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, Sly2 Members and 1 Fellow, National Academy of Inventors
Chang, Heyduk, Lodge2 Pew Scholars
Cole, Yap
Message from the Chair
Welcome to our website!
We recently celebrated 100 years since the founding of the department 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.
The department has an impressive legacy of excellence that continues to this day, fueled by strategic use of the Doisy Fund that supports our growth.
It is an exciting time to join us as a student, postdoc, or new faculty member.
Thank you for visiting!
Department Stats
External Grant Expenditures
Publications
Department Members
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Registration now open!
Doisy Conference on Coagulation
A one-day, free event for students, trainees, and researchers in the biomedical sciences.
Monday, May 5, 2025
Bayer Event Center, MO Botanical Garden
What's News
The Inaugural Doisy Conference on Coagulation (DCC) will take place on Monday, May 5, 2025,…
The Edward A. Doisy Department of Biochemistry & Molecular Biology celebrated 100 years since its…
Congratulations to Michelle Brennan, Ph.D., on her appointment as Assistant Research Professor, non-tenure track. Michelle…
Congratulations to Jaigeeth Deveryshetty, Ph.D., Research Scientist in the lab of Edwin Antony, on being…
Congratulations to Kevin Jagessar, Ph.D., Research Scientist in the lab of Reza Dastvan, who received…
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
- Edwin Antony, Ph.D.
- Yuna Ayala, Ph.D., Chair
- Susana Gonzalo, Ph.D.
- Tomasz Heyduk, Ph.D.
- LaChina McCoy
- Nathan Ponzar, Ph.D., Postdoc Rep
- Jaclyn Whalen, Ph.D. Student, Student Rep
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 non-salary incentive
- Salary bonus for faculty with salary recovery from extramural sources of at least 50% (Assistant Professor), 60% (Associate Professor), or 70% (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
Primary & Secondary Faculty
- Matching of JIT grants from the ICTS
- Student support through the Doisy Scholar Program
Doisy Scholars Program
Doisy Scholars
Biochemistry Ph.D. and M.D./Ph.D. students who have passed their qualifying exams are designated Doisy Scholars and receive the following benefits:
- The stipends of Doisy Scholars are supported in full by the BMB Doisy Fund through their 5th year of graduate school.
- Scholars receive an unrestricted grant each year toward their research and education activities, provided by the BMB Chair.
Scholar terms run from July 1 to June 30.
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
Advancing mitochondrial therapeutics: Synthesis and pharmacological evaluation of pyrazole-based inhibitors targeting the mitochondrial pyruvate carrier
Advancing mitochondrial therapeutics: Synthesis and pharmacological evaluation of pyrazole-based inhibitors targeting the mitochondrial pyruvate carrier
Inhibition of mitochondrial pyruvate transport via the mitochondrial pyruvate carrier (MPC) has shown beneficial effects in treating metabolic diseases, certain cancers, various forms of neurodegeneration, and hair loss. These benefits arise either from the direct inhibition of mitochondrial pyruvate metabolism or from the metabolic rewiring when pyruvate entry is inhibited. However, current MPC inhibitors are either nonspecific or possess poor pharmacokinetic properties. To address this, approximately 50 pyrazole-based MPC inhibitors were synthesized to explore the structure-activity relationship for MPC inhibition, evaluated through inhibition of mitochondrial pyruvate respiration. These inhibitors were designed with increased steric hindrance around electron-deficient double bonds, allowing for refined structural modifications that reduce their potential to act as Michael acceptors. Additionally, the new MPC inhibitors directly inhibited stellate cell activation, indicating their potential as therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). Unlike the thiazolidinedione class of MPC inhibitors, these compounds did not activate the nuclear receptor PPARγ. Molecular modeling was conducted to explore interactions between these novel inhibitors and the MPC complex. We have identified the chemical determinants critical for MPC inhibition and successfully developed novel inhibitors that are potent, specific and possess excellent physicochemical properties, high solubility, and outstanding metabolic stability in human liver microsomes.
Discovery of an Orally Efficacious Pyrazolo[3,4-]pyrimidine Benzoxaborole as a Potent Inhibitor of
Discovery of an Orally Efficacious Pyrazolo[3,4-]pyrimidine Benzoxaborole as a Potent Inhibitor of
Cryptosporidiosis is a diarrheal disease caused by the parasite resulting in over 100,000 deaths annually. Here, we present a structure-activity relationship study of the benzoic acid position (R) of pyrazolo[3,4-]pyrimidine lead SLU-2815 (), an inhibitor of parasite phosphodiesterase PDE1, resulting in the discovery of benzoxaborole SLU-10906 () as a benzoic acid bioisostere. Benzoxaborole is 10-fold more potent than against the parasite in a cell-based infection model (EC = 0.19 μM) and non-cytotoxic. Furthermore, has a fast rate of parasite-killing and is orally efficacious in a mouse infection model (50 mg/kg BID), although relapse was observed 7 days post-drug treatment. The partial selectivity profile versus human phosphodiesterases is preserved with the benzoxaborole motif and represents an important feature to improve in future optimization. Benzoxaborole represents an important advance toward the optimization of the pyrazolo[3,4-]pyrimidine series and the identification of a drug to treat cryptosporidiosis.
Replacement of a single residue changes the primary specificity of thrombin
Replacement of a single residue changes the primary specificity of thrombin
Thrombin prefers substrates carrying Arg at the site of cleavage (P1) because of the presence of D189 in the primary specificity (S1) pocket but can also cleave substrates carrying Phe at P1. The structural basis of this property is unknown.
Replacement of a single residue changes the primary specificity of thrombin
Replacement of a single residue changes the primary specificity of thrombin
Thrombin prefers substrates carrying Arg at the site of cleavage (P1) because of the presence of D189 in the primary specificity (S1) pocket but can also cleave substrates carrying Phe at P1. The structural basis of this property is unknown.
N-glycosylation in the SERPIN domain of C1-Esterase Inhibitor in hereditary angioedema
N-glycosylation in the SERPIN domain of C1-Esterase Inhibitor in hereditary angioedema
Hereditary angioedema is an autosomal dominant disorder caused by defects in C1-esterase inhibitor (C1-INH), resulting in poorly controlled activation of the kallikrein-kinin system and bradykinin overproduction. C1-INH is a heavily glycosylated protein in the serine protease inhibitor (SERPIN) family, yet the role of these glycosylation sites remains unclear. To elucidate the functional impact of N-glycosylation in the SERPIN domain of C1-INH, we engineered four sets consisting of 26 variants at or near the N-linked sequon (NXS/T). Among these, six are reported in HAE patients and five are known C1-INH variants without accessible clinical histories. We systematically evaluated their expression, structure and functional activity with C1¯s, FXIIa and kallikrein. Our findings showed that of the eleven reported variants, seven are deleterious. Deleting N at the three naturally occurring N-linked sequons (N238, N253 and N352) results in pathologic consequences. Altering these sites by substituting N to A disrupts N-linked sugar attachment but preserves protein expression or function. Further, an additional N-linked sugar generated at N272 impairs C1-INH function. These findings highlight the importance of N-linked sequons in modulating the expression and function of C1-INH. Insights gained from identifying the pathological consequences of N-glycan variants should assist in defining more tailored therapy.
SIX transcription factors are necessary for the activation of DUX4 expression in facioscapulohumeral muscular dystrophy
SIX transcription factors are necessary for the activation of DUX4 expression in facioscapulohumeral muscular dystrophy
Facioscapulohumeral muscular dystrophy (FSHD) is a common and progressive muscle wasting disease that is characterized by muscle weakness often first noticed in the face, the shoulder girdle and upper arms before progressing to the lower limb muscles. FSHD is caused by the misexpression of the Double Homeobox 4 (DUX4) transcription factor in skeletal muscle. While epigenetic derepression of D4Z4 macrosatellite repeats underlies DUX4 misexpression, our understanding of the complex transcriptional activation of DUX4 is incomplete.
Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer
Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer
Fructose consumption has increased considerably over the past five decades, largely due to the widespread use of high-fructose corn syrup as a sweetener. It has been proposed that fructose promotes the growth of some tumours directly by serving as a fuel. Here we show that fructose supplementation enhances tumour growth in animal models of melanoma, breast cancer and cervical cancer without causing weight gain or insulin resistance. The cancer cells themselves were unable to use fructose readily as a nutrient because they did not express ketohexokinase-C (KHK-C). Primary hepatocytes did express KHK-C, resulting in fructolysis and the excretion of a variety of lipid species, including lysophosphatidylcholines (LPCs). In co-culture experiments, hepatocyte-derived LPCs were consumed by cancer cells and used to generate phosphatidylcholines, the major phospholipid of cell membranes. In vivo, supplementation with high-fructose corn syrup increased several LPC species by more than sevenfold in the serum. Administration of LPCs to mice was sufficient to increase tumour growth. Pharmacological inhibition of ketohexokinase had no direct effect on cancer cells, but it decreased circulating LPC levels and prevented fructose-mediated tumour growth in vivo. These findings reveal that fructose supplementation increases circulating nutrients such as LPCs, which can enhance tumour growth through a cell non-autonomous mechanism.
Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways
Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways
One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1, PFKP, PDK3, PKM, and LDHA at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY, ACC1, FASN, SREBP1, and SCD1. Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways and leading to apoptosis. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications.
Resolving lipoxin A: Endogenous mediator or exogenous anti-inflammatory agent?
Resolving lipoxin A: Endogenous mediator or exogenous anti-inflammatory agent?
Seeding-competent TDP-43 persists in human patient and mouse muscle
Seeding-competent TDP-43 persists in human patient and mouse muscle
TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.
