title: Identification of human cathepsin G as a functional target of boswellic acids from the anti-inflammatory remedy frankincense.
abstract: Frankincense preparations, used in folk medicine to cure inflammatory diseases, showed anti-inflammatory effectiveness in animal models and clinical trials. Boswellic acids (BAs) constitute major pharmacological principles of frankincense, but their targets and the underlying molecular modes of action are still unclear. Using a BA-affinity Sepharose matrix, a 26-kDa protein was selectively precipitated from human neutrophils and identified as the lysosomal protease cathepsin G (catG) by mass spectrometry (MALDI-TOF) and by immunological analysis. In rigid automated molecular docking experiments BAs tightly bound to the active center of catG, occupying the same part of the binding site as the synthetic catG inhibitor JNJ-10311795 (2-[3-[methyl[1-(2-naphthoyl)piperidin-4-yl]amino]carbonyl)-2-naphthyl]-1-(1-naphthyl)-2-oxoethylphosphonic acid). BAs potently suppressed the proteolytic activity of catG (IC(50) of approximately 600 nM) in a competitive and reversible manner. Related serine proteases were significantly less sensitive against BAs (leukocyte elastase, chymotrypsin, proteinase-3) or not affected (tryptase, chymase). BAs inhibited chemoinvasion but not chemotaxis of challenged neutrophils, and they suppressed Ca(2+) mobilization in human platelets induced by isolated catG or by catG released from activated neutrophils. Finally, oral administration of defined frankincense extracts significantly reduced catG activities in human blood ex vivo vs placebo. In conclusion, we show that catG is a functional and pharmacologically relevant target of BAs, and interference with catG could explain some of the anti-inflammatory properties of frankincense.
authors: Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe-University Frankfurt, Frankfurt, Germany.
authors: Lars
authors: L
authors: Tausch
authors: Arne
authors: A
authors: Henkel
authors: Ulf
authors: U
authors: Siemoneit
authors: Daniel
authors: D
authors: Poeckel
authors: Nicole
authors: N
authors: Kather
authors: Lutz
authors: L
authors: Franke
authors: Bettina
authors: B
authors: Hofmann
authors: Gisbert
authors: G
authors: Schneider
authors: Carlo
authors: C
authors: Angioni
authors: Gerd
authors: G
authors: Geisslinger
authors: Carsten
authors: C
authors: Skarke
authors: Wolfgang
authors: W
authors: Holtmeier
authors: Tobias
authors: T
authors: Beckhaus
authors: Michael
authors: M
authors: Karas
authors: Johann
authors: J
authors: Jauch
authors: Oliver
authors: O
authors: Werz
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D001667:Binding, Competitive; D029743:Boswellia / Q000378:metabolism / Q000502:physiology*; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D016503:Drug Delivery Systems; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D008969:Molecular Sequence Data; D010936:Plant Extracts / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000097:blood / Q000378:metabolism*; D014315:Triterpenes / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C447943:11-keto-boswellic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010936:Plant Extracts; D014315:Triterpenes; C054625:boswellic acid; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G