L. Drennan

  Massachusetts Institute of Technology

  8 shared

• Leo A. Joyce

  Merck & Co., Inc., Rahway, NJ, USA (United States)

  5 shared

• Lara Zetzsche

  University of Michigan–Ann Arbor

  5 shared

Labs

• Lukowski LabPI

Education

• PhD, Program in Chemical Biology

  University of Michigan–Ann Arbor

  2020

• B.S. Biochemistry, Chemistry

  Saginaw Valley State University

  2015

Awards & honors

• NIH NRSA Postdoctoral Fellowship (2021)
• NIH NRSA Predoctoral Fellowship (2019)
• Rackham Predoctoral Fellowship (2019)
• American Chemical Society Outstanding Graduate in Chemistry…