Among presently used pharmaceuticals, about 60% were developed from natural products with unique chemical diversity and biological activities. Hence, the discovery of new bioactive compounds from ...natural products is still important for further drug development. In addition, breakthroughs in synthetic biology have also begun to produce many useful compounds through manipulations of the biosynthetic genes for secondary metabolites. Theoretically, this approach can also be exploited to generate new unnatural compounds by intermixing the genes from different biosynthetic pathways and/or engineering the secondary metabolite enzyme(s) with expanded substrate and product specificities. Δ9-Tetrahydrocannabinol (Δ9-THC), the heat-decarboxylated tetrahydrocannabinolic acid (Δ9-THCA) produced by Cannabis sativa, is the most important therapeutic cannabinoid due to its useful pharmacological features, such as analgesic, anti-emetic, anti-inflammatory, and anti-epileptic activities. In the structures of cannabinoids, the resorcinyl alkyl chain is a critical pharmacophore, and the therapeutic effects of Δ9-THC can be enhanced by converting the pentyl (C5) moiety at C-3 to other acyl moieties. Thus, the expansion of unnatural cannabinoids with different C-3 alkyl moiety analogs might establish an excellent platform for the further development of therapeutically beneficial cannabinoids. This article reviews the structure-based dual engineering of both enzymes responsible for the formation of the resorcinyl core of Δ9-THC and describes the effect of C-6 alkyl-length extension of olivetolic acid, along with related analogs, on the antibacterial activities against Bacillus subtilis and Staphylococcus aureus.
Covering: 2002 to 2009
This review covers recent advances in structure and function studies on the chalcone synthase (CHS) superfamily of plant type III polyketide synthases (PKSs), which catalyze ...iterative decarboxylative condensations of malonyl unit with a CoA-linked starter molecule to produce structurally diverse, pharmaceutically important plant secondary metabolites. The functional diversity and catalytic potential of the type III PKSs are remarkable. Studies on the enzymes are now progressing rapidly; recent crystallographic and site-directed mutagenesis studies have revealed intimate structural details of the enzyme reactions, which enabled the structure-based and precursor-directed engineered biosynthesis of unnatural novel polyketides. The literature of type III PKSs of plant origin published over the last eight years will be reviewed, and is intended to compliment the coverage of the literature by Austin and Noel in
Nat. Prod. Rep.
, 2003,
20
, 79-110.
This review covers recent advances in chemistry and enzymology of type III polyketide synthases of plant origin. The literature published from 2002 through 2009 is reviewed.
Type III polyketide synthases (PKSs) produce an incredibly diverse group of plant specialized metabolites with medical importance despite their structural simplicity compared with the modular type I ...and II PKS systems. The type III PKSs use homodimeric proteins to construct the molecular scaffolds of plant polyketides by iterative condensations of starter and extender CoA thioesters. Ever since the structure of chalcone synthase (CHS) was disclosed in 1999, crystallographic and mutational studies of the type III PKSs have explored the intimate structural features of these enzyme reactions, revealing that seemingly minor alterations in the active site can drastically change the catalytic functions and product profiles. New structures described in this review further build on this knowledge, elucidating the detailed catalytic mechanism of enzymes that make curcuminoids, use extender substrates without the canonical CoA activator, and use noncanonical starter substrates, among others. These insights have been critical in identifying structural features that can serve as a platform for enzyme engineering via structure-guided and precursor-directed engineered biosynthesis of plant polyketides. In addition, we describe the unique properties of the recently discovered “second-generation” type III PKSs that catalyzes the one-pot formation of complex molecular scaffolds from three distinct CoA thioesters or from “CoA-free” substrates, which are also providing exciting new opportunities for synthetic biology approaches. Finally, we consider post-type III PKS tailoring enzymes, which can also serve as useful tools for combinatorial biosynthesis of further unnatural novel molecules. Recent progress in the field has led to an exciting time of understanding and manipulating these fascinating enzymes.
Background:Obesity and metabolic disorders frequently coexist, and both are established risk factors for cardiovascular disease (CVD). Although the phenotype of obesity without metabolic disorders, ...referred to as metabolically healthy obesity (MHO), is attracting clinical interest, the pathophysiological impact of MHO remains unclear.Methods and Results:Using the Japan Medical Data Center database, we studied 802,288 subjects aged ≥20 years without any metabolic disorders or a prior history of CVD. MHO, defined as obesity (body mass index ≥25 kg/m2) with no metabolic disorders, was observed in 9.8% of the study population. The subjects’ mean (±SD) age was 42.8±9.4 years and 44.7% were men. The mean follow-up period was 1,126±849 days. Multivariable Cox regression analysis showed that MHO alone did not significantly increase the risk of any CVD. However, abdominal obesity alone increased the risk of heart failure and atrial fibrillation. Moreover, the coexistence of MHO and abdominal obesity increased the risk of myocardial infarction, angina pectoris, heart failure, and atrial fibrillation. The incidence of stroke was not associated with the presence of MHO and abdominal obesity.Conclusions:Among individuals with no metabolic disorders, MHO alone did not significantly increase the subsequent CVD risk. However, individuals with comorbid MHO and abdominal obesity had a higher risk of myocardial infarction, angina pectoris, heart failure, and atrial fibrillation, suggesting the prognostic importance of abdominal obesity in subjects with MHO.
Aim: Clinical evidence on cardiovascular health metrics of couples, as defined by the American Heart Association (AHA), remains to be scarce. This study aims to explore the correlation of the ...AHA-defined cardiovascular health metrics within couples using a nationwide epidemiological database. Methods: We examined the modified cardiovascular health metrics among 87,160 heterosexual couples using the health claims database from the Japan Medical Data Center. The ideal cardiovascular health metrics is comprised of (1) nonsmoking, (2) body mass index ＜25 kg/m2, (3) physical activity at goal, (4) untreated blood pressure ＜120/80 mm Hg, (5) untreated fasting glucose ＜100 mg/dL, and (6) untreated total cholesterol ＜200 mg/dL. Results: A correlation was noted on the ideal modified cardiovascular health metrics between couples. The prevalence of meeting ≥ 5 ideal components in the female partners increased from 32 % in the male partners meeting 0–1 ideal component to 56 % in those meeting 6 ideal components. The same trend has been observed in all generations (20–39 years, 40–49 years, 50–59 years, ≥ 60 years). The association between couples is found to be better in terms of smoking status, blood pressure, and fasting glucose level. Conclusion: There was an intracouple correlation of the ideal modified cardiovascular health metrics, suggesting the importance of couple-based intervention to improve cardiovascular health status.
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