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HTL has been highly linked to HHcy\u2010associated cardiovascular and neurodegenerative diseases. The protective role of HTL hydrolases against HTL\u2010associated vascular toxicity and neurotoxicity have been reported. Although several endogeneous enzymes capable of hydrolyzing HTL have been identified, the primary enzyme responsible for its metabolism remains unclear. In this study, three human carboxylesterases were screened to explore new HTL hydrolase and human carboxylesterase 1 (hCES1) demonstrates the highest catalytic activity against HTL. Given the abundance of hCES1 in the liver and the clinical significance of its single\u2010nucleotide polymorphisms (SNPs), six common hCES1 nonsynonymous coding SNP (nsSNPs) variants were examined and characterized for their kinetic parameters. Variants E220G and G143E displayed 7.3\u2010fold and 13.2\u2010fold lower catalytic activities than its wild\u2010type counterpart. In addition, the detailed catalytic mechanism of hCES1 for HTL hydrolysis was computational investigated and elucidated by Quantum mechanics\/molecular mechanics (QM\/MM) molecular dynamics (MD) method. The function of residues E220 and G143 in sustaining its hydrolytic activity of hCES1 was analyzed, and the calculated energy difference aligns well with experimental\u2010derived results, supporting the validity of our computational insights. These findings provide insights into the potential protective role of hCES1 against HTL\u2010associated toxicity, and warrant future studies on the possible association between specific genetic variants of hCES1 with impaired catalytic function and clinical susceptibility of HTL\u2010associated cardiovascular and neurodegenerative diseases.<\/jats:p>","DOI":"10.1002\/pro.5098","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T12:49:22Z","timestamp":1720529362000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of a novel homocysteine thiolactone hydrolase and the catalytic activity of its natural variants"],"prefix":"10.1002","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8402-5339","authenticated-orcid":false,"given":"Shurong","family":"Hou","sequence":"first","affiliation":[{"name":"School of Pharmacy, Hangzhou Normal University  Hangzhou Zhejiang 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