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U.S.A."],"published-print":{"date-parts":[[2026,6,2]]},"abstract":"<jats:p>\n                    The ADP-ribosylation of proteins is a versatile, reversible, posttranslational modification involved in the dynamic regulation of numerous cellular processes. Human ADP-ribosyltransferase 1 (\n                    <jats:italic toggle=\"yes\">hs<\/jats:italic>\n                    ART1, EC: 2.4.2.31) is a membrane-associated, GPI-anchored, mono-ADP-ribosyltransferase selective for mono-ADP ribosylation (MARylation) of L-arginine residues. Dysregulation of\n                    <jats:italic toggle=\"yes\">hs<\/jats:italic>\n                    ART1 activity has been shown to permit immune cell evasion in non\u2013small cell lung cancer (NSCLC) through elevated MARylation at Arg125 of the purinergic type 2 receptor (P2X7) in P2X7-positive T cells, resulting in NAD\n                    <jats:sup>+<\/jats:sup>\n                    -induced cell death (NICD) of tumor-penetrating immune cells. With\n                    <jats:italic toggle=\"yes\">hs<\/jats:italic>\n                    ART1 emerging as an immunotherapy target in select cancers, there is a need to develop small-molecule inhibitors. The transition state (TS) for the MARylation of P2X7 peptide was determined from kinetic isotope effect (KIE) measurements of\n                    <jats:sup>3<\/jats:sup>\n                    H-,\n                    <jats:sup>14<\/jats:sup>\n                    C-,\n                    <jats:sup>18<\/jats:sup>\n                    O-, and\n                    <jats:sup>15<\/jats:sup>\n                    N-labeled NAD\n                    <jats:sup>+<\/jats:sup>\n                    substrates. Quantum mechanical (QM) calculations of the reaction coordinate, mapped with experimental KIEs, identify a TS geometry consistent with a highly dissociative, asymmetric, concerted mechanism with minimal contributions from the leaving group nicotinamide (NAM) and minor contributions from the incoming L-arginine guanidinium. The absence of a normal deuterium solvent isotope effect identifies a positively charged guanidinium nucleophile, leading to a dication N-ribosyltransferase mechanism. Together with the unusual, normal\n                    <jats:sup>18<\/jats:sup>\n                    O\u2013O4\n                    <jats:sup>\u2032<\/jats:sup>\n                    KIE, we identified unique charge accumulation across the oxocarbenium at the TS caused by an increased bond order between the C1\n                    <jats:sup>\u2032<\/jats:sup>\n                    \u2013C2\n                    <jats:sup>\u2032<\/jats:sup>\n                    , and decreased bond order between the C4\n                    <jats:sup>\u2032<\/jats:sup>\n                    \u2013O4\n                    <jats:sup>\u2032<\/jats:sup>\n                    of the nicotinamide mononucleotide ribose. This is the first L-arginine-specific ADP-ribosylation TS to be characterized, a step toward the design of TS analogs.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2604770123","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T17:47:15Z","timestamp":1779904035000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Transition-state analysis of the arginine-specific human ADP-ribosyltransferase 1"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9353-1851","authenticated-orcid":false,"given":"Daniel P.","family":"Groom","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05cf8a891","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry","place":["Bronx"]},{"name":"Albert Einstein College of Medicine","place":["Bronx"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer T.","family":"Aguilan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05cf8a891","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology","place":["Bronx"]},{"name":"Albert Einstein College of Medicine","place":["Bronx"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Lopacinski","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05cf8a891","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry","place":["Bronx"]},{"name":"Albert Einstein College of Medicine","place":["Bronx"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott J.","family":"Garforth","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05cf8a891","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry","place":["Bronx"]},{"name":"Albert Einstein College of Medicine","place":["Bronx"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vern L.","family":"Schramm","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05cf8a891","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry","place":["Bronx"]},{"name":"Albert Einstein College of Medicine","place":["Bronx"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16142"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.06.013"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0711939105"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06429-2"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.030"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.17.5603"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2014.03.005"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2018.11.001"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","unstructured":"H. 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