Professor, 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 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.
Yuan, H., Du, Q., Sturm, M.B., and Schramm, V.L. “Soapwort Saporin L3 Expression in Yeast, Mutagenesis and RNA Substrate Specificity.” Biochemistry (2015) Epub ahead of print. PMID26091305
Freitas, E.O., Nico, D., Guan, R., Meyer-Fernandes, J.R., Clinch, K., Evans, G.B., Tyler, P.C., Schramm, V.L. and Palatnik-de-Sousa, C.B. “Immucillins Impair Leishmania (L.) infantum chagasi and Leishmania (L.) amazonensis Multiplication In Vitro.” PLoS One 10 (2015). PMCID: PMC4409337
Poulin, M.B., Du, Q. and Schramm, V.L. “Chemoenzymatic Synthesis of (36)S Isotopologues of Methionine and S-Adenosyl-l-methionine.” J. Org. Chem. 80, 5344-5347 (2015). PMID25884979
Schramm, V.L. “Transition states and transition state analogue interactions with enzymes.” Acc. Chem. Res. 48, 1032-1039 (2015). PMCID: PMC4482137
Thomas, K., Cameron, S.A., Almo, S.C., Burgos, E.S., Gulab, S.A. and Schramm, V.L. “Active site and remote contributions to catalysis in methylthioadenosine nucleosidases.” Biochemsitry 54, 2520-2529 (2015). PMCID: PMC25806409
Zoi, I., Motley, M.W., Antoniou, D. Schramm, V.L. and Schwartz, S.D. “Enzyme Homologues Have Distinct Reaction Paths Through Their Transition States” J Phys Chem B. 119, 3662-3668 (2015). PMCID: PMC4385586
Barta, M.L., Thomas, K., Yuan, H., Lovell, S., Battaile, K.P., Schramm, V.L. and Hefty, P.S. “Structural and Biochemical Characterization of Chlamydia trachomatis Hypothetical Protein CT263 Supports that Menaquinone Synthesis Occurs through the Futalosine Pathway” J Biol Chem. 289, 32214-32229 (2014) PMCID: PMC4231696
Hirsch, B.M., Burgos, E.S. and Schramm, V.L. “Transition-State Analysis of 2-O-Acetyl-ADP-Ribose Hydrolysis by Human Macrodomain 1” ACS Chem Biol. 9, 2255-2262 (2014) PMCID: PMC4201351
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 Soc. 136, 8333-8341 (2014). PMCID: PMC4063187
Wang, S., Thomas, K., and Schramm, V.L. “Catalytic Site Cooperativity in Dimeric Methylthioadenosine Nucleosidase.” Biochemistry 53, 1527-1535 (2014). PMCID: PMC3977580
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). PMCID: PMC4060479
Zhang, Y., Evans, G.B., Clinch, K., Crump, D.R., Harris, L.D., Frohlich, R.F., Tyler, P.C., Hazleton, K.Z., Cassera, M.B. and Schramm, V.L. “Transition State Analogues of Plasmodium falciparum and Human Orotate Phosphoribosylthransferases. J. Biol. Chem. 288, 34746-34752 (2013). PMCID: PMC3843086
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 PMCID: PMC3870587.
Vetticatt, M.J., Itin, B., Evans, G.B. and Schramm, V.L. “Distortional Binding of Transition State Analogues to Human PNP probed by MAS Solid State NMR.” Proc. Nat. Acad. Sci. USA 110, 15991-15996 (2013). PMCID: PMC3791767
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). PMCID: PMC3786605
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 PMID: 23859211 (2013). PMCID: PMC3819805
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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.