Crystal structure of olivetolic acid: a natural product from <i>Cetrelia sanguinea</i> (Schaer.)

Ismed, Friardi; Farhan, A R; Bakhtiar, Amri; Zaini, Erizal; Nugraha, Yuda Prasetya; Putra, Okky Dwichandra; Uekusa, Hidehiro

doi:10.1107/s2056989016016273

Cited by 9 publications

(13 citation statements)

References 8 publications

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“…Additional therapeutic uses are becoming more commonplace, including the treatment of anorexia in HIV patients and the reduction of spasticity in multiple sclerosis . In addition, olivetolic acid, the precursor of the monoaromatic cannabinoids tetrahydrocannabinol and CBD, is known to possess antimicrobial, cytotoxic and photo‐protective activities .…”

Section: Introductionmentioning

confidence: 99%

Structure of the Cannabis sativa olivetol‐producing enzyme reveals cyclization plasticity in type III polyketide synthases

et al. 2019

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In the native pathway to therapeutic cannabinoid biosynthesis in Cannabis sativa, the three‐step production of a key intermediate, olivetolic acid, is catalysed by the enzymes tetraketide synthase (TKS; linear tetraketide intermediate production in two stages) and olivetolic acid cyclase (OAC; final C2 → C7 aldol condensation). In the absence of OAC, a nonenzymatic C2 → C7 decarboxylative aldol condensation of the tetraketide intermediate occurs forming olivetol. TKS is a type III polyketide synthase, and the question arises why it is unable to form olivetolic acid directly, but instead forms this unwanted side product. We determined the TKS, CoA complex structure, and performed structurally guided mutagenesis studies to identify potential residues responsible for cyclization pathway discrimination in type III polyketide synthases. Prior studies suggested an ‘aldol switch’ is necessary to allow linear tetraketide intermediate release prior to cyclization, thereby enabling subsequent olivetolic acid production by OAC. However, our studies do not support the presence of a universal or predictable ‘aldol switch’ consensus sequence. Instead, we propose the mode of ordered active site water activation between type III polyketide synthases catalysing different cyclization mechanisms is subtle and homologue‐specific. Our work indicates that subtle structural variations between homologous enzymes can have a major mechanistic impact on the catalytic outcome. This highlights the importance of embedding high‐resolution structural analysis of multiple enzyme homologues with classical site‐directed mutagenesis studies when investigating highly similar enzymes with different mechanistic pathway outcomes. Enzymes TKS, EC 2.3.1.206; OAC, EC 4.4.1.26; chalcone synthase, EC 2.3.1.74; stilbene synthase, EC 2.3.1.95; 2‐PS, EC 2.3.1.-. Accession numbers The atomic coordinates and structure factors for the crystal structure of TKS have been deposited in the Protein Data Bank with accession number http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6GW3.

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Section: Introductionmentioning

confidence: 99%

Structure of the Cannabis sativa olivetol‐producing enzyme reveals cyclization plasticity in type III polyketide synthases

et al. 2019

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“…Some isolated compounds from Sumatran medicinal plants were available in our laboratory from previous work; ethyl haematommate from S. graminosum [8], eugenol from Syzygium aromaticum, hydroxychavicol from Piper betle, and curcumin from Curcuma xanthorrhiza [21], pinostrobin, pinocembrin and alpinetin from B. pandurata [7]. α-mangostin from Garcinia mangostana and andrographolide from Andrographis paniculata [22], deoxyelephantopin from E. scaber [23], angiopteroside from Angiopteris evecta [24], olivatolic acid from Cetrelia sanguinea [25], stevioside from Stevia rebaudiana [26].…”

Section: Methodsmentioning

confidence: 99%

Screening of some Sumatran medicinal plants and selected secondary metabolites for their cytotoxic potential against MCF-7 and HSC-3 cell lines

Husnunnisa¹,

Ismed²,

Bakhtiar³

et al. 2019

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How to cite this article: Husnunnisa, Ismed F, Taher M, Ichwan SJA, Bakhtiar A, Arbain D. Screening of some Sumatran medicinal plants and selected secondary metabolites for their cytotoxic potential against MCF-7 and HSC-3 cell lines. J Res Pharm. 2019; 23(4): 770-776. ABSTRACT:In continuation of our study of Sumatran plants and bioactivities of their constituents particularly their cytotoxic activities, we re-extracted lichen Stereocaulon graminosum Schaer (Stereocaulaceae), and isolated atranorin (1) and stictic acid (4).. These isolated compounds have been tested for their cytotoxic activities against human breast adenocarcinoma cancer cell (MCF-7) and human oral squamous carcinoma cancer cell (HSC-3) using MTT assay with a slight modification. Some methanolic extracts of the leaves of Elephantopus scaber, Piper betle, Andrographis paniculata, rhizomes of Boesenbergia pandurata, Alpinia galanga, Kaempferia galanga and isolated compounds; ethyl haematommate (2), olivatolic acid (3), deoxyelephantopin (5), andrographolide (6), hydroxychavicol (7), eugenol (8), curcumin (9), pinostrobin (10), pinocembrin (11), alpinetin (12), α-mangostin (13), angiopteroside (14), and stevioside (15) from Sumatran traditional medicinal plants have also been tested.

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“…An understanding of the biological pathwayf or (À)-2 synthesis requiredt he identification and characterization of its common intermediates, [77][78][79] addressing their origin [67,80,81] and how they transform into plant cells. [69] Previous studies recognized four important advanced intermediates as building blocks for the biosynthesis of CBD: [76,[82][83][84] cannabidiolic acid (4), [77,85] cannabigerolic acid (9), [85] olivetolic acid (10), [86,87] and geraniol diphosphate (11; [88] Scheme 3).…”

Section: Structural Elucidation Of Cbdmentioning

confidence: 99%

Cannabidiol Discovery and Synthesis—a Target‐Oriented Analysis in Drug Production Processes

Aguillón

Leão

Miranda

et al. 2021

Chemistry A European J

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Crystal structure of olivetolic acid: a natural product from Cetrelia sanguinea (Schaer.)

Abstract: The packing in olivetolic acid is similar to that in resorcinolic acid.

Cited by 9 publications

References 8 publications

Structure of the Cannabis sativa olivetol‐producing enzyme reveals cyclization plasticity in type III polyketide synthases

Structure of the Cannabis sativa olivetol‐producing enzyme reveals cyclization plasticity in type III polyketide synthases

Screening of some Sumatran medicinal plants and selected secondary metabolites for their cytotoxic potential against MCF-7 and HSC-3 cell lines

Cannabidiol Discovery and Synthesis—a Target‐Oriented Analysis in Drug Production Processes

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