Cyclooctatin, a new inhibitor of lysophospholipase, produced by Streptomyces melanosporofaciens MI614-43F2. Taxonomy, production, isolation, physico-chemical properties and biological activities.

Bacterial Diterpene Biosynthesis

“…[24] Ther ecombinant enzyme converts GGPP into cyclooctat-9-en-7-ol (1), which is subsequently oxidised by CotB3 to cyclooctat-9-en-5,7-diol (2)and then by CotB4 to cyclooctatin(3), apotent lysophospholipase inhibitor (Scheme 2A). [25] Thef unctions of the cytochrome P450 monooxygenases (CYP450) was demonstrated by heterologous expression in Streptomyces albus. [24] Thebiosynthetic gene cluster for 3 is also encoded in several other genome-sequenced streptomycetes and frequently contains an additional gene for at hird CYP450 monooxygenase,b ut the function of this enzyme is unknown.…”

An Unusual Terpene Cyclization Mechanism Involving a Carbon–Carbon Bond Rearrangement

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Terpene cyclization reactions are fascinating owing to the precise control of connectivity and stereochemistry during the catalytic process.C yclooctat-9-en-7-ol synthase (CotB2) synthesizes an unusual 5-8-5 fused-ring structure with six chiral centers from the universal diterpene precursor,t he achiral C 20 geranylgeranyl diphosphate substrate.A nu nusual new mechanism for the exquisite CotB2-catalyzed cyclization that involves ac arbon-carbon backbone rearrangement and three long-range hydride shifts is proposed, based on apowerful combination of in vivo studies using uniformly 13 C-labeled glucose and in vitro reactions of regiospecifically deuteriumsubstituted geranylgeranyl diphosphate substrates.T his study shows that CotB2 elegantly demonstrates the synthetic virtuosity and stereochemical control that evolution has conferred on terpene synthases.Cyclooctatin, ad iterpene with au nique tricyclic diterpene skeleton characterized by a5 -8-5 fused-ring system, is ap otent inhibitor of lysophospholipase,w hich catalyzes the hydrolysis of the fatty acid ester bonds of lysophospholipids. [1] This inhibitor was originally isolated from the culture broth of Streptomyces melanosporofaciens MI614-43F2 while screening for lead compounds for the development of antiinflammatory drugs that target lysophospholipase. [1] Recently, we revealed that the minimal cyclooctatin biosynthetic genes encode geranylgeranyl diphosphate (GGDP) synthase (CotB1), ad iterpene cyclase (CotB2), and two cytochrome P450 hydroxylases (CotB3 and CotB4).

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“…[1] This inhibitor was originally isolated from the culture broth of Streptomyces melanosporofaciens MI614-43F2 while screening for lead compounds for the development of antiinflammatory drugs that target lysophospholipase. [1] Recently, we revealed that the minimal cyclooctatin biosynthetic genes encode geranylgeranyl diphosphate (GGDP) synthase (CotB1), ad iterpene cyclase (CotB2), and two cytochrome P450 hydroxylases (CotB3 and CotB4). [2] CotB2 catalyzes the cyclization of GGDP to produce cyclooctat-9-en-7-ol, the parent tricyclic diterpene alcohol intermediate in cyclooctatin biosynthesis (Scheme 1).CotB2 has the unique ability to synthesize the characteristic 5-8-5 fused-ring system of cyclooctat-9-en-7-ol having six chiral centers by cyclization of the universal diterpene precursor,t he achiral C 20 allylic diphosphate GGDP.…”

“…Cyclooctatin, ad iterpene with au nique tricyclic diterpene skeleton characterized by a5 -8-5 fused-ring system, is ap otent inhibitor of lysophospholipase,w hich catalyzes the hydrolysis of the fatty acid ester bonds of lysophospholipids. [1] This inhibitor was originally isolated from the culture broth of Streptomyces melanosporofaciens MI614-43F2 while screening for lead compounds for the development of antiinflammatory drugs that target lysophospholipase. [1] Recently, we revealed that the minimal cyclooctatin biosynthetic genes encode geranylgeranyl diphosphate (GGDP) synthase (CotB1), ad iterpene cyclase (CotB2), and two cytochrome P450 hydroxylases (CotB3 and CotB4).…”

16,17-dihydroxycyclooctatin, a new diterpene from Streptomyces sp. LZ35

“…Cyclooctatin, a diterpene characterized by a novel 5-8-5-fused ring system, is a potent inhibitor of lysophospholipase, which was previously isolated from Streptomyces melanosporofaciens MI614-43F2 (1,2). The complete cyclooctatin biosynthesis gene cluster was cloned from S. melanosporofaciens MI614-43F2 and heterologously expressed with variations of cytochrome P450 genes in Streptomyces albus to produce cyclooctatin together with two new intermediates, cyclooctat-9-en-7-ol and cyclooactat-9-en-5,7-diol (3).…”