Summary flow-of-funds accounts 1950-55

Flow of funds

Coordination Chemistry of Nucleotides and Antivirally Active Acyclic Nucleoside Phosphonates, including Mechanistic Considerations

Considering that practically all reactions that involve nucleotides also involve metal ions, it is evident that the coordination chemistry of nucleotides and their derivatives is an essential corner stone of biological inorganic chemistry. Nucleotides are either directly or indirectly involved in all processes occurring in Nature. It is therefore no surprise that the constituents of nucleotides have been chemically altered—that is, at the nucleobase residue, the sugar moiety, and also at the phosphate group, often with the aim of discovering medically useful compounds. Among such derivatives are acyclic nucleoside phosphonates (ANPs), where the sugar moiety has been replaced by an aliphatic chain (often also containing an ether oxygen atom) and the phosphate group has been replaced by a phosphonate carrying a carbon–phosphorus bond to make the compounds less hydrolysis-sensitive. Several of these ANPs show antiviral activity, and some of them are nowadays used as drugs. The antiviral activity results from the incorporation of the ANPs into the growing nucleic acid chain—i.e., polymerases accept the ANPs as substrates, leading to chain termination because of the missing 3′-hydroxyl group. We have tried in this review to describe the coordination chemistry (mainly) of the adenine nucleotides AMP and ATP and whenever possible to compare it with that of the dianion of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA2− = adenine(N9)-CH2-CH2-O-CH2-PO32) [or its diphosphate (PMEApp4−)] as a representative of the ANPs. Why is PMEApp4− a better substrate for polymerases than ATP4−? There are three reasons: (i) PMEA2− with its anti-like conformation (like AMP2−) fits well into the active site of the enzyme. (ii) The phosphonate group has an enhanced metal ion affinity because of its increased basicity. (iii) The ether oxygen forms a 5-membered chelate with the neighboring phosphonate and favors thus coordination at the Pα group. Research on ANPs containing a purine residue revealed that the kind and position of the substituent at C2 or C6 has a significant influence on the biological activity. For example, the shift of the (C6)NH2 group in PMEA to the C2 position leads to 9-[2-(phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), an isomer with only a moderate antiviral activity. Removal of (C6)NH2 favors N7 coordination, e.g., of Cu2+, whereas the ether O atom binding of Cu2+ in PMEA facilitates N3 coordination via adjacent 5- and 7-membered chelates, giving rise to a Cu(PMEA)cl/O/N3 isomer. If the metal ions (M2+) are M(α,β)-M(γ)-coordinated at a triphosphate chain, transphosphorylation occurs (kinases, etc.), whereas metal ion binding in a M(α)-M(β,γ)-type fashion is relevant for polymerases. It may be noted that with diphosphorylated PMEA, (PMEApp4−), the M(α)-M(β,γ) binding is favored because of the formation of the 5-membered chelate involving the ether O atom (see above). The self-association tendency of purines leads to the formation of dimeric [M2(ATP)]2(OH)− stacks, which occur in low concentration and where one half of the molecule undergoes the dephosphorylation reaction and the other half stabilizes the structure—i.e., acts as the “enzyme” by bridging the two ATPs. In accord herewith, one may enhance the reaction rate by adding AMP2− to the [Cu2(ATP)]2(OH)− solution, as this leads to the formation of mixed stacked Cu3(ATP)(AMP)(OH)− species, in which AMP2− takes over the structuring role, while the other “half” of the molecule undergoes dephosphorylation. It may be added that Cu3(ATP)(PMEA) or better Cu3(ATP)(PMEA)(OH)− is even a more reactive species than Cu3(ATP)(AMP)(OH)−. – The matrix-assisted self-association and its significance for cell organelles with high ATP concentrations is summarized and discussed, as is, e.g., the effect of tryptophanate (Trp−), which leads to the formation of intramolecular stacks in M(ATP)(Trp)3− complexes (formation degree about 75%). Furthermore, it is well-known that in the active-site cavities of enzymes the dielectric constant, compared with bulk water, is reduced; therefore, we have summarized and discussed the effect of a change in solvent polarity on the stability and structure of binary and ternary complexes: Opposite effects on charged O sites and neutral N sites are observed, and this leads to interesting insights

Conceptualising uncertainty in environmental decision-making: The example of the EU Water Framework Directive

The question of how to deal with uncertainty in environmental decision-making is cur-rently attracting considerable attention on the part of scientists as well as of politicians and those involved in government administration. The existence of uncertainty becomes particularly apparent in the field of environmental policy because environmental prob-lems are regarded as highly complex and long-term and because far-reaching changes have to be taken into account; moreover, the knowledge available to practitioners and policy makers alike is often fragmentary and not systemised. One key issue arising from this is the challenge to develop scientific decision support methods that are capable of dealing with uncertainty in a systematic and differentiated way, integrating scientific and practical knowledge. This paper introduces a conceptual framework for perceiving and describing uncertainty in environmental decision-making. It is argued that perceiv-ing and describing uncertainty is an important prerequisite for deciding and acting under uncertainty. The conceptual framework consists of a general definition of uncertainty along with five complementary perspectives on the phenomenon, each highlighting one specific aspect of it. By using the conceptual framework, decision-makers are able to re-flect on their knowledge base with regard to its completeness and reliability and to gain a broad picture of uncertainty from various standpoints. The theoretical ideas presented here are based on two empirical studies looking at how uncertainty is dealt with in the implementation process of the EU Water Framework Directive (WFD). The rather ab-stract differentiations are illustrated by a number of examples in the form of interview statements and excerpts from the WFD and the WFD guidance documents Impress, Wateco und Proclan. --uncertainty,probability,lack of knowledge,pure ignorance,environ-mental decision-making,EU Water Framework Directive (WFD)

Adenosine 5'-triphosphate (ATP4-): Aspects of the coordination chemistry of a multitalented biological substrate

Firstly, the self-stacking properties of ATP4- and the effects of metal ions and protons on these properties are described. Some examples involving macrochelate formation between phosphate-coordinated metal ions (M2+) and N7 of the adenine residue in MATP2- are discussed, and this is followed by considerations on mixed ligand complexes consisting of ATP4-, M2+, and amino acid anions with side chains that allow either aromatic-ring stacking or hydrophobic interactions with the adenine moiety; this gives rise to selectivity. Next, the properties of diphosphorylated 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA2-; Adefovir), i.e., of PMEApp4-, are compared with those of (2'-deoxy)ATP4- with regard to their metal ion-binding qualities, and in this way it can be explained why PMEApp2- is initially an excellent substrate for nucleic acid polymerases. Of course, after incorporation of the PMEA residue into the growing nucleic acid chain, this is terminated and this is how PMEA exerts its antiviral properties [its bis(pivaloyloxymethyl)ester, Adefovir dipivoxil, was recently approved for use in hepatitis B therapy]. Finally, the change in free energy connected with (macro)chelate formation or intramolecular stacking interactions and the effect of a reduced dielectric constant of the solvent on the stability of complexes and their structures in solution is considere

Wissensorganisation, Topic Maps und Ontology Engineering: Die Verbindung bewährter Begriffsstrukturen mit aktueller XML-Technologie

Wie können begriffliche Strukturen an Topic Maps angebunden werden? Allgemeiner: Wie kann die Wissensorganisation dazu beitragen, dass im Semantic Web eine begriffsbasierte Infrastruktur verfügbar ist? Dieser Frage hat sich die Wissensorganisation bislang noch nicht wirklich angenommen. Insgesamt ist die Berührung zwischen semantischen Wissenstechnologien und wissensorganisatorischen Fragestellungen noch sehr gering, obwohl Begriffsstrukturen, Ontologien und Topic Maps grundsätzlich gut zusammenpassen und ihre gemeinsame Betrachtung Erkenntnisse für zentrale wissensorganisatorische Fragestellungen wie z.B. semantische Interoperabilität und semantisches Retrieval erwarten lässt. Daher motiviert und skizziert dieser Beitrag die Grundidee, nach der es möglich sein müsste, eine Sprache zur Darstellung von Begriffsstrukturen in der Wissensorganisation geeignet mit Topic Maps zu verbinden. Eine genauere Untersuchung und Implementation stehen allerdings weiterhin aus. Speziell wird vermutet, dass sich der Concepto zugrunde liegende Formalismus CLF (Concept Language Formalism) mit Topic Maps vorteilhaft abbilden lässt. Damit können Begriffs- und Themennetze realisiert werden, die auf expliziten Begriffssystemen beruhen. Seitens der Wissensorganisation besteht die Notwendigkeit, sich mit aktuellen Entwicklungen auf dem Gebiet des Semantic Web und Ontology Engineering vertraut zu machen, aber auch die eigene Kompetenz stärker aktiv in diese Gebiete einzubringen. Damit dies geschehen kann, führt dieser Beitrag zum besseren Verständnis zunächst aus Sicht der Wissensorganisation knapp in Ontologien und Topic Maps ein und diskutiert wichtige Überschneidungsbereiche

Acid-base properties of purine residues and the effect of metal ions: Quantification of rare nucleobase tautomers

The macro acidity constants valid for aqueous solutions of several adenine, guanine,and hypoxanthine derivatives are summarized. It is shown how the application of the corresponding constants, e.g., for 7,9-dimethyladenine, allows a quantification of the intrinsic acidic properties of the (N1)H0/+ and (N7)H+ sites via micro acidity constants, and how to use this information for the calculation of the tautomeric ratios regarding the monoprotonated species, that is, N7-N1*H versus H*N7-N1, meaning that in one isomer H+ is at the N1 site and in the other at N7. It is further shown that different metal ions coordinated to a given site, e.g., N7, lead to a different extent of acidification, e.g., at (N1)H; the effect decreases in the series Cu2+>Ni2+>Pt2+ ~Pd2+. Moreover, the application of micro acidity constants proves that the acidifications are reciprocal and identical. This means, Pt2+ coordinated to (N1)-/0 sites in guanine, hypoxanthine, or adenine residues acidifies the (N7)H+ unit to the same extent as (N7)-coordinated Pt 2+ acidifies the (N1)H0/+ site. In other words, an apparently increased basicity of N7 upon Pt2+ coordination at (N1)-/0 sites disappears if the micro acidity constants of the appropriate isocharged tautomers of the ligand are properly taken into account. There is also evidence that proton-proton interactions are more pronounced than divalent metal ion-proton interactions, and that these in turn are possibly larger than divalent metal ion-metal ion interactions. The indicated quantifications of the acid-base properties are meaningful for nucleic acids including the formation of certain nucleobase tautomers in low concentrations, which could give rise to mutation