https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

https://depositonce.tu-berlin.de/bitstream/11303/5674/1/c2np20085f.pdf

Ribosomally synthesized and post-translationally modified peptide natural products: Overview and recommendations for a universal nomenclature

Molybdenum is the only second-row transition metal required by most living organisms, and is nearly universally distributed in biology. Enzymes containing molybdenum in their active sites have long been recognized,1 and at present over 50 molybdenum-containing enzymes have been purified and biochemically characterized; a great many more gene products have been annotated as putative molybdenum-containing proteins on the basis of genomic and bioinformatic analysis.2 In certain cases, our understanding of the relationship between enzyme structure and function is such that we can speak with confidence as to the detailed nature of the reaction mechanism and, with the availability of high-resolution X-ray crystal structures, the specific means by which transition states are stabilized and reaction rate is accelerated within the friendly confines of the active site. At the same time, our understanding of the biosynthesis of the organic cofactor that accompanies molybdenum (variously called molybdopterin or pyranopterin), the manner in which molybdenum is incorporated into it, and then further modified as necessary prior to insertion into apoprotein has also (in at least some cases) become increasingly well understood.

It is now well-established that all molybdenum-containing enzymes other than nitrogenase (in which molybdenum is incorporated into a [MoFe7S9] cluster of the active site) fall into three large and mutually exclusive families, as exemplified by the enzymes xanthine oxidase, sulfite oxidase, and DMSO reductase; these enzymes represent the focus of the present account.3 The structures of the three canonical molybdenum centers in their oxidized Mo(VI) states are shown in Figure 1, along with that for the pyranopterin cofactor. The active sites of members of the xanthine oxidase family have an LMoVIOS-(OH) structure with a square-pyramidal coordination geometry. The apical ligand is a Mo=O ligand, and the equatorial plane has two sulfurs from the enedithiolate side chain of the pyranopterin cofactor, a catalytically labile Mo–OH group, and most frequently a Mo=S. Nonfunctional forms of these enzymes exist in which the equatorial Mo=S is replaced with a second Mo=O; in at least one member of the family the Mo=S is replaced by a Mo=Se, and in others it is replaced by a more complex –S–Cu–S–Cys to give a binuclear center. Members of the sulfite oxidase family have a related LMoVIO2(S–Cys) active site, again square-pyramidal with an apical Mo=O and a bidentate enedithiolate Ligand (L) in the equatorial plane but with a second equatorial Mo=O (rather than Mo–OH) and a cysteine ligand contributed by the protein (rather than a Mo=S) completing the molybdenum coordination sphere. The final family is the most diverse structurally, although all members possess two (rather than just one) equiv of the pyranopterin cofactor and have an L2MoVIY(X) trigonal prismatic coordination geometry. DMSO reductase itself has a catalytically labile Mo=O as Y and a serinate ligand as X completing the metal coordination sphere of oxidized enzyme. Other family members have cysteine (the bacterial Nap periplasmic nitrate reductases), selenocysteine (formate dehydrogenase H), –OH (arsenite oxidase), or aspartate (the NarGHI dissimilatory nitrate reductases) in place of the serine. Some enzymes have S or even Se in place of the Mo=O group. Members of the DMSO reductase family exhibit a general structural homology to members of the aldehyde:ferredoxin oxidoreductase family of tungsten-containing enzymes;4 indeed, the first pyranopterin-containing enzyme to be crystallographically characterized was the tungsten-containing aldehyde:ferredoxin oxidoreductase from Pyrococcus furiosus,5 a fact accounting for why many workers in the field prefer “pyranopterin” (or, perhaps waggishly, “tungstopterin”) to “molybdopterin”. The term pyranopterin will generally be used in the present account.




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Figure 1


Active site structures for the three families of mononuclear molybdenum enzymes. The structures shown are, from left to right, for xanthine oxidase, sulfite oxidase, and DMSO reductase. The structure of the pyranopterin cofactor common to all of these enzymes (as well as the tungsten-containing enzymes) is given at the bottom.

/pdf/the-mononuclear-molybdenum-enzymes-huemv59go8.pdf

The Mononuclear Molybdenum Enzymes

Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. This brief review aims to highlight historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery. Furthermore a discussion of how natural product chemistry has resulted in the identification of many drug candidates; the application of advanced hyphenated spectroscopic techniques to aid in their discovery, the future of natural product chemistry and finally adopting metabolomic profiling and dereplication approaches for the comprehensive study of natural product extracts will be discussed.

https://minerva-access.unimelb.edu.au/bitstream/handle/11343/265172/PMC3901206.pdf

A historical overview of natural products in drug discovery.

The application of (S)-1,10-binaphthyl-2,20-diol as NMR chiral solvating agent (CSA) for omeprazole, and three of its analogs (lanso-, panto-, and rabe-prazole) was investigated. The formation of diastereomeric host–guest complexes in solution between the CSA and the racemic substrates produced sufficient NMR signal splitting for the determination of enantiomeric excesses by Hor F-NMR spectroscopy. Using of hydrophobic deuterated solvents was mandatory for obtaining good enantiodiscrimination, thus suggesting the importance of intermolecular hydrogen bonds in the stabilization of the complexes. The method was applied to the fast quantification of the enantiomeric purity of in-process samples of S-omeprazole. Chirality 00:000–000, 2009. VC 2009

The assignment of absolute configuration by NMR

The photochemical reaction of La@C82 with 2-adamantane-2,3-[3H]-diazirine affords adduct 2, La@C82(Ad), in a quantitative and highly selective manner. The structure of compound 2 is confirmed by ESR, MS, and UV−vis−NIR spectroscopies, and the first X-ray crystallographic characterization of an endohedral monometallofullerene derivative is reported.

Isolation and characterization of a carbene derivative of La@C82.

Microviridin. A novel tricyclic depsipeptide from the toxic cyanobacterium Microcystis viridis

We report here the results on single crystal X-ray crystallographic analysis of the Gd@C82 carbene adduct (Gd@C82(Ad), Ad = adamantylidene). The Gd atom in Gd@C82(Ad) is located at an off-centered position near a hexagonal ring in the C2v-C82 cage, as found for M@C82 (M = Sc and La) and La@C82(Ad). Theoretical calculation also confirms the position of the Gd atom in the X-ray crystal structure.

Does Gd@C82 have an anomalous endohedral structure? Synthesis and single crystal X-ray structure of the carbene adduct.

Endohedral metallofullerenes have attracted special interest as promising spherical molecules for material and catalytic applications, because of their unique properties that are not expected from empty fullerenes. The successful isolation and purification of endohedral metallofullerenes in macroscopic quantities have made it possible to investigate the structures as well as the electronic properties and reactivities through a close interplay between theory and experiment. Since the first isolation and characterization of a metal carbide encapsulated metallofullerene (Sc2C2@C84) by MEM (maximum entropy method)/Rietveld analysis of synchrotron powder diffraction data, much attention has been paid to encapsulation of metal carbides. Recently, we found by C NMR spectroscopy and X-ray single-crystal structure analyses that Sc3C82 and Sc2C84 have the structures Sc3C2@ C80(Ih) [5] and Sc2C2@C82(C3v), [6,7] encapsulating metal carbides, although it had long been believed from the MEM/Rietveld analyses that they have the conventional structures Sc3@C82 [8] and Sc2@C84 [9] , respectively. The encapsulation of metal carbides has been confirmed by the recent improved MEM/ Rietveld analyses of Y2C2@C82(C3v) [10] as well as Sc2C2@ C82(C3v) [11] and Sc3C2@C80(Ih). [12] However, attempts to detect the C NMR chemical shifts of the C2 units of metal carbides encapsulated in the fullerenes have not been yet successful. This unsuccessful detection has been explained in term of the spin-rotation interaction, because the C2 unit may rotate rapidly inside carbon cages. It is an important task to observe the C NMR chemical shift of the C2 unit in an attempt to provide insight into its electronic and magnetic properties. We present herein the first detection of the C NMR chemical shifts of the C2 unit in Sc2C2@C82(C3v), Sc2C2@ C84(D2d), and [Sc3C2@C80(Ih)] by using C-enriched samples. We also successfully assigned all C NMR chemical shifts of the cage carbon atoms for the three compounds by 2D INADEQUATE (incredible natural abundance double quantum transfer experiment) NMR measurements. The C NMR spectrum of Sc2C2@C82(C3v) (Figure 1a) shows 17 chemical shifts of the C82 cage at d = 134.6– 151.9 ppm, as reported previously. To map the bond connectivity in the carbon cage and assign the C NMR

Midori O. Ishitsuka

Papers

Isolation and characterization of a carbene derivative of La@C82.

Microviridin. A novel tricyclic depsipeptide from the toxic cyanobacterium Microcystis viridis

Does Gd@C82 have an anomalous endohedral structure? Synthesis and single crystal X-ray structure of the carbene adduct.

Observation of 13C NMR Chemical Shifts of Metal Carbides Encapsulated in Fullerenes: Sc2C2@C82, Sc2C2@C84, and Sc3C2@C80†

Elucidation of the relative and absolute stereochemistry of lobatriene, a marine diterpene, by a modified Mosher method