![Vern L. Schramm](https://assets.montefioreeinstein.org/profiles/images/7856-vern-schramm.jpg)
Vern L. Schramm, Ph.D.
- Professor, Department of Biochemistry
- Ruth Merns Chair in Biochemistry
Area of research
- Enzymatic transition states are solved by isotope effects and quantum chemistry. This knowledge permits drug design for cancers, antibiotics and other disorders. Protein dynamics in catalysis is a second focus.
Phone
Location
- Albert Einstein College of Medicine Jack and Pearl Resnick Campus 1300 Morris Park Avenue Golding Building 301 Bronx, NY 10461
Research Profiles
Professional Interests
Overview
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
Harijan, R.K., Zoi, I., Antoniou, D., Schwartz, S.D., Schramm, V.L. “Inverse enzyme isotope effects in human purine nucleoside phosphorylase with heavy asparagine labels”. Proc Natl Acad Sci U S A. 115, E6209-E6216 (2018). PMC29915028
Schramm, V.L., Schwartz, S.D. “Promoting Vibrations and the Function of Enzymes. Emerging Theoretical and Experimental Convergence.” Biochemistry 57, 3299-3308 (2018). PMC6008225
Ducati, R.G., Namanja-Magliano, H.A., Harijan, R.K., Fajardo, J.E., Fiser, A., Daily, J.P., Schramm, V.L. “Genetic resistance to purine nucleoside phosphorylase inhibition in Plasmodium falciparum”. Proc Natl Acad Sci U S A. 115, 2114-2119 (2018). PMC5834662
Harris, L.D., Harijan, R.K., Ducati, R.G., Evans, G.B., Hirsch, B.M., Schramm, V.L. “Synthesis of bis-Phosphate Iminoaltritol Enantiomers and Structural Characterization with Adenine Phosphoribosyltransferase.” ACS Chem Biol. 13, 152-160 (2018). PMID29178779
Evans, G.B., Tyler, P.C., Schramm, V.L. “Immucillins in Infectious Diseases.” ACS Infect Dis. 4, 107-117 (2018). PMC6034505
Ducati RG, Firestone RS, Schramm VL. “Kinetic Isotope Effects and Transition State Structure for Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase from Plasmodium falciparum.” Biochemistry 56, 6368-6376 (2017). PMC5926801
Stratton, C.F., Poulin, M.B., Schramm, V.L. “Binding Isotope Effects for Interrogating Enzyme-Substrate Interactions.” Methods Enzymol 596, 1-21 (2017). PMID28911767
Firestone, R.S., Schramm, V.L. “The Transition-State Structure for Human MAT2A from Isotope Effects.” J. Am. Chem. Soc. 139, 13754-13760 (2017). PMC5674783
Moggré, G.J., Poulin, M.B., Tyler, P.C., Schramm, V.L., Parker, E.J. “Transition State Analysis of Adenosine Triphosphate Phosphoribosyltransferase.” ACS Chem Biol. 12, 2662-2670 (2017). PMID28872824
Namanja-Magliano HA, Evans GB, Harijan RK, Tyler PC, Schramm VL. “Transition State Analogue Inhibitors of 5'-Deoxyadenosine/5'-Methylthioadenosine Nucleosidase from Mycobacterium tuberculosis.” Biochemistry 56, 5090-5098 (2017). PMC6019266
Gebre, S.T., Cameron, S.A., Li, L., Babu, Y.S., Schramm, V.L. “Intracellular rebinding of transition-state analogues provides extended in vivo inhibition lifetimes on human purine nucleoside phosphorylase. J. Biol. Chem. 292, 15907-15915 (2017). PMC5612120
Harijan, R.K., Zoi, I., Antoniou, D., Schwartz, S.D. and Schramm, V.L. “Catalytic-site design for inverse heavy-enzyme isotope effects in human purine nucleoside phosphorylase.” Proc. Natl. Acad. Sci. 114, 6456-6461 (2017). PMC5488955
Firestone, R.S., Cameron, S.A., Karp, J.M., Arcus, V.L. and Schramm, V.L. “Heat Capacity Changes for Transition-State Analogue Binding and Catalysis with Human 5’-Methylthioadenosine.” ACS Chem Biol 12, 464-473 (2017). PMC5462123
Stratton, C.F., Poulin, M.B., Du, Q. and Schramm, V.L. “Kinetic Isotope Effects and Transition state Strucutre for Human Phenylethanolamine N-Methyltransferase.” ACS Chem Biol 12, 342-346 (2017) PMC5553282