About

Wei-Chen Chang is a professor in the Department of Chemistry at NC State University and a LORD Corporation Distinguished Scholar. His research focuses on elucidating the chemical and biological logics of enzymatic transformations through an interdisciplinary approach that involves molecular biology, biological chemistry, organic chemistry, and natural product chemistry. His work aims to understand the mechanisms and catalytic strategies of nonheme iron enzymes, including mono- and dinuclear iron enzymes, and their roles in biosynthetic pathways. Chang's contributions include investigating enzymatic reactions such as halogenation, C–C desaturation, and bond formation, providing mechanistic insights into these processes. His research advances the understanding of enzyme function and catalysis, contributing to the broader fields of biochemistry and chemical biology.

Research topics

• Stereochemistry
• Chemistry
• Biochemistry
• Organic chemistry
• Photochemistry
• Combinatorial chemistry
• Biology
• Ecology
• Medicinal chemistry

Selected publications

• Correction to “Regio- and Stereoselective Halogenation by an Iron(II)- and 2-Oxoglutarate-Dependent Halogenase in the Biosynthesis of Halogenated Nucleosides”

  Journal of the American Chemical Society · 2026-01-24

  articleOpen accessCorresponding
  PublisherDOI

• Recent discoveries in mono- and dinuclear nonheme iron enzymes: Emerging mechanisms and catalytic strategies

  Archives of Biochemistry and Biophysics · 2026-04-08

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Biocatalytic Applications and Mechanistic Insights of Deoxypodophyllotoxin Synthase

  Journal of the American Chemical Society · 2026-04-07

  articleSenior author

  -dimethoxy analogue of (+)-hydroxy-yatein indicate antarafacial C-C bond formation during the cyclization reaction and remain consistent with cation-mediated cyclization. A crystallographic study of DPS bound with vanadium(IV) oxide, succinate, and (-)-hydroxy-yatein suggests a subtle interplay of steric interactions between the substrate and the active site that can alter the course of the DPS-catalyzed reaction and thus cyclization versus hydroxylation. Finally, an efficient chemoenzymatic approach to (-)-podophyllotoxin is described that relies only on freeze-dried whole cells after DPS overexpression.

  PublisherDOI

• Testing the Luedemann hypothesis: the discovery of novel antimicrobials from slow-growing microbes from nutrient-limited environments

  mSphere · 2025-09-23

  articleOpen access

  ABSTRACT George Luedemann is known throughout the antimicrobial community as one of the discoverers of the natural product antibiotic gentamicin. He subsequently hypothesized that slow-growing organisms inhabiting inhospitable, nutrient-limited environments may represent an enriched source of previously undescribed microbes that produce novel antimicrobials to create a competitive advantage over faster-growing rival organisms. Accordingly, 750 slow-growing microorganisms were isolated from desert rock surfaces and archived prior to Dr. Luedemann’s passing in 2000. Here, we describe the characterization and antimicrobial screening of the first 147 members of the Luedemann collection. 16S rRNA and whole-genome sequencing revealed that the pilot isolate set is highly diverse and includes novel microbial species belonging to genera commonly associated with soil samples, including Geodermatophilus , Streptomyces , and Micromonospora . Antimicrobial screening and comparative genomics indicate that at least six members are likely to produce novel antimicrobials with activity toward the ESKAPE pathogens, Vibrio cholerae and/or Mycobacterium smegmatis . Indeed, we show that the library member “9005BA” produces a newly identified phenazine, pyocyanin A, which displays potent (0.625 µg/mL), selective bactericidal activity toward Acinetobacter baumannii and efficacy in animals. Genetic and biochemical assays revealed that the antimicrobial activity of pyocyanin A is likely to be mediated by oxidative stress and can be overcome by altering bacterial respiration and/or efflux. Taken together, the data suggest that slow-growing organisms inhabiting nutrient-limited environments represent a previously overlooked rich source of microbial and antimicrobial agent diversity. IMPORTANCE The discovery and study of novel bacterial species offer an opportunity to identify new microbial biological processes, molecular mechanisms, and secondary metabolites, such as new antibiotics. Our work indicates that slow-growing organisms inhabiting nutrient-limited environments may represent an enriched source of novel microbial species. Furthermore, we find that a subset of these organisms is likely to produce corresponding novel antimicrobials, presumably as a means to outcompete faster-growing rival organisms. Indeed, we show that a putative new Streptomyces species is capable of producing a previously undescribed antimicrobial, pyocyanin A, with potent, selective antibacterial toward Acinetobacter baumannii , a prominent cause of antibiotic-resistant infections.

  PublisherDOI

• Mechanistic and Structural Analyses of Non-Heme Iron Enzyme TqaM for α-Tertiary Amino Acid Synthesis

  Journal of the American Chemical Society · 2025-10-28 · 1 citations

  articleCorresponding

  α-Tertiary amino acids (ATAAs) are versatile building blocks for the synthesis of biologically active compounds. Although synthetic and enzymatic approaches to ATAA synthesis have been developed, additional methods for ATAA production remain in high demand. Here, we report detailed mechanistic and structural analyses of TqaM, a non-heme iron-dependent oxygenase that catalyzes the key oxidative decarboxylation of a β-amino acid to generate 2-aminoisobutyric acid, a representative ATAA. In vitro analyses revealed that TqaM strictly recognizes the stereochemistry at the C2 position of the substrate and initiates the reaction by abstracting a C2-hydrogen atom with one equivalent of molecular oxygen. Structural analysis and site-directed mutagenesis suggested that an active site histidine residue functions as an acid/base catalyst and the N-terminal loop of the enzyme plays a critical role in substrate selectivity. Finally, we demonstrate TqaM’s remarkable substrate promiscuity toward α-hydroxy-β-amino acids, enabling the efficient synthesis of diverse ATAAs with potential biocatalytic applications.

  PublisherDOI

• Discovery of Noncanonical Iron and 2-Oxoglutarate Dependent Enzymes Involved in C–C and C–N Bond Formation in Biosynthetic Pathways

  ACS Bio & Med Chem Au · 2025-03-10 · 6 citations

  reviewOpen accessSenior authorCorresponding

  =O species to catalyze the functionalization of otherwise chemically inert C-H bonds. In addition to the more familiar canonical reactions of hydroxylation and chlorination, they also catalyze several other types of reactions that contribute to the diversity and complexity of natural products. In the past decade, several new Fe/2OG enzymes that catalyze C-C and C-N bond formation have been reported in the biosynthesis of structurally complex natural products. Compared with hydroxylation and chlorination, the catalytic cycles of these Fe/2OG enzymes involve distinct mechanistic features to enable noncanonical reaction outcomes. This Review summarizes recent discoveries of Fe/2OG enzymes involved in C-C and C-N bond formation with a focus on reaction mechanisms and their roles in natural product biosynthesis.

  PublisherOA PDFDOI

• Beyond the β–α–β Fold: Characterization of a SnoaL Domain in the Tautomerase Superfamily

  Biochemistry · 2025-04-15 · 1 citations

  articleOpen access

  Tautomerase superfamily (TSF) members are constructed from a single β–α–β unit or two consecutively joined β–α–β units, and most have a catalytic Pro1. This pattern prevails throughout the superfamily consisting of more than 11,000 members where homo- or heterohexamers are localized in the 4-oxalocrotonate tautomerase (4OT)-like subgroup and trimers are found in the other four subgroups except for a small subset of 4OT trimers, symmetric and asymmetric, that are found in the 4OT-like subgroup. During a sequence similarity network (SSN) update, a small cluster of sequences (117 sequences) was discovered in the 4OT-like subgroup that begins with Pro1. These sequences consist of a 4OT-like domain fused to a SnoaL domain at the C-terminus (except for one), as annotated in the UniProt database. The Pseudooceanicola atlanticus one (designated “4OT-SnoaL”) was chosen for kinetic, mechanistic, and crystallographic analysis. 4OT-SnoaL did not display detectable activity with known TSF substrates, suggesting a new activity. A genome neighborhood diagram (GND) places 4OT-SnoaL in an operon for a hydantoin degradation/utilization pathway. Treatment of 4OT-SnoaL with 3-bromopropiolate results in covalent modification of Pro1 by a 3-oxopropanoate adduct. Crystallographic analysis of the apo and modified enzymes shows that the 4OT domain is a hexamer of six identical subunits (a trimer of dimers), where each dimer consists of two β–α–β building blocks. Each C-terminus is attached to a SnoaL-like domain that displays a distorted α + β-barrel. The motif is a new one in the TSF and adds structural diversity to the TSF by using a SnoaL-like domain.

  PublisherOA PDFDOI

• Bioinformatic, structural, and biochemical analysis leads to the discovery of novel isonitrilases and decodes their substrate selectivity

  RSC Chemical Biology · 2025-01-01 · 1 citations

  articleOpen accessSenior authorCorresponding

  conventional analytical techniques. In this study, we focus on non-heme iron and 2-oxoglutarate (Fe/2OG) dependent isonitrilases that exhibit inherent selectivity toward the alkyl chain length of the substrate, thus enabling the structural elucidation of INPs. Based on two known isonitrilase structures, we identified eight residue positions that control substrate selectivity. Using a custom Python program that we developed, BioSynthNexus, over 350 Fe/2OG isonitrilase genes were identified. One of these enzymes was engineered through mutations at eight selected positions, effectively modifying its substrate preference to favor either a shorter or a longer alkyl chain. Furthermore, by examining several annotated isonitrilases at eight selected positions, substrate preferences of several isonitrilases were predicted and validated through biochemical assays. Together, these findings allow for effective identification of isonitrilases and INPs, and establish a predictive framework for determining the preferred alkyl chain of β-isonitrile amide moieties.

  PublisherDOI

• The Mosher Method in the Study of Natural Products

  ACS in focus · 2025-12-19 · 1 citations

  bookSenior author
  PublisherDOI

• Correction to “Discovery and Mechanism of a Diiron Enzyme in Ethylidene Azetidine Formation”

  Journal of the American Chemical Society · 2025-11-05

  erratumSenior author
  PublisherDOI

Recent grants

• Understanding How Nonheme Iron-Dependent Enzymes Assemble Pharmacophores: Studies of Cyclopropane, Aziridine, and Isonitrile Formation

  NIH · $2.8M · 2018–2028

• CAREER: Investigating Non-heme Iron Enzyme Catalyzed Nitrile Formation Mechanisms in Etoposide and Other Natural Product Biosynthetic Pathways

  NSF · $400k · 2019–2025

Frequent coauthors

• Yisong Guo

  Carnegie Mellon University

  45 shared

• Lide Cha

  North Carolina State University

  32 shared

• Tzu‐Yu Chen

  North Carolina State University

  28 shared

• Hung‐wen Liu

  The University of Texas at Austin

  27 shared

• Carsten Krebs

  Pennsylvania State University

  20 shared

• J. Martin Bollinger

  Pennsylvania State University

  20 shared

• Jiahai Zhou

  Shenzhen Institutes of Advanced Technology

  20 shared

• Pinghua Liu

  Boston University

  16 shared

Labs

• Wei-Chen Chang LabPI