GGPP

Astaxanthin is a fascinating molecule with powerful antioxidant activity, synthesized exclusively by specific microorganisms and higher plants. To expand astaxanthin production, numerous studies have employed metabolic engineering to introduce and optimize astaxanthin biosynthetic pathways in microorganisms and plant hosts. Here, we report the metabolic engineering of animal cells in vitro to biosynthesize astaxanthin. This was accomplished through a two-step study to introduce the entire astaxanthin pathway into human embryonic kidney cells (HEK293T)...

Terpene cyclization, one of the most complex chemical reactions in nature, is generally catalyzed by two classes of terpene cyclases (TCs). Cytochrome P450s that act as unexpected TC-like enzymes are known but are very rare. In this study, we genome-mined a cryptic bacterial terpenoid gene cluster, named ari, from the thermophilic actinomycete strain Amycolatopsis arida. By employing a heterologous production system, we isolated and characterized three highly oxidized eunicellane derived diterpenoids, aridacins A-C (1-3), that possess a 6/7/5-fused tricyclic scaffold...

BACKGROUND: Transplantation of stem cells for treating neurodegenerative disorders is a promising future therapeutic approach. However, the molecular mechanism underlying the neuronal differentiation of dental pulp-derived stem cells (DPSC) remains inadequately explored. The current study aims to define the regulatory role of KLF2 (Kruppel-like factor 2) during the neural differentiation (ND) of DPSC. METHODS: We first investigated the transcriptional and translational expression of KLF2, autophagy, and mitophagy-associated markers during the ND of DPSC by using quantitative RT-PCR and western blot methods...

Leishmaniasis is a debilitating and often fatal neglected tropical disease. Males from sub-populations of the Leishmania-harbouring sandfly, Lutzomyia longipalpis, produce the diterpene sex and aggregation pheromone, sobralene, for which geranylgeranyl diphosphate (GGPP) is the likely isoprenoid precursor. We have identified a GGPP synthase (lzGGPPS) from L. longipalpis, which was recombinantly expressed in bacteria and purified for functional and kinetic analysis. In vitro enzymatic assays using LC-MS showed that lzGGPPS is an active enzyme, capable of converting substrates dimethylallyl diphosphate (DMAPP), (E)-geranyl diphosphate (GPP), (E,E)-farnesyl diphosphate (FPP) with co-substrate isopentenyl diphosphate (IPP) into (E,E,E)-GGPP, while (Z,E)-FPP was also accepted with low efficacy...

Emerging research and clinical evidence suggest that the metabolic activity of oocytes may play a pivotal role in reproductive anomalies. However, the intrinsic mechanisms governing oocyte development regulated by metabolic enzymes remain largely unknown. Our investigation demonstrates that Ggps1, the crucial enzyme in the mevalonate pathway responsible for synthesizing isoprenoid metabolite GGPP from FPP, is essential for oocyte maturation in mice. Our findings reveal that the deletion of Ggps1 that prevents protein prenylation in fully-grown oocytes leads to subfertility and offspring metabolic defects without affecting follicle development...

As the traditional herb with pharmacological compounds in China, the key genes related with terpenoid biosynthesis are still unveiled in Nelumbo nucifera. Geranylgeranyl pyrophosphate synthase (GGPPS) is one of the key enzymes in terpenoids biosynthesis, synthesizing the common precursor of GGPP for downstream enzymes for generating various terpenoids. In this study, four NnGGPPS genes were isolated from N. nucifera. Sequence and phylogenetic analyses indicate that NnGGPPS1 and NnGGPPS2 belong to large subunit (LSU)...

Carotenoids are photoprotectant pigments and precursors of hormones such as strigolactones (SL). Carotenoids are produced in plastids from geranylgeranyl diphosphate (GGPP), which is diverted to the carotenoid pathway by phytoene synthase (PSY). In tomato (Solanum lycopersicum), three genes encode plastid-targeted GGPP synthases (SlG1 to SlG3) and three genes encode PSY isoforms (PSY1 to PSY3). Here, we investigated the function of SlG1 by generating loss-of-function lines and combining their metabolic and physiological phenotyping with gene co-expression and co-immunoprecipitation analyses...

Optimization of supply and conversion efficiency of geranylgeranyl diphosphate (GGPP) is important for enhancing geranylgeraniol (GGOH) production in Saccharomyces cerevisiae . In this study, first, a strain producing 26.92 ± 1.59 mg/g of dry cell weight squalene was constructed with overexpression of all genes of the mevalonate (MVA) pathway, and an engineered strain producing 597.12 mg/L GGOH at the shake flask level was obtained. Second, through additional expression of PaGGPPs - ERG20 and PaGGPPs - DPP1 , and downregulating expression of ERG9 , the GGOH titer was increased to 1221...

The terpenoid substrate analogs (7R)-6,7-dihydrogeranylgeranyl diphosphate (6,7-dihydro-GGPP) and (7R)-6,7-dihydrogeranylfarnesyl diphosphate (6,7-dihydro-GFPP) were synthesised from (S)-citronellol and enzymatically converted with nine diterpene and two sesterterpene synthases, respectively. In two cases the substrate analogs were converted into diterpenes in cyclisation reactions corresponding to those observed for the native substrate GGPP, while the cyclisation cascade was disrupted or redirected in the other nine cases, leading to products that were named ruptenes...

BACKGROUND: Isoprenoids are a very large class of metabolites playing a key role in plant physiological processes such as growth, stress resistance, fruit flavor, and color. In chloroplasts and chromoplasts, the diterpene compound geranylgeranyl diphosphate (GGPP) is the metabolic precursor required for the biosynthesis of tocopherols, plastoquinones, phylloquinone, chlorophylls, and carotenoids. Despite its key role for the plant metabolism, reports on GGPP physiological concentrations in planta have been extremely scarce...

BACKGROUND & AIMS: Ferroptosis is a form of regulated cell death and its promotion in hepatic stellate cells (HSCs) attenuates liver fibrosis. Statins, which are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, may induce ferroptosis via the downregulation of glutathione peroxidase 4 (GPX4) by inhibiting the mevalonate pathway. However, little evidence is available regarding the association between statins and ferroptosis. Therefore, we investigated the association between statins and ferroptosis in HSCs...

Cadmium (Cd) could pose threats to human health by affecting Salvia miltiorrhiza (SM) safety. Cd enrichment trait and its effects on the active ingredient synthesis in SM remain unknown. Here we investigated the Cd concentration using ICP-MS-based method, physiologies (contents of malondialdehyde and proline, and activities of superoxide dismutase, peroxidase [POD], and catalase [CAT]), and LC-MS/MS-based metabolites of SM under 25, 50, and 100 mg kg-1 Cd stress. The results revealed that Cd concentrations, as it rose in soil, increased in roots and leaves of SM with transfer factors and bioconcentration factors below 1 in Cd-treated groups; POD and CAT activities and proline content increased and then declined...

Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We analyzed the impact of statins on prenylation of Rab27b and Rap1a in platelets and the downstream effects on fibrin clot properties. Whole blood thromboelastography revealed that atorvastatin (ATV) delayed clot formation time ( P  < .005) and attenuated clot firmness ( P  < ...

Sanghuangporus baumii is a medicinal fungi with anti-inflammatory, liver protection and antitumour effects. Terpenoids are one of the main medicinal ingredients of S. baumii. However, terpenoid production by wild-type S. baumii cannot meet the market demand, which affects its application in medical care. Therefore, exploring how to increase terpenoid content in S. baumii is a promising path in this research field. Salicylic acid (SA) is a secondary metabolite. In this study, a concentration of 350 μmol/L SA was added into fungal cultivations for 2 and 4 days, and then the transcriptome and metabolome of untreated mycelia and treated with SA were analysed...

BACKGROUND: Pitavastatin is a cholesterol-lowering drug and is widely used clinically. In addition to this effect, pitavastatin has shown the potential to induce apoptosis in cutaneous squamous cell carcinoma (SCC) cells. OBJECTIVE: The purpose of this study is to investigate the effects and possible action mechanisms of pitavastatin. METHODS: SCC cells (SCC12 and SCC13 cells) were treated with pitavastatin, and induction of apoptosis was confirmed by Western blot...

Terpenoids constitute the largest class of plant primary and secondary metabolites with a broad range of biological and ecological functions. They are synthesized from isopentenyl diphosphate and dimethylallyl diphosphate, which in plastids are condensed by geranylgeranyl diphosphate synthases (GGPPSs) to produce GGPP (C20) for diterpene biosynthesis and by geranyl diphosphate synthases (GPPSs) to form GPP (C10) for monoterpene production. Depending on the plant species, unlike homomeric GGPPSs, GPPSs exist as homo- and heteromers, the latter of which contain catalytically inactive GGPPS-homologous small subunits (SSUs) that can interact with GGPPSs...

The high thermogenic activity of brown adipose tissue (BAT) has received considerable attention. Here, we demonstrated the role of the mevalonate (MVA) biosynthesis pathway in the regulation of brown adipocyte development and survival. The inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme in the MVA pathway and the molecular target of statins, suppressed brown adipocyte differentiation by suppressing protein geranylgeranylation-mediated mitotic clonal expansion. The development of BAT in neonatal mice exposed to statins during the fetal period was severely impaired...

BACKGROUND: Acute lung injury (ALI) is a severe inflammatory disease with high morbidity and mortality in patients and lung transplant recipients. Tumor necrosis factor-α-induced protein 8-like 3 (TIPE3) is one of the members of the TIPE family. While TIPE2 has been demonstrated to be protective against lipopolysaccharide (LPS)-induced ALI, the role of TIPE3 in ALI is currently unidentified. METHODS: To examine the role of TIPE3 in ALI, we pretreated C57BL/6 mice with control or TIPE3-lentivirus in LPS-induced ALI models...

As one of the most imperative antioxidants in higher plants, carotenoids serve as accessory pigments to harvest light for photosynthesis and photoprotectors for plants to adapt to high light stress. Here, we report a small subunit (SSU) of geranylgeranyl diphosphate synthase (GGPPS) in Nicotiana tabacum , NtSSU II, which takes part in the regulation carotenoid biosynthesis by forming multiple enzymatic components with NtGGPPS1 and downstream phytoene synthase (NtPSY1). NtSSU II transcript is widely distributed in various tissues and stimulated by low light and high light treatments...

Geranylgeranyl diphosphate synthase (GGDPS), an enzyme in the isoprenoid biosynthesis pathway, is responsible for the production of geranylgeranyl pyrophosphate (GGPP). GGPP serves as a substrate for the post-translational modification (geranylgeranylation) of proteins, including those belonging to the Ras superfamily of small GTPases. These proteins play key roles in signalling pathways, cytoskeletal regulation and intracellular transport, and in the absence of the prenylation modification, cannot properly localise and function...