<p><strong>Enzymes </strong>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. For example: Human genetic deficiency of purine nucleoside phosphorylase causes a specific T-cell insufficiency. Our inhibitors of this enzyme are powerful anti T-cell agents. One of these (Immucillin-H, aka Forodesine) has been approved for use against peripheral T-cell lymphoma in Japan. Phase II clinical trials have been completed for gout using our second-generation inhibitor. Other inhibitors in the same family show antiviral properties and have been in clinical trials against Covid-19 and the Yellow Fever virus.</p>
<h6>Ongoing projects:</h6>
<p>Drug design by transition state analysis includes SAMHD1, a rare triphosphohydrolase activity. SAMHD1 inhibition has potential to enhance T-cell anticancer outcomes. The privileged enzyme-reactant geometry at the transition state will be enlisted as an inhibitor design element. Drug candidates designed to stabilize the SAMHD1 protein geometry at the transition state will be powerful inhibitors. Chemical screening with fragment libraries, some with covalent potential, coupled by click chemistries, will be used in combinatorial inhibitor design as an alternative approach. SAMHD1 inhibitors, used in combination with Forodesine, are expected to provide improved therapeutic approaches to the spectrum of T-cell malignancies.</p>
<p>Methylthioadenosine phosphorylase (MTAP) uniquely recycles methylthioadenosine (MTA) in humans. The 15% of MTAP-deleted (<em>MTAP</em>-/-) tumors are uniquely sensitive to inhibition of <em>MAT2A </em>or <em>PRMT5</em>, a synthetic-lethal approach to cancer therapy. Over a dozen clinical trials with MAT2A and/or PRMT5 inhibitors target 15% of human tumors that are <em>MTAP</em>-/-. However, 85% of patients have <em>MTAP</em>+/+ cancers. Pharmacological MTAP inhibition can convert <em>MTAP</em>+/+ tumors to the MTAP-/- phenotype. We developed MTAP transition state analog inhibitors with picomolar efficacy and their prodrugs to optimize pharmacodynamics. Our MTAP inhibitors are highly specific, non-toxic agents that recapitulate the MTAP-/- phenotype in otherwise isogenic cells. MTAP inhibitors have potential to augment MAT2A and/or PRMT5 inhibitors to all cancer patients.</p>
<p>S-Adenosylmethionine recycling and methyl transfer reactions are central to the epigenetic control pathways regulating growth, development, gene expression and cancer. PRMT5 and PRMT1 are targets for transition state analysis.</p>
<p>Resistance-proof antibacterials: Transition state analogues of <em>Helicobacter pylori</em> MTAN have potential as agents for treating stomach ulcers and for preventing stomach cancer, without disrupting the human gut microbiome. Steps toward implementation include animal efficacy studies, toxicity testing, resistance potential and gut microbiome analysis. <em>Clostridioides difficile (C.diff.)</em> infections are an urgent threat (CDC Antibiotic Resistance Threats Report) because <em>C.diff.</em> toxins kill colon cells. We are discovering and developing of transition state analogs to neutralize the toxins and prevent colon tissue damage.</p>
<p>Emerging cancer targets (DNPH1, UPP1 and ART1) exhibit chemistries optimal for design of transition state analogs. Intrinsic kinetic isotope effects and computational chemistry will provide bond geometry and electrostatic potential maps to design tight-binding transition state analogs. Our long-time chemistry synthetic team in New Zealand provides chemical synthesis of potential inhibitors for their cognate targets.</p>
<p>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.</p>

<p class="MsoNormal" style="line-height: 15.6pt;"><span style="font-size: 9.0pt;">Dr. Schramm is a member of the National Academy of Sciences and associate editor of the<span>&nbsp;</span><em>Journal of the American Chemical Society</em>.&nbsp; His pioneering work in biochemistry has resulted in powerful new strategies for treating cancer, antibiotic resistance and autoimmune diseases.</span></p>
<p class="MsoNormal" style="line-height: 15.6pt;"><span style="font-size: 9.0pt;">Dr. Schramm has created molecules that block key enzymes from functioning. These powerful inhibitors have shown promise in muzzling cancers and bacteria that depend on those key enzymes to grow and spread. Two of those inhibitors have entered clinical trials: one for treating leukemia that does not respond to other therapies and another for possible treatment for autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, and for preventing tissue transplant rejection in organ transplantation.</span></p>
<p class="MsoNormal" style="line-height: 15.6pt;"><span style="font-size: 9.0pt;">Dr. Schramm&rsquo;s other recent work includes developing a simple and highly sensitive test to detect ricin, the potent toxin with potential use as a bioterrorism agent. He is also using his enzyme-inhibiting strategy to create novel antibiotics that do not provoke bacterial resistance.</span></p>

<ol>
<li><a href="https://pubmed.ncbi.nlm.nih.gov/40375736/&quot; target="_blank">The anti-cancer transition-state inhibitor MTDIA inhibits human MTAP, inducing autophagy in humanized yeast. </a>Coorey NV, Tollestrup I, Bircham PW, Sheridan JP, Evans GB, Schramm VL, Atkinson PH, Munkacsi AB. Dis Model Mech. 2025 Jun 1;18(6):dmm052173. doi: 10.1242/dmm.052173. Epub <strong>2025</strong> Jun 30. PMID: 40375736 Free PMC article. </li>
<li><a href="https://pubmed.ncbi.nlm.nih.gov/40273333/&quot; target="_blank">Kinetic Mechanism of the Emergent Anticancer Target, Human ADP-ribosyltransferase 1. </a>Groom DP, Lopacinski A, Garforth SJ, Schramm VL<strong>.</strong> Biochemistry. <strong>2025</strong> May 6;64(9):2077-2088. doi: 10.1021/acs.biochem.5c00105. Epub 2025 Apr 24. PMID: 40273333 </li>
<li><a href="https://pubmed.ncbi.nlm.nih.gov/40014869/&quot; target="_blank">Transition State Analysis of SAMHD1 from Primary 18O, 33P, and Solvent Kinetic Isotope Effects. </a>Ghosh AK, Groom DP, Schramm VL<strong>.</strong> J Am Chem Soc. <strong>2025</strong> Mar 12;147(10):8852-8863. doi: 10.1021/jacs.5c00521. Epub 2025 Feb 27. PMID: 40014869 </li>
<li><a href="https://pubmed.ncbi.nlm.nih.gov/39818772/&quot; target="_blank">Transition State Analogs of Human DNPH1 Reveal Two Electrophile Migration Mechanisms. </a>Wagner AG, Lang TBD, Ledingham ET, Ghosh A, Brooks D, Eskandari R, Suthagar K, Almo SC, Lamiable-Oulaidi F, Tyler PC, Schramm VL<strong>.</strong> J Med Chem. <strong>2025</strong> Feb 13;68(3):3653-3672. doi: 10.1021/acs.jmedchem.4c02778. Epub 2025 Jan 16. PMID: 39818772 </li>
<li><a href="https://pubmed.ncbi.nlm.nih.gov/38334357/&quot; target="_blank">Isofagomine Inhibits Multiple TcdB Variants and Protects Mice from <em>Clostridioides difficile</em>-Induced Mortality. </a>Paparella AS, Brew I, Hong HA, Ferriera W, Cutting S, Lamiable-Oulaidi F, Popadynec M, Tyler PC, Schramm VL. ACS Infect Dis. <strong>2024</strong> Mar 8;10(3):928-937. doi: 10.1021/acsinfecdis.3c00507. Epub 2024 Feb 9. PMID: 38334357 </li>
<li><a href="https://pubmed.ncbi.nlm.nih.gov/38000655/&quot; target="_blank">Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition. </a>Bedard GT, Gilaj N, Peregrina K, Brew I, Tosti E, Shaffer K, Tyler PC, Edelmann W, Augenlicht LH, Schramm VL. J Biol Chem. <strong>2024 </strong>Jan;300(1):105492. doi: 10.1016/j.jbc.2023.105492. Epub 2023 Nov 23. PMID: 38000655 Free PMC article. </li>
<li><a href="https://pubmed.ncbi.nlm.nih.gov/37812583/&quot; target="_blank">Phosphate Binding in PNP Alters Transition-State Analogue Affinity and Subunit Cooperativity. </a>Minnow YVT, Schramm VL, Almo SC, Ghosh A. Biochemistry. 2023 Nov 7;62(21):3116-3125. doi: 10.1021/acs.biochem.3c00264. Epub <strong>2023</strong> Oct 9. PMID: 37812583 </li>
<li><a href="https://pubmed.ncbi.nlm.nih.gov/37788145/&quot; target="_blank">Decreased Transition-State Analogue Affinity in Isotopically Heavy MTAN with Increased Catalysis. </a>Brown M, Schramm VL. Biochemistry. <strong>2023</strong> Oct 17;62(20):2928-2933. doi: 10.1021/acs.biochem.3c00434. Epub 2023 Oct 3. PMID: 37788145 Free PMC article. </li>
<li><a href="https://pubmed.ncbi.nlm.nih.gov/37467463/&quot; target="_blank">Cell-Effective Transition-State Analogue of Phenylethanolamine <em>N</em>-Methyltransferase. </a>Mahmoodi N, Minnow YVT, Harijan RK, Bedard GT, Schramm VL. Biochemistry. <strong>2023</strong> Aug 1;62(15):2257-2268. doi: 10.1021/acs.biochem.3c00103. Epub <strong>2023</strong> Jul 19. PMID: 37467463 Free PMC article. </li>
</ol>

<p style="text-align: justify;">Our laboratory is interested in the development and application of strategies and technologies that enable the high-throughput/large-scale exploration of biological function. These efforts typically take advantage of automation and robotics to achieve the efficiencies and speed required to realize the desired rates of data generation and discovery. This cutting-edge infrastructure has been applied to a number of important biomedical areas to achieve new understanding and new therapeutic opportunities.</p>
<p style="text-align: justify;">Our work on the large-scale annotation of enzyme function is helping to define the metabolic repertoire that exists in Nature and is providing new insights into the contributions of the gut microbiome to human health, the realization of new chemical processes for industry, and expanding our understanding of critical environmental issues, including global nutrient cycles and the evolution of complex microbial communities. Our high-resolution structural and functional analysis of the mammalian immune system has resulted in unprecedented understanding of the molecular mechanisms that control immunity and are guiding the development of novel strategies and reagents (e.g., biologics) for the treatment of infectious diseases, autoimmune diseases and cancers.</p>

<p>Dr. Steven Almo is an internationally recognized leader in the field of structural biology. His lab uses high-resolution X-ray crystallography to determine the shapes and structures of proteins to better understand their function and help develop new drugs. The goal is to make immunotherapy treatments that more precisely and effectively treat a variety of cancers while causing far fewer side effects than current therapies.&nbsp;</p>
<p>Dr. Almo&rsquo;s large-scale work on enzyme function has provided insights on both the gut microbiome&rsquo;s contributions to human health and new chemical processes for industry. His research also has expanded the understanding of critical environmental issues, including global nutrient cycles and the evolution of complex microbial communities.</p>
<p>He is a member of the American Society for Cell Biology and the American Crystallographic Association. He has served on NIH study sections and review panels, on the American Cancer Society&rsquo;s Peer Review Committee on Cancer Drug Development, and on the editorial board of the <em>International Archives of Allergy and Immunology</em>.&nbsp;</p>

<p style="text-align: justify;">Quayle SN, Girgis N, Thapa DR, Merazga Z, Kemp MM, Histed A, Zhao F, Moreta M, Ruthardt P, Hulot S, Nelson A, Kraemer LD, Beal DR, Witt L, Ryabin J, Soriano J, Haydock M, Spaulding E, Ross JF, Kiener PA, Almo S, Chaparro R, Seidel R, Suri A, Cemerski S, Pienta KJ, Simcox ME. (2020) "CUE-101, a Novel E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen-Specific T-Cell Activation for the Treatment of HPV16-Driven Malignancies." <em>Clin Cancer Res.</em> <strong>26(8)</strong>, 1953-1964. PMID:31964784.</p>
<p style="text-align: justify;">Funabashi M, Grove TL, Wang M, Varma Y, McFadden ME, Brown LC, Guo C, Higginbottom S, Almo SC, Fischbach MA. (2020) "A metabolic pathway for bile acid dehydroxylation by the gut microbiome." <em>Nature</em>&nbsp;<strong>582(7813)</strong>, 566-570. PMC7319900.</p>
<p style="text-align: justify;">Liu W, Garrett SC, Fedorov EV, Ramagopal UA, Garforth SJ, Bonanno JB, Almo SC. (2019) "Structural Basis of CD160:HVEM Recognition." <em>Structure</em> <strong>27(8)</strong>, 1286-1295.e4. PMC7477951.</p>
<p style="text-align: justify;">Gizzi AS, Grove TL, Arnold JJ, Jose J, Jangra RK, Garforth SJ, Du Q, Cahill SM, Dulyaninova NG, Love JD, Chandran K, Bresnick AR, Cameron CE, Almo SC. &nbsp;(2018) &ldquo;A naturally occurring antiviral ribonucleotide encoded by the human genome.&rdquo; <em>Nature </em><strong>558</strong>, 610-614.&nbsp; PMC6026066.</p>
<p style="text-align: justify;">Ghosh A, Ramagopal UA, Bonanno JB, Brenowitz M, Almo SC. (2018) &ldquo;Structures of the L27 Domain of Disc Large Homologue 1 Protein Illustrate a Self-Assembly Module.&rdquo; <em>Biochemistry</em> <strong>57, </strong>1293-1305. PMC6568269.</p>
<p style="text-align: justify;">Ramagopal UA, Liu W, Garrett-Thomson SC, Bonanno JB, Yan Q, Srinivasan M, Wong SC, Bell A, Mankikar S, Rangan VS, Deshpande S, Korman AJ, Almo SC. (2017) &ldquo;Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab.&rdquo; &nbsp;<em>Proc Natl Acad Sci U S A</em>. <strong>114</strong>, E4223-E4232. &nbsp;PMC5448203.</p>
<p style="text-align: justify;">L&aacute;z&aacute;r-Moln&aacute;r E, Scandiuzzi L, Basu I, Quinn T, Sylvestre E, Palmieri E, Ramagopal UA, Nathenson SG, Guha C, Almo SC. (2017) &ldquo;Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy.&rdquo; &nbsp;<em>EBioMedicine.</em> <strong>17</strong>, 30-44. PMC5360572.&nbsp;</p>
<p style="text-align: justify;">Samanta D, Guo H, Rubinstein R, Ramagopal UA, Almo SC. (2017) &ldquo;Structural, mutational and biophysical studies reveal a canonical mode of molecular recognition between immune receptor TIGIT and nectin-2.&rdquo; <em>Mol Immunol</em>. <strong>81</strong>, 51-159. PMC5220579.</p>
<p style="text-align: justify;">Liu W, Ramagopal U, Cheng H, Bonanno JB, Toro R, Bhosle R, Zhan C, Almo SC. (2016) &ldquo;Crystal Structure of the Complex of Human FasL and Its Decoy Receptor DcR3.&rdquo; <em>Structure</em> <strong>24</strong>, 2016-2023. PMID:27806260.</p>
<p style="text-align: justify;">Yadava U, Vetting MW, Al Obaidi N, Carter MS, Gerlt JA, Almo SC. (2016) &ldquo;Structure of an ABC transporter solute-binding protein specific for the amino sugars glucosamine and galactosamine.&rdquo; <em>Acta Crystallogr F Struct Biol Commun.</em> <strong>72</strong>, 467-472. PMC4909247.</p>
<p style="text-align: justify;">Liu W, Vigdorovich V, Zhan C, Patskovsky Y, Bonanno JB, Nathenson SG, Almo SC. (2015) &ldquo;Increased Heterologous Protein Expression in Drosophila S2 Cells for Massive Production of Immune Ligands/Receptors and Structural Analysis of Human HVEM.&rdquo; <em>Mol Biotechnol.</em><strong> 57</strong>, 914-922. PMID:26202493.</p>
<p style="text-align: justify;">Kim J, Xiao H, Koh J, Wang Y, Bonanno JB, Thomas K, Babbitt PC, Brown S, Lee YS, Almo SC. (2015) &ldquo;Determinants of the CmoB carboxymethyl transferase utilized for selective tRNA wobble modification.&rdquo; <em>Nucleic Acids Res</em>. <strong>43</strong>, 4602-4613.&nbsp; PMC4482062.</p>
<p style="text-align: justify;">&nbsp;Vetting MW, Al-Obaidi N, Zhao S, San Francisco B, Kim J, Wichelecki DJ, Bouvier JT, Solbiati JO, Vu H, Zhang X, Rodionov DA, Love JD, Hillerich BS, Seidel RD, Quinn RJ, Osterman AL, Cronan JE, Jacobson MP, Gerlt JA, Almo SC. (2015) &ldquo;Experimental strategies for functional annotation and metabolism discovery: targeted screening of solute binding proteins and unbiased panning of metabolomes.&rdquo; <em>Biochemistry </em><strong>54</strong>, 909-931. PMC4310620.</p>
<p style="text-align: justify;">Samanta D, Almo SC. (2015) &ldquo;Nectin family of cell-adhesion molecules: structural and molecular aspects of function and specificity.&rdquo; <em>Cell Mol Life Sci</em>. <strong>72</strong>, 645-658. PMID: 25326769.</p>
<p style="text-align: justify;">Liu W, Zhan C, Cheng H, Kumar PR, Bonanno JB, Nathenson SG, Almo SC. (2014) &ldquo;Mechanistic basis for functional promiscuity in the TNF and TNF receptor superfamilies: structure of the LIGHT:DcR3 assembly.&rdquo; <em>Structure</em> <strong>22</strong>, 1252-1262.&nbsp; PMC4163024.</p>
<p style="text-align: justify;">Bandaranayake AD, Almo SC. (2014) &ldquo;Recent advances in mammalian protein production.&rdquo; <em>FEBS Lett.</em> <strong>588</strong>, 253-260. PMC3924552.</p>
<p style="text-align: justify;">Kim J, Xiao H, Bonanno JB, Kalyanaraman C, Brown S, Tang X, Al-Obaidi NF, Patskovsky Y, Babbitt PC, Jacobson MP, Lee YS, Almo SC. (2013) &ldquo;Structure-guided discovery of the metabolite carboxy-SAM that modulates tRNA function.&rdquo; <em>Nature </em><strong>498</strong>, 123-126. &nbsp;PMC3895326.</p>
<p style="text-align: justify;">Kim J, Almo SC. (2013) &ldquo;Structural basis for hypermodification of the wobble uridine in tRNA by bifunctional enzyme MnmC.&rdquo; <em>BMC Struct Biol. </em><strong>13:</strong>5. PMC3648344.</p>
<p style="text-align: justify;">Vigdorovich V, Ramagopal UA, L&aacute;z&aacute;r-Moln&aacute;r E, Sylvestre E, Lee JS, Hofmeyer KA, Zang X, Nathenson SG, Almo SC. (2013) &ldquo;Structure and T cell inhibition properties of B7 family member, B7-H3.&rdquo; <em>Structure </em><strong>21</strong>, 707-717. PMC3998375.</p>
<p style="text-align: justify;">Soniat M, Sampathkumar P, Collett G, Gizzi AS, Banu RN, Bhosle RC, Chamala S, Chowdhury S, Fiser A, Glenn AS, Hammonds J, Hillerich B, Khafizov K, Love JD, Matikainen B, Seidel RD, Toro R, Rajesh Kumar P, Bonanno JB, Chook YM, Almo SC. (2013) &ldquo;Crystal structure of human Karyopherin &beta;2 bound to the PY-NLS of Saccharomyces cerevisiae Nab2.&rdquo; <em>J Struct Funct Genomics </em><strong>14</strong>, 31-35. PMC3681870.</p>
<p style="text-align: justify;">Sampathkumar P, Kim SJ, Upla P, Rice WJ, Phillips J, Timney BL, Pieper U, Bonanno JB, Fernandez-Martinez J, Hakhverdyan Z, Ketaren NE, Matsui T, Weiss TM, Stokes DL, Sauder JM, Burley SK, Sali A, Rout MP, Almo SC. (2013) &ldquo;Structure, dynamics, evolution, and function of a major scaffold component in the nuclear pore complex.&rdquo; <em>Structure </em><strong>21</strong>, 560-571. PMC3755625.</p>