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Structurally, PON1 is a six-bladed \u03b2-propeller with a flexible loop (residues 70\u201381) covering the active site. This loop contains a functionally critical Tyr at position 71. We have performed detailed experimental and computational analyses of the role of selected Y71 variants in the active site stability and catalytic activity in order to probe the role of Y71 in PON1\u2019s lactonase and organophosphatase activities. We demonstrate that the impact of Y71 substitutions on PON1\u2019s lactonase activity is minimal, whereas the kcat for the paraoxonase activity is negatively perturbed by up to 100-fold, suggesting greater mutational robustness of the native activity. Additionally, while these substitutions modulate PON1\u2019s active site shape, volume, and loop flexibility, their largest effect is in altering the solvent accessibility of the active site by expanding the active site volume, allowing additional water molecules to enter. This effect is markedly more pronounced in the organophosphatase activity than the lactonase activity. Finally, a detailed comparison of PON1 to other organophosphatases demonstrates that either a similar \u201cgating loop\u201d or a highly buried solvent-excluding active site is a common feature of these enzymes. We therefore posit that modulating the active site hydrophobicity is a key element in facilitating the evolution of organophosphatase activity. This provides a concrete feature that can be utilized in the rational design of next-generation organophosphate hydrolases that are capable of selecting a specific reaction from a pool of viable substrates.<\/jats:p>","DOI":"10.1021\/jacs.6b10801","type":"journal-article","created":{"date-parts":[[2016,12,27]],"date-time":"2016-12-27T12:48:24Z","timestamp":1482842904000},"page":"1155-1167","source":"Crossref","is-referenced-by-count":82,"title":["Active\nSite Hydrophobicity and the Convergent Evolution\nof Paraoxonase Activity in Structurally Divergent Enzymes: The Case\nof Serum Paraoxonase 1"],"prefix":"10.1021","volume":"139","author":[{"given":"David","family":"Blaha-Nelson","sequence":"first","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, S-751 24"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis M.","family":"Kru\u0308ger","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, S-751 24"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaudia","family":"Szeler","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, S-751 24"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moshe","family":"Ben-David","sequence":"additional","affiliation":[{"name":"Weizmann Institute of Science , , ,","place":["Rehovot, Israel, 76100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3190-1173","authenticated-orcid":true,"given":"Shina Caroline Lynn","family":"Kamerlin","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, S-751 24"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2016,12,27]]},"reference":[{"key":"2026090304583200000_cit1","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1146\/annurev-biochem-030409-143718","volume":"79","author":"Khersonsky","year":"2010","journal-title":"Annu. 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