The biosynthetic pathways of natural products are complicated, and it is difficult to fully elucidate their details using experimental chemistry alone. In recent years, efforts have been made to ...elucidate the biosynthetic reaction mechanisms by combining computational and experimental methods. In this review, we will discuss the biosynthetic studies using computational chemistry for various terpene compounds such as cyclooctatin, sesterfisherol, quiannulatene, trichobrasilenol, asperterpenol, preasperterpenoid, spiroviolene, and mangicol.
Salmahyritisol A, similan A, and hippospongide A, which are scalarane‐type sesterterpenoids, feature 6/6/5/7/5 pentacyclic skeletons. Although their biosyntheses have been previously proposed to ...involve a unique skeletal rearrangement reaction, the detailed reaction mechanism remains unclear as none of the corresponding biosynthetic enzymes for this reaction have been reported. Herein, this skeletal rearrangement reaction was investigated using computational techniques, which revealed the following four key features: (i) the distal 24‐Me substituent controls both the concertedness and activation energy of this transformation, (ii) enzymes are not responsible for the observed regioselectivity of C12−C20 bond formation, (iii) stereoselectivity is enzyme‐regulated, and (iv) protonation is a key step in this skeletal rearrangement process. These new findings provide insight into the C‐ring‐contraction and D‐ring‐expansion mechanisms in scalarane‐type sesterterpenoid biosyntheses.
DFT calculations revealed that the distal methyl group controls both concertedness and energy barrier during the skeletal rearrangement reaction involved in scalarane‐type sesterterpenoid biosynthesis. Furthermore, the unique skeletal rearrangement‘s protonation process, regioselectivity, and stereoselectivity were elucidated.
The biosynthetic pathway to asperterpenol, a sesterterpenoid featuring a 6/6/8/5 tetracyclic ring system, was proposed to involve three secondary (2°) carbocation intermediates (
,
, and
), but it ...remains controversial whether or not these are viable. Further, the proposed 11/6/5 tricyclic intermediate
has the same "ChemDraw" structure as an intermediate in the biosynthesis of preasperterpenoid, which has a very different 5/7/(3)6/5 pentacyclic skeleton. Here, we present a detailed scrutiny of the asperterpenol/preasperterpenoid biosynthetic pathways based on comprehensive DFT calculations.
Brasilane-type sesquiterpenes have been known for a long time, but their biosynthetic pathways and mechanisms remain elusive. Recently, two groups independently characterized a Trichoderma terpene ...cyclase that produces trichobrasilenol, a brasilane-type sesquiterpene, and a plausible biosynthetic pathway was proposed based on isotopic labeling experiments. In the proposed mechanism, the characteristic brasilane-type 5/6 bicyclic skeleton is synthesized from a 5/7/3 tricyclic intermediate via a complicated concerted reaction, including six chemical events of C–C σ bond metathesis and rearrangements, ring-contraction, π bond formation, and regioselective hydroxylation. However, our density functional theory (DFT) calculations do not support this mechanism. On the basis of DFT calculations, we propose a new pathway for trichobrasilenol biosynthesis, involving a multistep carbocation cascade in which cyclopropylcarbinyl cations in equilibrium with homoallyl cations play a pivotal role. This pathway and mechanism is in good agreement with previous biosynthetic studies on brasilane-type compounds and related terpenoids, including isotope-labeling experiments and byproducts analysis.
Efforts to improve the management of medical incidents have derived from two main perspectives, namely, the promotion of patient safety and quality improvement, and the strategic management of ...organizational crisis. These two streams have produced different sets of policies and endeavors, although they are sometimes closely interrelated and supplementary. Around the turn of the century, promotion of medical safety came to focus mainly on systemic failures, institutional learning, risk communication, and a safety culture, which resulted in a shift away from risk management toward safety management, and then from safety management to a safety culture and (service/ treatment) quality management.Although a crisis management perspective has thus moved away from being the central topic of public policy, its importance undoubtedly remains. With increased expectations of medical services, as well as lawsuits, effective management of health crises is called for, more than ever, and healthcare organizations and professionals should be sufficiently prepared to address these events. Depending on the phase of a crisis (i.e., before, during. and after a crisis), a set of actions is required, along with advanced planning and coordination. Basic principles for risk and crisis management should be applied to the management of medical incidents, which in turn improves patient safety. In addition, communications play a key part in this regard. Advance plans (for preparation, response, and recovery) are especially imperative, aside from efforts to prevent medical incidents.This article first presents the basic components of crisis management, along with the promotion of patient safety, with a focus on communications. It then introduces recent policies regarding safety promotion, as well as efforts to manage the crises caused by medical incidents in Japan.
Spiroviolene is a spirocyclic triquinane diterpene produced by Streptomyces violens. Recently, a biosynthetic pathway that includes secondary carbocation intermediates and a complicated concerted ...skeletal rearrangement was proposed for spiroviolene, based upon careful labeling experiments. On the basis of density functional theory (DFT) calculations, we propose a revised pathway for spiroviolene biosynthesis, involving a multistep carbocation cascade that bypasses the formation of unstable secondary carbocations by breaking the adjacent C–C bond to form a more stable tertiary carbocation (IM3) and by Wagner–Meerwein 1,2-methyl rearrangement (IM7).
•Oxygen-glucose deprivation (OGD) causes rapid membrane depolarization.•OGD-induced intracellular Ca2+ rises contribute to generation of rapid depolarization.•OGD-induced NO and ROS production ...contributes to generation of rapid depolarization.•Dysfunction of Na+-K+-ATPase contributes to generation of rapid depolarization.
Cortical pyramidal neurons show rapid and irreversible membrane depolarization in response to oxygen-glucose depolarization (OGD). In this study, we investigated cellular mechanisms responsible for rapid depolarization caused by OGD in layer III pyramidal neurons of the mouse somatosensory cortex. When OGD solution was perfused in the presence of Ca2+ chelator and inhibitors of ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs) in the pipette solution or in the presence of inhibitors of NMDA receptors (NMDARs), voltage-gated Ca2+ channels (VGCCs), and canonical transient receptor potential (TRPC) channels in the perfusion solution, the latency of the rapid depolarization was significantly prolonged compared to the control. In addition, when OGD solution was perfused in the presence of scavengers of nitric oxide and reactive oxygen species in the perfusion solution or in the presence of calcineurin inhibitors in the pipette solution, the latency of the rapid depolarization was significantly prolonged compared to the control. These data indicate that OGD-induced intracellular Ca2+ increases mediated by Ca2+ influx through NMDARs, VGCCs and TRPC channels as well as by Ca2+ release from RyRs and IP3Rs lead to mitochondrial impairment, which may facilitate the generation of the rapid depolarization via dysfunction of Na+-K+-ATPase due to decreased ATP production.
The results of quantum chemical calculations on the mechanism of the carbocation cascade of reactions in the biosynthetic pathways leading to the pentacyclic sesterterpenes quiannulatene and ...sesterfisherol provide reasonable answers to several persistent mechanistic questions in sesterterpene biosynthesis, including: 1) the reaction pathways of the multicyclic ring system construction and skeletal rearrangements, 2) the mechanism of triquinane skeleton formation, which requires more complicated rearrangements than previously proposed, 3) the stereochemistry of the final carbocation intermediate, and 4) the determining factor of biosynthetic selection for either 5/6/4/6/5 or 5/6/5/5/5 pentacyclic skeleton formation. This in‐depth mechanistic study on sesterterpene biosynthesis revealed that the shape of the final product and the type of triquinane skeleton formed are regulated by the stereochemistry and conformation of the common starting material, geranylfarnesyl diphosphate (GFPP).
Taking shape: The pentacyclic sesterterpenes quiannulatene and sesterfisherol are derived from the same starting material geranylfarnesyl diphosphate (GFPP), but by different biosynthetic pathways. This in‐depth mechanistic study on sesterterpene biosynthesis reveals that the shape of the final product and the type of triquinane skeleton formed are regulated by the stereochemistry and conformation of GFPP.
PDF
