Липстатин

Description

Lipstatin is a natural β-lactone, an irreversible inhibitor of pancreatic lipase. Producer: actinomycete Streptomyces toxytricini; the compound was isolated and characterized as an inhibitor of a key enzyme for the breakdown of fats in the intestine. The industrial importance of lipstatin is determined by the fact that the hydrogenation of its double bonds produces tetrahydrolipstatin - orlistat, the active ingredient of the drugs Xenical and Alli.

Basic Attributes

• CAS No.: 96829-59-3
• Chemical formula: C29H49NO5
• Calculated molecular weight according to gross formula: 491.7
• English name: Lipstatin
• Synonyms: (−)-lipstatin; L-leucine, N-formyl-, (1S,3Z,6Z)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-3,6-dodecadien-1-yl ester

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Structure

The molecule is built on the skeleton of 2-hexyl-3,5-dihydroxy-7,10-hexadecadienoic acid, closed in a β-lactone. The N-formyl-L-leucine residue is attached to the 5-hydroxyl group by an ester bond. The two double bonds of the chain have a Z configuration (positions 3 and 6 of the dodecadienyl moiety).

Mechanism of action

The strained four-membered β-lactone ring acylates a serine residue in the active site of the lipase. The bond is covalent, so inhibition of the enzyme is irreversible, and unsplit triglycerides are not absorbed in the intestine. The IC50 for pancreatic lipase is 0.14 µM.

Biosynthesis

A fragment of an α-branched 3,5-dihydroxy acid β-lactone is formed in S. toxytricini cells by Claisen condensation of two fatty acid substrates, which are obtained by incomplete oxidative cleavage of linoleic acid. The genes responsible for assembling the molecule are organized into a separate operon.

Applications

• parent compound for orlistat (tetrahydrolipstatin), an FDA-approved long-term obesity treatment drug
• reference lipase inhibitor in biochemical and enzymatic studies
• object of work on the biosynthesis of polyketides and β-lactones, including engineering of the producer strain

Safety Information

The product card does not contain any hazard instructions, precautionary measures, transport codes or WGK class - there are no notifications for the position in the register. Handling - according to the general rules for biologically active substances: gloves, eye and respiratory protection, avoiding direct contact.