Tetrahydrolipstatin: Degradation products produced by human carboxyl‐ester lipase

Stalder, Henri; Oesterhelt, G.; Borgström, Bengt

doi:10.1002/hlca.19920750513

Cited by 30 publications

(11 citation statements)

References 12 publications

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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.…”

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confidence: 99%

Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase

Bai

Zhang

Lin

et al. 2014

Appl Environ Microbiol

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c Lipstatin, isolated from Streptomyces toxytricini as a potent and selective inhibitor of human pancreatic lipase, is a precursor for tetrahydrolipstatin (also known as orlistat, Xenical, and Alli), the only FDA-approved antiobesity medication for long-term use. Lipstatin features a 2-hexyl-3,5-dihydroxy-7,10-hexadecadienoic-␤-lactone structure with an N-formyl-L-leucine group attached as an ester to the 5-hydroxy group. It has been suggested that the ␣-branched 3,5-dihydroxy fatty acid ␤-lactone moiety of lipstatin in S. toxytricini is derived from Claisen condensation between two fatty acid substrates, which are derived from incomplete oxidative degradation of linoleic acid based on feeding experiments. In this study, we identified a six-gene operon (lst) that was essential for the biosynthesis of lipstatin by large-deletion, complementation, and single-gene knockout experiments. lstA, lstB, and lstC, which encode two ␤-ketoacyl-acyl carrier protein synthase III homologues and an acyl coenzyme A (acyl-CoA) synthetase homologue, were indicated to be responsible for the generation of the ␣-branched 3,5-dihydroxy fatty acid backbone. Subsequently, the nonribosomal peptide synthetase (NRPS) gene lstE and the putative formyltransferase gene lstF were involved in decoration of the ␣-branched 3,5-dihydroxy fatty acid chain with an N-formylated leucine residue. Finally, the 3␤-hydroxysteroid dehydrogenase-homologous gene lstD might be responsible for the reduction of the ␤-keto group of the biosynthetic intermediate, thereby facilitating the formation of the unique ␤-lactone ring.

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confidence: 99%

Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase

Bai

Zhang

Lin

et al. 2014

Appl Environ Microbiol

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“…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.…”

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confidence: 99%

Activity-Based Proteomics of Lipolytic Enzymes

Birner‐Gruenberger¹,

Hermetter

2007

CDDT

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Lipases play fundamental roles in biological processes since hydrolysis of triacylglycerols and cholesteryl esters is a key event in energy homeostasis of animals. Perturbations in the metabolism and the cellular retention of lipids result in common diseases such as obesity, type 2 diabetes, and atherosclerosis. The introduction of active site-directed chemical probes for enzymatic activity profiling in complex mixtures, known as activity-based proteomics, has greatly facilitated and accelerated global analysis and functional annotation of lipolytic proteins. Here we review probe design and application for discovery and discrimination of lipolytic and esterolytic enzymes. These probes are usually detected by their fluorescent or affinity tags and their protein targets are analyzed using established proteomics techniques. Moreover, microarray technologies can be applied for higher throughput screenings of enzyme or probe specificity.

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“…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%

Pharmaceuticals

Schaefer

2014

Natural Products in the Chemical Industry

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A boy who is born in Germany today has a probable life expectancy of around 77 years, and a girl one of 82 years -twice as long as in the year 1880. This increase is a consequence of both, better living circumstances -working conditions, food, clothing, housing -, and also a result of more comprehensive medical care. Thus, a whole range of infectious diseases has been wiped out, or brought at least under control, and the mortality rate for civilisation-and age-related diseases has dropped. Vaccinations and drugs play a key role in this outcome. The 20th century is characterised especially by the worldwide blossoming of the pharmaceutical industry. More and more, the targeted search for and development of new drugs have replaced serendipitous discoveries (Fig. 5.1). Pharmaceuticals of the last century.

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Tetrahydrolipstatin: Degradation products produced by human carboxyl‐ester lipase

Cited by 30 publications

References 12 publications

Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase

Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase

Activity-Based Proteomics of Lipolytic Enzymes

Pharmaceuticals

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