Tetrahydrolipstatin: Degradation products produced by human carboxyl-ester lipase
✍ Scribed by Henri Stalder; Gottfried Oesterhelt; Bengt Borgström
- Publisher
- John Wiley and Sons
- Year
- 1992
- Tongue
- German
- Weight
- 746 KB
- Volume
- 75
- Category
- Article
- ISSN
- 0018-019X
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✦ Synopsis
The fate of tetrahydrolipstatin (1) incubated with human carboxyl-ester lipase (HCEL) was investigated. The primary metabolite was identified as 6-(N-formyl-~-leucyloxy)-P-hydroxy acid 2a with conserved configuration. It is formed by attack of the active-site serine of HCEL at the carbonyl C-atom of the /I-lactone ring of 1 followed by hydrolysis of the intermediate serine ester. Further products isolated were identified and a complete degradation scheme is proposed. 1. Introduction. -Tetrahydrolipstatin (THL = ( S ) -1 -{ [(2S,3S)-3-hexyl-4-oxooxetan-2-yl]methyl}dodecyl N-formyl-L-leucinate; US-adopted name: 'orlistat'; 1) is a specific inhibitor of triacylglycerol lipases, especially of pancreatic lipase, and at present is in phase I11 of clinical development as an antiobesity agent [l-31. It forms a covalent bond with the active-site serine of pancreatic lipase (PL) from pig and man [4] [5]. Other serine hydrolases such as gastric lipase and pancreatic carboxyl-ester lipase') (CEL) are also inhibited by 1, and CEL was shown to undergo temporary inhibition [2]. This CHO-Leu-9 CHO-Le+ 'llH23 OR C6H13 ,,,.NH-CHO CllH23 C6H13 2 a R = H b R=Me 3 a R = H b R=Me 1 tetrahydrolipstatin CHO-Leu = N-formyl-L-leucyl ') Synonyma: cholesterol esterase, steryl-ester hydrolase, carboxyl-ester hydrolase, carboxyl esterase, nonspecific lipase [6].