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Severe hyperhomocysteinemia causes neurological deficits and worsens behavioral and biochemical traits associated with AD. Although Hcy is precluded from entering the Genetic Code by proofreading mechanisms of aminoacyl-tRNA synthetases, and thus is a non-protein amino acid, it can be attached to proteins via an N-homocysteinylation reaction mediated by Hcy-thiolactone. Because N-homocysteinylation is detrimental to a protein\u2019s function and biological integrity, Hcy-thiolactone-detoxifying enzymes\u2014PON1, BLMH, BPHL\u2014have evolved. This narrative review provides an account of the biological function of these enzymes and of the consequences of their impairments, leading to the phenotype characteristic of AD. Overall, accumulating evidence discussed in this review supports a hypothesis that Hcy-thiolactone contributes to neurodegeneration associated with a dysregulated Hcy metabolism.<\/jats:p>","DOI":"10.3390\/ijms25158095","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T06:11:36Z","timestamp":1721887896000},"page":"8095","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Homocysteine Thiolactone Detoxifying Enzymes and Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5845-4409","authenticated-orcid":false,"given":"Hieronim","family":"Jakubowski","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biotechnology, University of Life Sciences, 60-637 Pozna\u0144, Poland"},{"name":"Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers University, International Center for Public Health, Newark, NJ 07103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2021). 2021 Alzheimer\u2019s disease facts and figures. 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