{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:29:50Z","timestamp":1790713790485,"version":"4.1.0"},"reference-count":55,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T00:00:00Z","timestamp":1648080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["ESF\/14-BM-A55-0046\/16"],"award-info":[{"award-number":["ESF\/14-BM-A55-0046\/16"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ambroxol (ABX) is a mucolytic agent used for the treatment of respiratory diseases. Bioactivity has been demonstrated as an enhancement effect on lysosomal acid \u03b2-glucosidase (\u03b2-Glu) activity in Gaucher disease (GD). The positive effects observed have been attributed to a mechanism of action similar to pharmacological chaperones (PCs), but an exact mechanistic description is still pending. The current study uses cell culture and in vitro assays to study the effects of ABX on \u03b2-Glu activity, processing, and stability upon ligand binding. Structural analogues bromohexine, 4-hydroxybromohexine, and norbromohexine were screened for chaperone efficacy, and in silico docking was performed. The sugar mimetic isofagomine (IFG) strongly inhibits \u03b2-Glu, while ABX exerts its inhibitory effect in the micromolar range. In GD patient fibroblasts, IFG and ABX increase mutant \u03b2-Glu activity to identical levels. However, the characteristics of the banding patterns of Endoglycosidase-H (Endo-H)-digested enzyme and a substantially lower half-life of ABX-treated \u03b2-Glu suggest different intracellular processing. In line with this observation, IFG efficiently stabilizes recombinant \u03b2-Glu against thermal denaturation in vitro, whereas ABX exerts no significant effect. Additional \u03b2-Glu enzyme activity testing using Bromohexine (BHX) and two related structures unexpectedly revealed that ABX alone can refunctionalize \u03b2-Glu in cellula. Taken together, our data indicate that ABX has little in vitro ability to act as PC, so the mode of action requires further clarification.<\/jats:p>","DOI":"10.3390\/ijms23073536","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T15:31:21Z","timestamp":1648222281000},"page":"3536","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Mechanistic Insight into the Mode of Action of Acid \u03b2-Glucosidase Enhancer Ambroxol"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9630-1999","authenticated-orcid":false,"given":"Supansa","family":"Pantoom","sequence":"first","affiliation":[{"name":"Translational Neurodegeneration Section \u201cAlbrecht-Kossel\u201d, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa","family":"Hules","sequence":"additional","affiliation":[{"name":"Translational Neurodegeneration Section \u201cAlbrecht-Kossel\u201d, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Sch\u00f6ll","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Catalysis, University of Rostock, 18059 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andranik","family":"Petrosyan","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Catalysis, University of Rostock, 18059 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3136-2138","authenticated-orcid":false,"given":"Maria","family":"Monticelli","sequence":"additional","affiliation":[{"name":"Department of Biology, University Federico II, 80126 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jola","family":"Pospech","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Catalysis, University of Rostock, 18059 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6147-6553","authenticated-orcid":false,"given":"Maria Vittoria","family":"Cubellis","sequence":"additional","affiliation":[{"name":"Department of Biology, University Federico II, 80126 Napoli, Italy"},{"name":"Istituto di Chimica Biomolecolare\u2014CNR, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7364-7791","authenticated-orcid":false,"given":"Andreas","family":"Hermann","sequence":"additional","affiliation":[{"name":"Translational Neurodegeneration Section \u201cAlbrecht-Kossel\u201d, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany"},{"name":"Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE) Rostock\/Greifswald, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Lukas","sequence":"additional","affiliation":[{"name":"Translational Neurodegeneration Section \u201cAlbrecht-Kossel\u201d, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany"},{"name":"Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1007\/s00216-011-4671-6","article-title":"Inhibitor screening of pharmacological chaperones for lysosomal \u03b2-glucocerebrosidase by capillary electrophoresis","volume":"399","author":"Shanmuganathan","year":"2011","journal-title":"Anal. 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