EDWARD A. DOISY
Department of
Biochemistry & Molecular Biology
EST. 1924
Saint Louis University School of Medicine
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Our Legacy
1 Nobel Laureate
Doisy2 Members, National Academy of Sciences
Doisy, Sly1 Member, National Academy of Medicine
Roth3 Members, American Academy of Arts & Sciences
Doisy, Roth, Shilatifard1 Member, Leopoldina
Kutchan11 Fellows, American Association for the Advancement of Science
Di Cera, Doisy, Elliott, Katzman, Kutchan, Lee, Lodge, McKee, Olson, Shilatifard, Sly4 Members and 1 Fellow, National Academy of Inventors
Chang, Di Cera, Heyduk, Lodge, Pozzi2 Pew Scholars
Cole, Yap
Message from the Chair
Welcome to our website!
Our department was founded in 1924 by Dr. Edward A. Doisy, discoverer of estrogens and recipient of the 1943 Nobel Prize in Physiology or Medicine for his work on the synthesis of vitamin K.
We have an impressive legacy of excellence, continued by Doisy’s successors Dr. Robert Olson and Dr. William Sly, and by the work of our current outstanding students, postdocs, staff and faculty.
It is an exciting time to join the BMB family.
Thank you for visiting!
Department Stats
External Grant Expenditures
Publications
Department Members
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What's News
William S. Sly, M.D., Emeritus Professor and Chair of Biochemistry from 1984 - 2010, has…
Congratulations to our BMB students who received their Ph.D. degrees this year! Pictured below, from…
The inaugural Doisy Conference on Coagulation (DCC) was held on Monday, May 5, 2025, at…
Congratulations to Ayush Mistry, Graduate Student in the lab of Edwin Antony, on winning 1st…
Congratulations to Sergey Korolev, Ph.D., on being promoted to the rank of Full Professor, effective…
Department Committees
Doisy Fund
- Yuna Ayala, Ph.D.
- Ángel Baldán, Ph.D.
- Enrico Di Cera, M.D., Chair
- Kathleen E. Doisy, M.S.
- Oleg Kisselev, Ph.D.
- Krista Lentine, M.D., Ph.D.
- LaChina McCoy
- Eleonore Stump, Ph.D.
Instrumentation and Cores
- Edwin Antony, Ph.D., Chair
- Yuna Ayala, Ph.D.
- Ángel Baldán, Ph.D.
- Michelle Brennan, Ph.D.
- Reza Dastvan, Ph.D.
- Nicola Pozzi, Ph.D.
Training
- Madison Adolph, Ph.D., Co-Director of the BMB Graduate Program
- Yuna Ayala, Ph.D., Chair
- Susana Gonzalo, Ph.D.
- Tomasz Heyduk, Ph.D., Co-Director of the BMB Graduate Program
- LaChina McCoy
BMB Faculty Incentives
SLU Incentives
- F&A Rebate: Percentage of F&A rebated to 2-fund
- Non-salary incentive: Half of salary recovered beyond 50% rebated to 2-fund
- Salary bonus from the faculty compensation plan for faculty who have recovered 50% or more of their total compensation from extramural sources as a 3-year rolling average from preceding FYs
Primary Faculty
- Matching of the SLU F&A rebate
- Salary bonus for faculty with salary recovery from extramural sources of at least 50% (Assistant Professor), 65% (Associate Professor), or 75% (Professor). Salary recovery in excess of these levels will be rebated to a 2- fund for research use
- Salary bonus for any grant, new or renewal, with BMB faculty as the PI, generating full indirect costs, and providing at least 4 years of funding
- Salary bonus for new publications with BMB faculty as the corresponding author in journals with an impact factor greater than 10 and a travel award for the leading author of the publication, if a member of BMB
- Full support of the stipend of Ph.D. and M.D./Ph.D. students for 12 months from the date they pass their qualifying exam
Primary & Secondary Faculty
- Matching of JIT grants from the ICTS
- Student support through the Doisy Scholar Program
Doisy Scholar Program
Doisy Scholars
Biochemistry Ph.D. and M.D./Ph.D. students may be appointed as Doisy Scholars at any time during their training.
- Appointment to Doisy Scholar is recommended by the BMB Training Committee and reviewed for approval by the Chair of BMB.
- Doisy Scholarship is an honor reserved for students who have distinguished themselves academically through course work and have achieved scholarly recognition through peer-reviewed publications and poster/oral presentations at meetings or extramural fellowships.
- The stipend and student fees of a Doisy Scholar are supported in full by the BMB Doisy Fund for 24 months.
Click to read more about our Doisy Scholars.
High Impact Publications
Papers highlighted below were published in journals with an impact factor of 10 or greater.
All papers were published within the past year.
All papers were published within the past year.
Recent Publications
Lupus anticoagulant and antiprothrombin antibodies: embracing the future
Lupus anticoagulant and antiprothrombin antibodies: embracing the future
Lupus anticoagulant (LAC) is a well-known laboratory test used to explore potential reasons for the prolongation of phospholipid-dependent coagulation tests. An extended clotting time in a coagulation test typically suggests a bleeding tendency, as the plasma takes longer to clot. However, a positive LAC result, defined as normalization of prolonged clotting time by adding anionic phospholipids in the system, does not necessarily imply this. In fact, quite the opposite is true: a positive LAC often strongly correlates with an increased risk of thromboembolic events. Therefore, despite being conceptually counterintuitive, LAC remains extremely valuable in routine clinical practice for identifying individuals at risk for thromboembolic events. Over the years, various factors have been recognized as potential inducers of LAC, with antiphospholipid antibodies associated with antiphospholipid syndrome (APS) playing a significant role. Today, research indicates that, among antiphospholipid antibodies, those targeting plasma proteins β-glycoprotein I and prothrombin are central to LAC. This article offers a historical perspective on LAC, emphasizing recent developments in antiprothrombin antibodies, their connection to LAC, and novel detection methods. Our premise is that a deeper understanding of how antiprothrombin antibodies contribute to LAC and the identification of subpopulations of these antibodies potentially responsible for it in thrombotic APS patients could lead to transformative advancements, offering new strategies for risk stratification and personalized treatments for patients with APS and beyond.
At last: the mitochondrial pyruvate carrier structure revealed!
At last: the mitochondrial pyruvate carrier structure revealed!
Mitochondrial pyruvate carrier (MPC) inhibitors have shown promise as therapeutics for treating several chronic diseases. However, the structure of MPC and the molecular mechanisms by which it interacts with inhibitors have remained unclear, impeding rational drug design. Multiple groups have now independently resolved the structure of the MPC heterodimer.
Cryo-EM structure of coagulation factor Va bound to activated protein C
Cryo-EM structure of coagulation factor Va bound to activated protein C
Coagulation factor Va (FVa) is the cofactor component of the prothrombinase complex required for rapid generation of thrombin from prothrombin in the penultimate step of the coagulation cascade. In addition, FVa is a target for proteolytic inactivation by activated protein C (APC). Like other protein-protein interactions in the coagulation cascade, the FVa-APC interaction has long posed a challenge to structural biology and its molecular underpinnings remain unknown. A recent cryogenic electron microscopy (cryo-EM) structure of FVa has revealed the arrangement of its A1-A2-A3-C1-C2 domains and the environment of the sites of APC cleavage at R306 and R506. Here, we report the cryo-EM structure of the FVa-APC complex at 3.15 Å resolution in which the protease domain of APC engages R506 in the A2 domain of FVa through electrostatic interactions between positively charged residues in the 30-loop and 70-loop of APC and an electronegative surface of FVa. The auxiliary γ-carboxyglutamic acid and epidermal growth factor domains of APC are highly dynamic and point to solvent, without making contacts with FVa. Binding of APC displaces a large portion of the A2 domain of FVa and projects the 654VKCIPDDDEDSYEIFEP670 segment as a "latch," or exosite ligand, over the 70-loop of the enzyme. The latch induces a large conformational change of the autolysis loop of APC, which in turn promotes docking of R506 into the primary specificity pocket. The cryo-EM structure of the FVa-APC complex validates the bulk of existing biochemical data and offers molecular context for a key regulatory interaction of the coagulation cascade.
Structural determinants of protease-activated receptor 1 cleavage by activated protein C
Structural determinants of protease-activated receptor 1 cleavage by activated protein C
Activated protein C (APC) performs cytoprotective functions mediated by cleavage of the protease-activated receptor 1 (PAR1) in the presence of the endothelial protein C receptor and signaling through β-arrestin-2. APC cleaves PAR1 at R41 and R46, but the specificity of the reaction is low. In contrast, thrombin cleaves PAR1 at R41 only in a reaction that is independent of endothelial protein C receptor, producing a proinflammatory response mediated by signaling through G-protein intermediates and features high specificity. The molecular basis of this difference between APC and thrombin remains unknown.
Dietary control of peripheral adipose storage capacity through membrane lipid remodelling
Dietary control of peripheral adipose storage capacity through membrane lipid remodelling
Genetic and dietary cues are known drivers of obesity, yet how they converge at the molecular level is incompletely understood. Here we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, an endoplasmic reticulum (ER)-resident O-acyltransferase that selectively enriches diet-derived omega-6 polyunsaturated fatty acids (n-6 PUFAs) in the membrane lipidome. In mice fed a high-fat diet, lowering membrane n-6 PUFA levels through genetic or dietary interventions results in aberrant adipose triglyceride (TG) turnover, ectopic fat deposition and insulin resistance. Additionally, we detail a non-canonical adaptive response in 'lipodystrophic' Lpcat3 adipose tissues that engages a futile lipid cycle to increase metabolic rate and offset lipid overflow to ectopic sites. Live-cell imaging, lipidomics and molecular dynamics simulations reveal that adipocyte LPCAT3 activity enriches n-6 arachidonate in the phosphatidylethanolamine (PE)-dense ER-lipid droplet interface. Functionally, this localized PE remodelling optimizes TG storage by driving the formation of large droplets that exhibit greater resistance to adipose TG lipase activity. These findings highlight the PPARγ-LPCAT3 axis as a mechanistic link between dietary n-6 PUFA intake, adipose expandability and systemic energy balance.
Mechanistic insights into direct DNA and RNA strand transfer and dynamic protein exchange of SSB and RPA
Mechanistic insights into direct DNA and RNA strand transfer and dynamic protein exchange of SSB and RPA
Single-stranded DNA-binding proteins (SSBs) are essential for genome stability, facilitating replication, repair, and recombination by binding single-stranded DNA (ssDNA), recruiting other proteins, and dynamically relocating in response to cellular demands. Using single-molecule fluorescence resonance energy transfer assays, we elucidated the mechanisms underlying direct strand transfer from one locale to another, protein exchange, and RNA interactions at high resolution. Both bacterial SSB and eukaryotic replication protein A (RPA) exhibited direct strand transfer to competing ssDNA, with rates strongly influenced by ssDNA length. Strand transfer proceeded through multiple failed attempts before a successful transfer, forming a ternary intermediate complex with transient interactions, supporting a direct transfer mechanism. Both proteins efficiently exchanged DNA-bound counterparts with freely diffusing molecules, while hetero-protein exchange revealed that SSB and RPA could replace each other on ssDNA, indicating that protein exchange does not require specific protein-protein interactions. Additionally, both proteins bound RNA and underwent strand transfer to competing RNA, with RPA demonstrating faster RNA transfer kinetics. Competitive binding assays confirmed a strong preference for DNA over RNA. These findings provide critical insights into the dynamic behavior of SSB and RPA in nucleic acid interactions, advancing our understanding of their essential roles in genome stability, regulating RNA metabolism, and orchestrating nucleic acid processes.
Structural dynamics of sphingosine kinase 1 regulation and inhibition
Structural dynamics of sphingosine kinase 1 regulation and inhibition
Sphingosine kinase 1 (SK1) produces sphingosine-1-phosphate, a bioactive lipid implicated in cancer progression and other diseases. Despite its clinical relevance, the structural and dynamic basis of SK1 regulation and inhibition remains poorly understood. Using an integrated spectroscopic and computational approach, we uncover conformational transitions that govern substrate entry, catalysis, and inhibitor binding. Phosphorylation of Ser225 triggers regulatory loop rearrangements and salt bridge reshuffling, priming SK1 for membrane engagement and catalytic activity. We identify a previously uncharacterized catalytic intermediate featuring a distinct conformation with a highly dynamic lipid-binding loop 1 (LBL-1), sensitive to potent inhibitors such as PF-543. This inhibitor locks SK1 in an inactive state by restricting LBL-1 dynamics and globally stabilizing a non-catalytic conformation. Notably, SK1 forms functionally distinct dimers stabilized by ligand or membrane interactions, revealing a dynamic, multilayered regulatory mechanism governed by structural flexibility. These findings define a novel inhibitory mechanism and offer a structural framework for developing next-generation SK1-targeted therapeutics.
Technical recommendations for analyzing oxylipins by liquid chromatography-mass spectrometry
Technical recommendations for analyzing oxylipins by liquid chromatography-mass spectrometry
Several oxylipins are potent lipid mediators that regulate diverse aspects of health and disease and whose quantitative analysis by liquid chromatography-mass spectrometry (LC-MS) presents substantial technical challenges. As members of the lipidomics community, we developed technical recommendations to ensure best practices when quantifying oxylipins by LC-MS.
Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates
Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates
Cytosolic aggregation of the nuclear protein TAR DNA-binding protein 43 (TDP-43) is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to a dynamic TDP-43-enriched phase within stress granules, which subsequently transition into pathological aggregates. Intra-condensate demixing of TDP-43 is observed in iPS-motor neurons, a disease mouse model, and patient samples. Mechanistically, intra-condensate demixing is triggered by local unfolding of the RRM1 domain for intermolecular disulfide bond formation and by increased hydrophobic patch interactions in the C-terminal domain. By engineering TDP-43 variants resistant to intra-condensate demixing, we successfully eliminate pathological TDP-43 aggregates in cells. We suggest that up-concentration inside condensates followed by intra-condensate demixing could be a general pathway for protein aggregation.
Cryo-EM captures the coordination of asymmetric electron transfer through a di-copper site in DPOR
Cryo-EM captures the coordination of asymmetric electron transfer through a di-copper site in DPOR
Enzymes that catalyze long-range electron transfer (ET) reactions often function as higher order complexes that possess two structurally symmetrical halves. The functional advantages for such an architecture remain a mystery. Using cryoelectron microscopy we capture snapshots of the nitrogenase-like dark-operative protochlorophyllide oxidoreductase (DPOR) during substrate binding and turnover. DPOR catalyzes reduction of the C17 = C18 double bond in protochlorophyllide during the dark chlorophyll biosynthetic pathway. DPOR is composed of electron donor (L-protein) and acceptor (NB-protein) component proteins that transiently form a complex in the presence of ATP to facilitate ET. NB-protein is an αβ heterotetramer with two structurally identical halves. However, our structures reveal that NB-protein becomes functionally asymmetric upon substrate binding. Asymmetry results in allosteric inhibition of L-protein engagement and ET in one half. Residues that form a conduit for ET are aligned in one half while misaligned in the other. An ATP hydrolysis-coupled conformational switch is triggered once ET is accomplished in one half. These structural changes are then relayed to the other half through a di-nuclear copper center at the tetrameric interface of the NB-protein and leads to activation of ET and substrate reduction. These findings provide a mechanistic blueprint for regulation of long-range electron transfer reactions.
