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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular evolution 41 (1995), S. 693-702 
    ISSN: 1432-1432
    Keywords: Orthophosphate ; Polyphosphates ; Phosphorus pentoxide ; Phosphate minerals ; High-energy organic compounds ; Thermal condensation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract It is widely held that there was a phosphate compound in prebiotic chemistry that played the role of adenosine triphosphate and that the first living organisms had ribose-phosphate in the backbone of their genetic material. However, there are no known efficient prebiotic synthesis of high-energy phosphates or phosphate esters. We review the occurrence of phosphates in Nature, the efficiency of the volcanic synthesis of P4O10, the efficiency of polyphosphate synthesis by heating phosphate minerals under geological conditions, and the use of high-energy organic compounds such as cyanamide or hydrogen cyanide. These are shown to be inefficient processes especially when the hydrolysis of the polyphosphates is taken into account. For example, if a whole atmosphere of methane or carbon monoxide were converted to cyanide which somehow synthesized polyphosphates quantitatively, the polyphosphate concentration in the ocean would still have been insignificant. We also attempted to find more efficient high-energy polymerizing agents by spark discharge syntheses, but without success. There may still be undiscovered robust prebiotic syntheses of polyphosphates, or mechanisms for concentrating them, but we conclude that phosphate esters may not have been constituents of the first genetic material. Phosphoanhydrides are also unlikely as prebiotic energy sources.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 373 (1995), S. 683-685 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] The complexity of coenzyme A (Fig. 1) is puzzling, as almost any thiol would be able to perform its function of activating carboxyl groups. One possibility6 is that pantetheine was simply formed rather easily in the prebiotic world. Pantetheine is essentially coenzyme A without the adenosine ...
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    [s.l.] : Macmillian Magazines Ltd.
    Nature 410 (2001), S. 715-718 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Functional primordial proteins presumably originated from random sequences, but it is not known how frequently functional, or even folded, proteins occur in collections of random sequences. Here we have used in vitro selection of messenger RNA displayed proteins, in which each protein is ...
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Origins of life and evolution of the biospheres 26 (1996), S. 15-25 
    ISSN: 1573-0875
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences
    Notes: Abstract In view of the importance of a prebiotic source of high energy phosphates, we have investigated a number of potentially prebiotic processes to produce condensed phosphates from orthophosphate and cyclic trimetaphosphate from tripolyphosphate. The reagents investigated include polymerizing nitriles, acid anhydrides, lactones, hexamethylene tetramine and carbon suboxide. A number of these processes give substantial yields of pyrophosphate from orthophosphate and trimetaphosphate from tripolyphosphate. Although these reactions may have been applicable in local areas, they are not sufficiently robust to have been of importance in the prebiotic open ocean.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Origins of life and evolution of the biospheres 25 (1995), S. 99-110 
    ISSN: 1573-0875
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences
    Notes: Abstract The origin of the biosynthetic pathways for the branched-chain amino acids cannot be understood in terms of the backwards development of the present acetolactate pathway because it contains unstable intermediates. We propose that the first biosynthesis of the branched-chain amino acids was by the reductive carboxylation of short branched chain fatty acids giving keto acids which were then transaminated. Similar reaction sequences mediated by nonspecific enzymes would produce serine and threonine from the abundant prebiotic compounds glycolic and lactic acids. The aromatic amino acids may also have first been synthesized in this way, e.g. tryptophan from indole acetic acid. The next step would have been the biosynthesis of leucine from α-ketoisovaleric acid. The acetolactate pathway developed subsequently. The first version of the Krebs cycle, which was used for amino acid biosynthesis, would have been assembled by making use of the reductive carboxylation and leucine biosynthesis enzymes, and completed with the development of a single new enzyme, succinate dehydrogenase. This evolutionary scheme suggests that there may be limitations to inferring the origins of metabolism by a simple back extrapolation of current pathways.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Origins of life and evolution of the biospheres 26 (1996), S. 111-129 
    ISSN: 1573-0875
    Keywords: Ferrocyanide ; ferricyanide ; Prussian Blue ; blueprint ; hydrogen cyanide production rates ; prebiotic synthesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences
    Notes: Abstract Hydrogen cyanide is the starting material for a diverse array of prebiotic syntheses, including those of amino acids and purines. Hydrogen cyanide also reacts with ferrous ions to give ferrocyanide, and so it is possible that ferrocyanide was common in the early ocean. This can only be true if the hydrogen cyanide concentration was high enough and the rate of reaction of cyanide with ferrous ions was fast enough. We show experimentally that the rate of formation of ferrocyanide is rapid even at low concentrations of hydrogen cyanide in the pH range 6–8, and therefore an equilibrium calculation is valid. The equilibrium concentrations of ferrocyanide are calculated as a function of hydrogen cyanide concentration, pH and temperature. The steady state concentration of hydrogen cyanide depends on the rate of synthesis by electric discharges and ultraviolet light and the rate of hydrolysis, which depends on pH and temperature. Our conclusions show that ferrocyanide was a major species in the prebiotic ocean only at the highest production rates of hydrogen cyanide in a strongly reducing atmosphere and at temperatures of 0°C or less, although small amounts would have been present at lower hydrogen cyanide production rates. The prebiotic application of ferrocyanide as a source of hydrated electrons, as a photochemical replication process, and in semi-permeable membranes is discussed.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Origins of life and evolution of the biospheres 26 (1996), S. 230-231 
    ISSN: 1573-0875
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Journal of inclusion phenomena and macrocyclic chemistry 5 (1987), S. 499-504 
    ISSN: 1573-1111
    Keywords: Metallocene calix[4]arenes ; synthesis ; variable temperature NMR studies ; electrochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The condensation of 1,1′-bis(chlorocarbonyl)metallocenes andp-tert-butylcalix[4]arene in toluene leads to novel metallocene calix[4]arenes in which the metallocene subunit bridges the opposite hydroxy groups of the parent calixarene.
    Type of Medium: Electronic Resource
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  • 9
    Publication Date: 2016-11-18
    Description: Millions of individuals are infected with and die from tuberculosis (TB) each year, and multidrug-resistant (MDR) strains of TB are increasingly prevalent. As such, there is an urgent need to identify novel drugs to treat TB infections. Current frontline therapies include the drug isoniazid, which inhibits the essential NADH-dependent enoyl–acyl-carrier protein (ACP) reductase, InhA. To inhibit InhA, isoniazid must be activated by the catalase-peroxidase KatG. Isoniazid resistance is linked primarily to mutations in the katG gene. Discovery of InhA inhibitors that do not require KatG activation is crucial to combat MDR TB. Multiple discovery efforts have been made against InhA in recent years. Until recently, despite achieving high potency against the enzyme, these efforts have been thwarted by lack of cellular activity. We describe here the use of DNA-encoded X-Chem (DEX) screening, combined with selection of appropriate physical properties, to identify multiple classes of InhA inhibitors with cell-based activity. The utilization of DEX screening allowed the interrogation of very large compound libraries (1011 unique small molecules) against multiple forms of the InhA enzyme in a multiplexed format. Comparison of the enriched library members across various screening conditions allowed the identification of cofactor-specific inhibitors of InhA that do not require activation by KatG, many of which had bactericidal activity in cell-based assays.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 10
    Publication Date: 2001-12-01
    Print ISSN: 1046-5928
    Electronic ISSN: 1096-0279
    Topics: Biology , Medicine
    Published by Elsevier
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