In our search for inhibitors of the antiapoptotic protein Bcl-xL, investigation of Xylopia caudata afforded a new diterpenoid, ent-trachyloban-4beta-ol (2), and five known ent-trachylobane or ent-atisane compounds. Only ent-trachyloban-18-oic acid (1) exhibited weak binding activity to Bcl-xL. These compounds exhibited cytotoxicity against KB and HCT-116 cell lines with IC(50) values between 10 and 30 microM. Bioconversion of compound 1 by Rhizopus arrhizus afforded new hydroxylated metabolites (3-7) of the ent-trachylobane and ent-kaurene type and compound 8, with a rearranged pentacyclic carbon framework that was named rhizopene. Compounds 3-8 were noncytotoxic to the two cancer cell lines, and compounds 3 and 5 exhibited only weak binding affinity for Bcl-xL.
Diterpene pyrones (DTPs) are a group of well-known, mainly fungal, natural products, first isolated in 1966. As the name indicates, they are composed of two main structural features: a diterpenyl moiety and a pyrone ring. Various names have been given to this class of metabolites; however, biogenetic evidence indicates that they originate through the same metabolic pathway. Based on their biosynthesis, which leads to differences in their structural architecture, the DTPs can be classified into three main types. In addition to their intriguing chemistry, these compounds demonstrate a wide range of biological activities rendering them a desirable target for total synthesis. To date, sixty-seven DTPs have been isolated from various fungal species, with one example originating from the plant kingdom. This review aims at unifying the classification of these compounds, in addition to presenting a detailed description of their isolation, bioactivities, biosynthesis, and total synthesis.
The genus Aureispira consisting of two species, Aureispira marina and Aureispira maritima is an arachidonic acid-producing bacterium and produces secondary metabolites. In this study, we isolated a new Aureispira strain, Aureispira sp. CCB-QB1 from coastal area of Penang, Malaysia and the genome sequence of this strain was determined. The draft genome of this strain is composed of 185 contigs for 7,370,077 bases with 35.6% G+C content and contains 5911 protein-coding genes and 76 RNA genes. Linoleoyl-CoA desaturase, the key gene in arachidonic acid biosynthesis, is present in the genome. It was found that this strain uses mevalonate pathway for the synthesis of geranylgeranyl diphosphate (GGPP), which is precursor of diterpenoid, and novel pathway via futalosine for the synthesis of menaquinones. This is the first draft genome sequence of a member of the genus Aureispira.
Pharmaceutically active compounds from medical plants are attractive as a major source for new drug development. Prenylated stilbenoids with increased lipophilicity are valuable secondary metabolites which possess a wide range of biological activities. So far, many prenylated stilbenoids have been isolated from Morus alba but the enzyme responsible for the crucial prenyl modification remains unknown. In the present study, a stilbenoid-specific prenyltransferase (PT), termed Morus alba oxyresveratrol geranyltransferase (MaOGT), was identified and functionally characterized in vitro. MaOGT recognized oxyresveratrol and geranyl diphosphate (GPP) as natural substrates, and catalyzed oxyresveratrol prenylation. Our results indicated that MaOGT shared common features with other aromatic PTs, e.g. multiple transmembrane regions, conserved functional domains and targeting to plant plastids. This distinct PT represents the first stilbenoid-specific PT accepting GPP as a natural prenyl donor, and could help identify additional functionally varied PTs in moraceous plants. Furthermore, MaOGT might be applied for high-efficiency and large-scale prenylation of oxyresveratrol to produce bioactive compounds for potential therapeutic applications.
The inhibition of carbohydrate-hydrolyzing enzymes in human digestive organs is crucial in controlling blood sugar levels, which is important in treating type 2 diabetes. In the current study, pahangensin A (1), a bis-labdanic diterpene characterized previously in the rhizomes of Alpinia pahangensis Ridl., was identified as an active dual inhibitor for α-amylase (IC50 =114.80 μm) and α-glucosidase (IC50 =153.87 μm). This is the first report on the dual α-amylase and α-glucosidase inhibitory activities of a bis-labdanic diterpene. The Lineweaver-Burk plots of compound 1 indicate that it is a mixed-type inhibitor with regard to both enzymes. Based on molecular docking studies, compound 1 docked in a non-active site of both enzymes. The dual inhibitory activity of compound 1 makes it a suitable natural alternative in the treatment of type 2 diabetes.
Vitex agnus-castus L. (Lamiaceae) is a medicinal plant historically used throughout the Mediterranean region to treat menstrual cycle disorders, and is still used today as a clinically effective treatment for premenstrual syndrome. The pharmaceutical activity of the plant extract is linked to its ability to lower prolactin levels. This feature has been attributed to the presence of dopaminergic diterpenoids that can bind to dopamine receptors in the pituitary gland. Phytochemical analyses of V. agnus-castus show that it contains an enormous array of structurally related diterpenoids and, as such, holds potential as a rich source of new dopaminergic drugs. The present work investigated the localisation and biosynthesis of diterpenoids in V. agnus-castus. With the assistance of matrix-assisted laser desorption ionisation-mass spectrometry imaging (MALDI-MSI), diterpenoids were localised to trichomes on the surface of fruit and leaves. Analysis of a trichome-specific transcriptome database, coupled with expression studies, identified seven candidate genes involved in diterpenoid biosynthesis: three class II diterpene synthases (diTPSs); three class I diTPSs; and a cytochrome P450 (CYP). Combinatorial assays of the diTPSs resulted in the formation of a range of different diterpenes that can account for several of the backbones of bioactive diterpenoids observed in V. agnus-castus. The identified CYP, VacCYP76BK1, was found to catalyse 16-hydroxylation of the diol-diterpene, peregrinol, to labd-13Z-ene-9,15,16-triol when expressed in Saccharomyces cerevisiae. Notably, this product is a potential intermediate in the biosynthetic pathway towards bioactive furan- and lactone-containing diterpenoids that are present in this species.
Andrographolides, the diterpene lactones, are major bioactive phytochemicals which could be found in different parts of the medicinal herb Andrographis paniculata. A number of such compounds namely andrographolide (AG), neoandrographolide (NAG), and 14-deoxy-11,12-didehydroandrographolide (DDAG) have already attracted a great deal of attention due to their potential therapeutic effects in hard-to-treat diseases such as cancers and HIV. Recently, they have also been considered as substrates for the discovery of novel pharmaceutical compounds. Nevertheless, there is still a huge gap in knowledge on the genetic pattern of the biosynthesis of these bioactive compounds. Hence, the present study aimed to investigate the genetic mechanisms controlling the biosynthesis of these phytochemicals using a diallel analysis. The high performance liquid chromatography analysis of the three andrographolides in 210 F1 progenies confirmed that the biosynthesis of these andrographolides was considerably increased via intraspecific hybridization. The results revealed high, moderate and low heterosis for DDAG, AG and NAG, respectively. Furthermore, the preponderance of non-additive gene actions was affirmed in the enhancement of the three andrographolides contents. The consequence of this type of gene action was the occurrence of high broad-sense and low narrow-sense heritabilities for the above mentioned andrographolides. The prevalence of non-additive gene action suggests the suitability of heterosis breeding and hybrid seed production as a preferred option to produce new plant varieties with higher andrographolide contents using the wild accessions of A. paniculata. Moreover, from an evolutionary point of view, the occurrence of population bottlenecks in the Malaysian accessions of A. paniculata was unveiled by observing a low level of additive genetic variance (VA ) for all the andrographolides.