William W. Metcalf
· G. William Arends Professor in Molecular & Cellular BiologyVerifiedUniversity of Illinois Urbana-Champaign · Microbiology
Active 1880–2026
About
William W. Metcalf is the G. William Arends Professor of Microbiology at the University of Illinois and a faculty member at the Carl R. Woese Institute for Genomic Biology. He holds B.S. degrees in Anthropology and Microbiology from the University of Illinois and a Ph.D. in Microbiology from Purdue University, followed by postdoctoral training at Purdue and the University of Illinois. His research program focuses on two unusual microbial metabolic processes with significant biomedical, biotechnological, and environmental implications: the metabolism of reduced phosphorus compounds, particularly phosphonic acid antibiotics, and the genetic analysis of methane-producing Archaea. Metcalf's work aims to elucidate the genes and metabolic pathways involved in the biosynthesis and catabolism of phosphonate compounds, which have potent bioactivities and applications in medicine and agriculture. His group has cloned and characterized genes for many phosphonate antibiotics, developed engineered strains to overproduce these compounds, and uncovered novel biochemical reactions and metabolic pathways. In parallel, Metcalf studies methanogenic Archaea, microorganisms that produce methane and play a critical role in the global carbon cycle, renewable energy production, waste treatment, and climate change. His laboratory has developed advanced genetic tools for the methanogen Methanosarcina, enabling detailed analysis of methanogenesis pathways and microbial interactions in anaerobic environments. These studies have revealed new insights into the metabolic diversity and physiology of methanogens, including the role of specific pathways in carbon fixation and electron transfer. Metcalf's research contributes to understanding fundamental microbial processes with broad impacts on health, agriculture, energy, and the environment.
Research topics
- Data Mining
- Biology
- Computer Science
- Computational biology
- Physics
- Genetics
- Chemistry
- Astronomy
- Biotechnology
- Biochemistry
- Microbiology
- Particle physics
- Nuclear physics
Selected publications
Zenodo (CERN European Organization for Nuclear Research) · 2026-05-06
datasetOpen accessAbout This repository contains the complete codebase and infrastructure for the IDBac platform, a centralized knowledgebase and analysis system for bacterial dereplication using MALDI-TOF mass spectrometry protein signatures. Please note: While the current IDBac knowledgebase contains version 4.2 of the RKI database, the JSON file listed here intentionally excludes this. Please find the source data for RKI used in the publication here. Abstract The identification of bacteria is central to microbiological sciences. While gene sequencing methods have been the standard to identify bacteria, use of MALDI-TOF mass spectrometry (MS) in clinical microbiology provides high-throughput identification to the subspecies level. However, biotyping has yet to be adopted outside of clinical microbiology due to the lack of a centralized public database of MS protein signatures that would facilitate strain identification via spectral comparison. Herein we present the IDBac web platform, a crowd-sourced central knowledgebase of protein MS signatures of >1400 strains spanning 6 bacterial phyla. Accompanying the knowledgebase is analysis infrastructure to identify unknown isolates, probe relationships within culture collections, and visualize specialized metabolite differences within groups of closely related bacteria. We highlight this utility by demonstrating the dereplication of bacterial isolates using the seed knowledgebase, identifying trends in culture collections using metadata integration, and reporting the discovery of a new metabolite from a Paraburkholderia isolate.
Open MIND · 2026-05-06
datasetOpen accessAbout This repository contains the complete codebase and infrastructure for the IDBac platform, a centralized knowledgebase and analysis system for bacterial dereplication using MALDI-TOF mass spectrometry protein signatures. Please note: While the current IDBac knowledgebase contains version 4.2 of the RKI database, the JSON file listed here intentionally excludes this. Please find the source data for RKI used in the publication here. Abstract The identification of bacteria is central to microbiological sciences. While gene sequencing methods have been the standard to identify bacteria, use of MALDI-TOF mass spectrometry (MS) in clinical microbiology provides high-throughput identification to the subspecies level. However, biotyping has yet to be adopted outside of clinical microbiology due to the lack of a centralized public database of MS protein signatures that would facilitate strain identification via spectral comparison. Herein we present the IDBac web platform, a crowd-sourced central knowledgebase of protein MS signatures of >1400 strains spanning 6 bacterial phyla. Accompanying the knowledgebase is analysis infrastructure to identify unknown isolates, probe relationships within culture collections, and visualize specialized metabolite differences within groups of closely related bacteria. We highlight this utility by demonstrating the dereplication of bacterial isolates using the seed knowledgebase, identifying trends in culture collections using metadata integration, and reporting the discovery of a new metabolite from a Paraburkholderia isolate.
mBio · 2025-01-08 · 5 citations
articleOpen accessSenior authorABSTRACT Methyl-coenzyme M reductase (MCR), the key catalyst in the anoxic production and consumption of methane, contains an unusual 2-methylglutamine residue within its active site. In vitro data show that a B12-dependent radical SAM (rSAM) enzyme, designated MgmA, is responsible for this post-translational modification (PTM). Here, we show that two different MgmA homologs are able to methylate MCR in vivo when expressed in Methanosarcina acetivorans , an organism that does not normally possess this PTM. M. acetivorans strains expressing MgmA showed small, but significant, reductions in growth rates and yields on methylotrophic substrates. Structural characterization of the Ni(II) form of Gln-methylated M. acetivorans MCR revealed no significant differences in the protein fold between the modified and unmodified enzyme; however, the purified enzyme contained the heterodisulfide reaction product, as opposed to the free cofactors found in eight prior M. acetivorans MCR structures, suggesting that substrate/product binding is altered in the modified enzyme. Structural characterization of MgmA revealed a fold similar to other B12-dependent rSAMs, with a wide active site cleft capable of binding an McrA peptide in an extended, linear conformation. IMPORTANCE Methane plays a key role in the global carbon cycle and is an important driver of climate change. Because MCR is responsible for nearly all biological methane production and most anoxic methane consumption, it plays a major role in setting the atmospheric levels of this important greenhouse gas. Thus, a detailed understanding of this enzyme is critical for the development of methane mitigation strategies.
Journal of Biological Chemistry · 2025-06-16 · 2 citations
articleOpen accessHere, we investigate the thermodynamic driving force of internal electron transfer of pyruvate:ferredoxin oxidoreductases (PFORs), by comparing the redox properties of a series of PFORs from Chlorobaculum tepidum, Magnetococcus marinus, Methanosarcina acetivorans, as well as revisiting the single historical precedent, the enzyme from Desulfovibrio africanus. These enzymes require a thiamine pyrophosphate cofactor, three [4Fe-4S] clusters, and CoA for activity and are found within anaerobic organisms that utilize the reverse tricarboxylic acid cycle, or other reductive pathways, performing carbon dioxide reduction and pyruvate synthesis. Yet, PFOR is often invoked as an oxidative enzyme responsible for generating reducing equivalents in the form of the redox carrier ferredoxin. Previous efforts to understand the mechanism of PFOR have relied upon a prior report of the iron-sulfur redox potentials derived from an incomplete redox titration. Here, we use direct protein film electrochemistry to provide a side-by-comparison of four PFOR enzymes, providing a new assessment of the iron-sulfur cluster redox potentials. As the Methanosarcina acetivorans PFOR is comprised of multiple polypeptides, our investigation of the recombinant PorD subunit allows us to construct a model, where the revised redox potentials are mapped to specific iron-sulfur clusters.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-15
preprintOpen accessAbstract The identification and analysis of bacteria is central to the microbiological sciences. While gene sequencing methods have been the standard to achieve this, use of MALDI-TOF mass spectrometry (MS), particularly in clinical microbiology, provides high-throughput identification to the subspecies level. However, biotyping has yet to be adopted outside of clinical settings due to the lack of a centralized public database of MS protein signatures that would facilitate isolate identification via spectral comparison. Further, current platforms lack meaningful ways to compare multiple properties from large numbers of bacterial isolates. Herein we present the IDBac web platform, a crowd-sourced central knowledgebase of protein MS signatures of >1400 strains spanning 6 bacterial phyla. Accompanying the knowledgebase is analysis infrastructure to identify unknown isolates, probe relationships within culture collections using metadata integration, and visualize specialized metabolite differences within groups of closely related bacteria. To highlight this utility and encourage wide community contribution, examples of each are presented.
SSRN Electronic Journal · 2024-01-01
preprintOpen accessMicrobiology Spectrum · 2024-10-30 · 1 citations
articleOpen accessSenior authorABSTRACT Methane-producing archaea are key organisms in the anaerobic carbon cycle. These organisms, also called methanogens, grow by converting substrate to methane gas in a process called methanogenesis. Previous research showed that the reduction of the terminal electron acceptor is the rate-limiting step in methanogenesis by Methanosarcina acetivorans . In order to gain insight into how the cells sense and respond to the availability of the terminal electron acceptor, we designed an experiment to deplete cells of the essential terminal oxidase enzyme, HdrED. We found that the depletion of HdrED in vivo results in a higher abundance of transcripts for methyltransferases ( mtaC2, mtaB3, mtaC3 ), coenzyme B biosynthesis, C1 metabolism, and pyrimidine compounds. In most cases, these changes were distinct from transcript abundance changes observed during the transition from exponential growth to stationary phase cultures. These data implicate the methylotrophic methanogenesis regulator MsrC (MA4383) in CoM-S-S-CoB heterodisulfide sensing and indicate cells have a specific mechanism to sense intracellular ratio of CoM-S-S-CoB, coenzyme M, and coenzyme B thiols and further suggest transcripts encoding translation and methanogenesis functions are controlled by feed-forward regulation depending on substrate availability. IMPORTANCE Methanosarcina is an emerging model archaeon and synthetic biology platform for the production of renewable energy and sustainable chemicals to reduce dependence on petroleum. Research into metabolic networks and gene regulation in this organism and other methanogens will inform genome-scale metabolic modeling and microbial function prediction in uncultured or non-model anaerobes and archaea. This study suggests methanogens use unknown mechanisms to efficiently couple methanogenesis to gene regulation via CoM-S-S-CoB and ATP availability.
Structure · 2024-09-11 · 6 citations
articleOpen accessNo evidence for methanotrophic growth of diverse marine methanogens
Proceedings of the National Academy of Sciences · 2024-05-02 · 10 citations
letterOpen accessSenior authorCorrespondingNucleic Acids Research · 2023 · 2168 citations
- Data Mining
- Computer Science
- Biology
Microorganisms produce small bioactive compounds as part of their secondary or specialised metabolism. Often, such metabolites have antimicrobial, anticancer, antifungal, antiviral or other bio-activities and thus play an important role for applications in medicine and agriculture. In the past decade, genome mining has become a widely-used method to explore, access, and analyse the available biodiversity of these compounds. Since 2011, the 'antibiotics and secondary metabolite analysis shell-antiSMASH' (https://antismash.secondarymetabolites.org/) has supported researchers in their microbial genome mining tasks, both as a free to use web server and as a standalone tool under an OSI-approved open source licence. It is currently the most widely used tool for detecting and characterising biosynthetic gene clusters (BGCs) in archaea, bacteria, and fungi. Here, we present the updated version 7 of antiSMASH. antiSMASH 7 increases the number of supported cluster types from 71 to 81, as well as containing improvements in the areas of chemical structure prediction, enzymatic assembly-line visualisation and gene cluster regulation.
Recent grants
Genetic Analysis of Methanogenesis by Methanosarcina species
NSF · $160k · 2008–2009
NIH · $2.1M · 2009
Discovery, biosynthesis and bioactivity of phosphonic acid natural products
NIH · $2.2M · 2018–2026
Development of genetic systems for human-associated methanogens
NIH · $418k · 2016–2018
NIH · $91k
Frequent coauthors
- 56 shared
Kevin R. Sowers
Biotechnology Institute
- 48 shared
Wilfred A. van der Donk
Howard Hughes Medical Institute
- 46 shared
Jun Kai Zhang
University of Illinois Urbana-Champaign
- 37 shared
Dennis Maeder
National Cancer Institute
- 37 shared
Barry L. Wanner
Harvard University
- 31 shared
Paul Gilna
Oak Ridge National Laboratory
- 31 shared
David Bruce
Abcam (United Kingdom)
- 31 shared
Thomas Brettin
Argonne National Laboratory
Labs
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Awards & honors
- Fellow in the American Association for the Advancement of Sc…
- Fellow in the American Academy of Microbiology, 2010
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