1992
DOI: 10.1002/hlca.19920750513
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Tetrahydrolipstatin: Degradation products produced by human carboxyl‐ester lipase

Abstract: 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.

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Cited by 30 publications
(11 citation statements)
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“…1, structure 1). Opening of the 4-membered ring results in an almost complete loss of the lipase-inhibitory activity of lipstatin, suggesting that the ␤-lactone moiety of the molecule is pivotal to its enzymatic inhibition (10). Other ␤-lactone natural products produced by microorganisms include esterastin (11,12), panclicins (13), valilactone (14), and ebelactones (15,16), which differ only in the structure of the side chains and the nature of the linked amino acids.…”
mentioning
confidence: 99%
“…1, structure 1). Opening of the 4-membered ring results in an almost complete loss of the lipase-inhibitory activity of lipstatin, suggesting that the ␤-lactone moiety of the molecule is pivotal to its enzymatic inhibition (10). Other ␤-lactone natural products produced by microorganisms include esterastin (11,12), panclicins (13), valilactone (14), and ebelactones (15,16), which differ only in the structure of the side chains and the nature of the linked amino acids.…”
mentioning
confidence: 99%
“…Orlistat (Xenical; Roche), an approved drug, reduces absorption of dietary fat by inhibiting digestive lipases [36]. Orlistat is a synthetic derivative of lipstatin, a natural product of Streptomyces toxytricini, which is a potent inhibitor of intestinal lipases [38], and acts by covalent bonding to the serine residue of the active site of digestive lipases [39][40][41]. The chemical reactivity of the -lactone group of lipstatin and its analogues is responsible for their biological effects.…”
mentioning
confidence: 99%
“…Though, it is known that tetrahydrolipstatin also inhibits other serine-hydrolases such as stomach-lipase and pancreas-carboxylic-ester lipase. [253] All these inhibitors have as their central pharmacophore a β-lactone structure, which is formed by a branched long-chain carboxylic acid, carrying hydroxy-groups at the 3-and 5-positions, and mostly linked to an amino acid. All Lipstatin Esterastin Streptomyces lavendulae Valilactone Streptomyces albolongus Panclicin D Streptomyces sp.…”
Section: Inhibitors Of the Pancreaslipasementioning
confidence: 99%