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Faculty Profile

Vern L. Schramm, Ph.D.

Dr. Vern L. Schramm

Professor, Department of Biochemistry

Chair, Department of Biochemistry

Ruth Merns Chair in Biochemistry


Professional Interests


Enzymes catalyze virtually all of the chemical transformations necessary for biological life. Knowledge of the transition-state structure of enzymatic reactions permits the design of powerful inhibitors. Methods have been developed in this laboratory for the experimental determination of the geometric and charge features which characterize enzymatic transition states. This information is then used for the logical design of transition-state inhibitors which have the potential to be new biologically active agents. Specific projects include:

Human genetic deficiency of purine nucleoside phosphorylase causes a specific T-cell insufficiency. Our inhibitors of this enzyme are powerful anti T-cell agents. Two inhibitors are now in human clinical trials against human T-cell cancers and gout. Three T-cell cancer indications for these drugs have received orphan drug status from the FDA and several phase II trials are in progress. Phase II clinical trials have been completed for gout using our second-generation inhibitor. Third-generation and fourth-generation inhibitors are now being characterized.

Purine salvage is essential for growth of parasitic protozoa. A family of powerful inhibitors has been prepared against these enzymes from the malaria parasite. Promising results have been obtained in cell culture studies. One of these inhibitors stops the growth of malaria parasites in primate malaria. Preclinical research is underway, intended to lead to human trials in the next few years.

Experimental cancer chemotherapy uses plant toxins coupled to a recognition element for cancer cells. The transition state structure of saporin is being determined to guide the design of inhibitors. These will limit the side-effects of the toxin molecules remaining in the circulation or released from lysed cancer cells. Inhibitors are being synthesized and tested for efficiency, and constructs with saporin are being investigated as anticancer agents.

Research projects also involve S-adenosylmethionine recycling and methyl transfer reactions.  Methyltransfer reactions are central to the epigenetic control pathways regulating growth, development, gene expression and cancer.  New targets for transition state analysis and drug design are DNA methyltransferases, protein methyltransferases and metabolic enzymes forming and using S-adenosylmethionine.  Related to these pathways are MTAP, a cancer target and MTAN, a target for bacterial antibiotics.

Students in this laboratory can receive training in enzymology, catalysis, protein expression, inhibitor design, computer modeling, inhibitor synthesis, and in drug metabolism studies in cells and animals. Active collaborations occur with laboratories specializing in NMR, X-ray crystallography, mass spectroscopy, synthetic organic chemistry, cancer and medicine. Projects can be designed to include several of these research approaches through active collaborative research programs.



Selected Publications

Wang, Z., Singh, P., Czekster, C.M., Kohen, A. and Schramm, V.L. “Protein mass-modulated effects in the catalytic mechanism of dihydrofolate reductase:  beyond promoting vibrations.”  J. Am. Chem. 136, 8333-8341 (2014).

Donaldson, T.M., Cassera, M.B., Ho, M.C., Zhan, C., Merino, E.F., Evans, G.B., Tyler, P.C., Almo, S.C., Schramm, V.L. and Kim, K. “Inhibition and structure of Toxoplasma gondii purine nucleoside phosphorylase.”  Eukaryot Cell. 13, 572-579 (2014).

Wang, S., Thomas, K. and Schramm, V.L. “Catalytic site cooperativity in dimeric methylthioadenosine nucleosidase.”  Biochemistry 53, 1527-1535 (2014).

Zhang, Y., Evans, G.B., Clinch, K., Crump, D.R., Harris, L.D., Fröhlich, R.F., Tyler, P.C., Hazleton, K.Z., Cassera, M.B. and Schramm, V.L. “Transition state analogues of Plasmodium falciparum and human orotate phosphoribosyltransferases”.  J. Biol Chem 288, 34746-34754 (2013).

Guan, R., Tyler, P.C., Evans, G.B. and Schramm, V.L. “Thermodynamic analysis of transition-state features in picomolar inhibitors of human 5’-methylthioadenosine phosphorylase.”  Biochemistry 52, 8313-8322 (2013).

Vetticatt, M.J., Itin, B., Evans, G.B. and Schramm, V.L. “Distortional binding of transition state analogs to human purine nucleoside phosphorylase probed by magic angle spinning solid-state NMR.”  Proc. Natl. Acad. Sci. USA 110, 15991-15996 (2013).

Motley, M.W., Schramm, V.L. and Schwartz, S.D. “Conformational freedom in tight binding enzymatic transition-state analogues”  J. Phys.Chem B. 117, 9591-9597 (2013).

Ducati, R.G., Namanja-Magliano, H.A. and Schramm, V.L. “Transition-state inhibitors of purine salvage and other prospective enzyme targets in malaria.”  Future Med. Chem. 5, 1341-1360 (2013).  

Clinch, K., Crump, D.R., Evans, G.B., Hazleton, K.Z., Mson, J.M, Schramm, V.L. and Tyler, P.C. “Acyclic phosp(on)ate inhibitors of Plasmodium falciparum hypoxanthine-quanine-xanthine phosphoribosyltransferase.”  Bioorg. Med. Chem. 21, 5629-5646 (2013).

Haapalainen, A.M., Thomas, K., Tyler, P.C., Evans, G.B., Almo, S.C. and Schramm, V.L. “Salmonella enteric MTAN at 1.36 Å Resolution: A Structure-Based Design of Tailored Transition State Analogs.”  Structure 21, 963-974 (2013).

Suarez, J. Haapalainen, A.M., Cahill, S.M., Ho, M.C., Yan, F., Almo, S.C. and Schramm, V.L. “Catalytic Site Conformations in Human PNP by (19)F-NMR and Crystallography.”  Chem Biol.  20,  212-222 (2013).  PMID: 2348750.

Stratton, C.F. and Schramm, V.L.  “Immucillin-H, a purine nucleoside phosphorylase transition state analog,causes non-lethal attenuation of growth in Staphylococcus aureus.”  Bioinformation 9, 9-17 (2013).  PMID:  23390338

Burgos, E.S., Vetticatt, M.J. and Schramm, V.L.  “Recyling Nicotinamide.  The Transition-State Structure of Human Nicotinamide Phosphoribosyltransferase.”  J. Am. Chem. Soc.   135, 3485-3493 (2013).  PMID:  23373462

Schramm, V.L.  “Transition States, Analogues, and Drug Development.”  ACS Chem. Biol. 8, 71-81 (2013). PMID:  23259601

Guan, R., Ho, M.C., Fröhlich, R.F., Tyler, P.C., Almo, S.C. and Schramm, V.L. “Methylthioadenosine Deaminase in an Alternative Quorum Sensing Pathway in Pseudomonas aeruginosa.Biochemistry 51, 9094-9103. PMID: 23050701

Thomas, K., Haapalainen, A.M., Burgos, E.S., Evans, G.B., Tyler, P.C., Gulam, S., Guan, R. and Schramm, V.L. “Femtomolar Inhibitors Bind to 5’-Methylthioadenosine Nucleosidases with Favorable Enthalpy and Entropy.”  Biochemistry 51, 7541-7550 (2012). PMID: 22931458

Wang, S., Haapalainen, A.M., Yan, F., Du, Q., Tyler, P.C., Evans, G.B., Rinaldo-Matthis, A., Brown, R.L., Norris, G.E., Almo, S.C. and Schramm, V.L. “A Picomolar Transition State Analogue Inhibitor of MTAN as a Specific Antibiotic for Helicobacter pylori.”  Biochemistry 51, 6892-6894 (2012).  PMID: 22891633

Silva, R.G., Kipp, D.R. and Schramm, V.L. “Constrained Bonding Environment in the Michaelis Complex of Trypanosoma cruzi Uridine Phosphorylase.”  Biochemisry 51, 6715-6717 (2012).  PMID 22870934

Clinch, K., Evans, G.B., Fröhlich, R.F., Gulab, S.A., Gutierrez, J.A., Mason, J.M., Schramm, V.L., Tyler, P.C. and Woolhouse, A.D. Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics. Bioorg. Med. Chem. 20, 5181-5187 (2012). PMID: 22854195.

Hazleton, K.Z., Ho, M.C., Cassera, M.B., Clinch, K., Crump, D.R., Rosario, I. Jr., Merino, E.F., Almo, S.C., Tyler, P.C., Schramm, V.L. “Acyclic Immucillin Phosphonates: Second-Generation Inhibitors of Plasmodium falciparum   Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase.” Chem Biol. 19, 721-730 (2012).  PMID:22726686

Frame, I.J., Merino, E.F., Schramm, V.L., Cassera, M.B., and Akabas, M.H. “Malaria Parasite Type 4 Equilibrative Nucleoside Transporters with Distinct Substrate Specificity.”  Biochem. J. 446, 179-190 (2012). PMID: 22670848

Kipp, D.R., Hirschi, J.S., Wakata, A., Goldstein, H. and Schramm, V.L. “Transition states of native and drug-resistant HIV-1 protease are the same.”  Proc. Natl. Acad. Sci. U.S.A. 109, 6543-6548 (2012).

Burgos, E.S., Gulab, S.A., Cassera, M.B., and Schramm, V.L. “Luciferase-Based Assay for Adenosine:  Application to S-Adenyl-l-homocysteine Hydrolase.”  Anal. Chem. 84, 3593-3598 (2012).



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Media Coverage

TheScientist features a cover article by Dr. Vern Schramm on transition-state analogs, compounds he synthesizes that bind to enzymes and short-circuit specific chemical reactions, and their potential for a powerful new line of drugs.

New Scientist interviews Vern Schramm, Ph.D., about his research on transition state analogs, a class of drugs he has been developing that target and neutralize specific enzymes in order to combat disease. Dr. Schramm is professor and Ruth Merns Chair in Biochemistry at Einstein.

More media coverage