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Biosynthesis of polyprenylated xanthones in Hypericum perforatum roots involves 4-prenyltransferase.Plant Physiology Aug 2023Polyprenylated xanthones are natural products with a multitude of biological and pharmacological activities. However, their biosynthetic pathway is not completely...
Polyprenylated xanthones are natural products with a multitude of biological and pharmacological activities. However, their biosynthetic pathway is not completely understood. In this study, metabolic profiling revealed the presence of 4-prenylated 1,3,5,6-tetrahydroxyxanthone derivatives in St. John's wort (Hypericum perforatum) root extracts. Transcriptomic data mining led to the detection of 5 variants of xanthone 4-prenyltransferase (HpPT4px) comprising 4 long variants (HpPT4px-v1 to HpPT4px-v4) and 1 short variant (HpPT4px-sh). The full-length sequences of all 5 variants were cloned and heterologously expressed in yeast (Saccharomyces cerevisiae). Microsomes containing HpPT4px-v2, HpPT4px-v4, and HpPT4px-sh catalyzed the addition of a prenyl group at the C-4 position of 1,3,5,6-tetrahydroxyxanthone; 1,3,5-trihydroxyxanthone; and 1,3,7-trihydroxyxanthone, whereas microsomes harboring HpPT4px-v1 and HpPT4px-v3 additionally accepted 1,3,6,7-tetrahydroxyxanthone. HpPT4px-v1 produced in Nicotiana benthamiana displayed the same activity as in yeast, while HpPT4px-sh was inactive. The kinetic parameters of HpPT4px-v1 and HpPT4px-sh chosen as representative variants indicated 1,3,5,6-tetrahydroxyxanthone as the preferred acceptor substrate, rationalizing that HpPT4px catalyzes the first prenylation step in the biosynthesis of polyprenylated xanthones in H. perforatum. Dimethylallyl pyrophosphate was the exclusive prenyl donor. Expression of the HpPT4px transcripts was highest in roots and leaves, raising the question of product translocation. C-terminal yellow fluorescent protein fusion of HpPT4px-v1 localized to the envelope of chloroplasts in N. benthamiana leaves, whereas short, truncated, and masked signal peptides led to the disruption of plastidial localization. These findings pave the way for a better understanding of the prenylation of xanthones in plants and the identification of additional xanthone-specific prenyltransferases.
Topics: Hypericum; Dimethylallyltranstransferase; Saccharomyces cerevisiae; Xanthones; Plant Extracts
PubMed: 37061818
DOI: 10.1093/plphys/kiad219 -
Molecular and Cellular Biochemistry Aug 2023Statins are known to block cholesterol synthesis in the liver. They also exhibit non-lipid pleiotropic effects due to the inhibition of protein prenylation, thereby... (Review)
Review
Statins are known to block cholesterol synthesis in the liver. They also exhibit non-lipid pleiotropic effects due to the inhibition of protein prenylation, thereby modulating various signaling pathways of cellular homeostasis and integrity. Both lipid control and pleiotropic action of statins are clinically used, mainly for treatment of hypercholesterolemia and primary and secondary prevention of cardiovascular diseases. Because the prescription of statins is increasing and statin therapy is often lifelong, in particular in patients with other risk factors, safety issues being associated with polymorbidity and polypragmasia as well as the persistence with and adherence to statins are specific points of attention of clinicians and clinical pharmacologists. Furthermore, because skeletal myocytes have a cholesterol inhibitory sensitivity greater than hepatocytes, a choice of an appropriate statin based on its lipophilicity and the associated likelihood of its side effects on skeletal muscle cells and bone is warranted in such polymorbid patients. These approaches can effectively modulate the risk: benefit ratio and highlight a need for personalized therapy as much as possible, thereby minimizing risk of discontinuation of therapy and poor compliance.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol; Hypercholesterolemia; Muscle Fibers, Skeletal; Muscle, Skeletal
PubMed: 36471123
DOI: 10.1007/s11010-022-04621-y