Professor, Department of Biochemistry
Chair, Department of Biochemistry
Ruth Merns Chair in Biochemistry
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 autoimmune disorders. Three T-cell cancer indications for these drugs have received orphan drug status from the FDA and several phase II trials are in progress. A phase II clinical trial has been initiated for psoriasis using our second-generation inhibitor. Third-generation and fourth-generation inhibitors are now being characterized.
Angiogenesis is required for tumor growth. One angiogenetic factor is thymidine phosphorylase, an enzyme that synthesizes deoxyribose 1-phosphase, a precursor to deoxyribose, the angiogenic molecule. We have solved the transition state structure of this enzyme and are now designing transition state analogues. It is hypothesized that such inhibitors will be useful as anticancer agents.
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. Plans are underway to initiate 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 ricin has been 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 the plant toxins ricin, saporin and gelosin are being investigated as anticancer agents.
Additional projects involve S-adenosylmethionine recycling and methyl transfer reactions in bacterial quorum sensing, cancer and DNA methylation reactions.
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.
Wang, S., Lim, J., Thomas, K., Yan, F., Angeletti, R.H. and Schramm, V.L. “A complex of methylthioadenosine/s-adenosylhomocysteine nucleosidase, transition state analogue, and nucleophilic water identified by mass spectrometry.” J. Am. Chem. Soc. 134, 1468-1470 (2012).
Silva, R.G. and Schramm, V.L. “Uridine Phosphorylase from Trypanosoma cruzi: Kinetic and Chemical Mechanisms.” Biochemistry 50, 9158-9166 (2011).
Guan, R., Ho, M.C. Brenowitz, M.D., Tyler, P.C., Evans, G.B., Almo, S.C. and Schramm, V.L. “Entropy-driven binding of picomolar transition state analogue inhibitors to human 5’methylthioadenosine phosphorylase.” Biochemistry 50, 10408-10417 (2011).
Cassera, M.B., Hazleton, K.Z., Merino, E.F., Obaldia III, N., Ho, M.-C., Murkin, A.S., DePinto, R., Gutierrez, J.A., Almo, S.C., Evans, G.B., Babu, Y.S., and Schramm, V.L. “Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model.” PLOS One 6, 6, e26916 (2011).
Kipp, D.R., Silva, R.G. and Schramm, V.L. “Mass-Dependent Bond Vibrational Dynamics Influence Catalysis by HIV-1 Protease.” J. Am. Chem. Soc. 133, 19358-19361 (2011).
Silva, R.G., Murkin, A.S. and Schramm, V.L. “Femtosecond dynamics coupled to chemical barrier crossing in a Born-Oppenheimer enzyme.” PNAS 108, 18661-18665 (2011).
Schramm, V.L. “Chemical Mechanisms in Biochemical Reactions.” J. Am. Chem. Soc. 133, 13207-13212 (2011).
Schramm, V.L. “Enzymatic Transition States, transition-state analogs, dynamics, thermodynamics, and lifetimes.” Annu. Rev. Biochem. 80, 703-732 (2011).
Cassera, M.B., Zhang, Y. Hazleton, K.Z. and Schramm, V.L. “Purine and Pyrimidine Pathways as Targets in Plasmodium falciparium.” Curr. Top. Med. Chem. 11, 2103-2115 (2011).
Silva, R.G., Vetticatt, M.J., Merino, E.F., Cassera, M.B. and Schramm, V.L. “Transition state analysis of Trypanosoma cruzi uridine phosphorylase-catalyzed arsenolysis of uridine.” J. Am. Chem. Soc. 133, 9923-9931 (2011).
Hemeon I., Gutierrez, J.A., Ho, M.C. and Schramm, V.L. “Characterizing DNA Methyltransferaes With An Ultrasensitive Luciferase-Linked Continuous Assay.” Anal. Chem. 83, 4996-5004 (2011).
Zhang, Y. and Schramm, V.L. “Ground-State Destabilization in Orotate Phosphoribosyltransferases by Binding Isotope Effects.” Biochemistry 50, 4813-4818 (2011).
Silva, R.G., Hirsch, J.S., Ghanem, M., Murkin, A.S. and Schramm, V.L. “Arsenate and phosphate as nucleophiles at the transition states of human purine nucleoside phosphorylase.” Biochemistry 50, 2701-2709 (2011).
Cassera, M.B., Ho, M.C., Merino, E.F., Burgos, E.S., Rinaldo-Matthis, A., Almo, S.C. and Schramm, V.L. “A High-Affinity Adenosine Kinase from Anopheles gambiae.” Biochemistry 50, 1885-1893 (2011).
Schwartz, P.A., Vetticatt, M.J. and Schramm, V.L. “Transition state analysis of the arsenolytic depyrimidination of thymidine by human thymidine phosphorylase.” Biochemistry 50, 1412-1420 (2011).
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Albert Einstein College of Medicine
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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.