See also: Divergent prebiotic synthesis of pyrimidine and 8-oxo-purine ribonucleotides
We have demonstrated the generational relationship between pyrimidine and purine nucleotides by constructing both heterocycles on the same sugar scaffold. The formal (C8)-oxidation level of the 8-oxo-purine moiety allows constitutional assembly of the 8-oxo-purine ribonucleotides at the same oxidation level as the canonical pyrimidine ribonucleotides. It is also of note that glycine nitrile adduct 10d, which is not at the correct oxidation level to yield an aminoimidazole, is not observed to undergo cyclization; cyclization is only observed with hydrogen cyanide trimers 10b and 10c to form the core imidazole motif of the purines. These highly selective cyclizations strongly suggest that renewed investigation of prebiotic aminonitrile 2b is warranted7,54, avoiding the uncontrolled high-pH oligomerization of hydrogen cyanide. The recent observation that stepwise redox coupling of cyanide and aldehydes, under mild photoredox conditions, negates the requirement for uncontrolled high-pH formaldehyde oligomerization during prebiotic sugar synthesis25, suggests that similar redox coupling strategies could provide an alternative mechanism for hydrogen cyanide oligomerizations in a controlled and stepwise manner. We are also currently investigating the chemoselective reduction of the 8-oxo-purine ribonucleotide-2′,3′-cyclic phosphates 3OA and 3OI to the canonical ribonucleotides 3A and 3I. However, given the strongly disfavoured Hoogsteen pairing in RNA55, it is also possible that the 8-oxo-purine ribonucleotides would allow for reasonably accurate information transfer during the non-enzymatic copying of RNA templates. Given the parity between pyrimidine and 8-oxo-purine ribonucleotide-2′,3′-cyclic phosphate 3OA and 3OI syntheses, 3OA and 3OI are good candidates for monomeric units in the early stage of replication and template-directed RNA synthesis. Moreover, 8-oxo-purines have remarkably stable glycosidic linkages56,57, and when incorporated into RNA strands can mimic the function of a flavin in photorepair suggesting this motif could have provided an essential role in prebiotic redox and repair processes17. Although purine-pyrimidine Watson–Crick base pairing is thermodynamically less stable with 8-oxo-nucleotides58, the resulting lower melting temperature of the RNA duplex may have been advantageous by facilitating thermal strand separation. Accordingly, our results suggest that further investigation of the informational and functional properties of the 8-oxo-purine ribonucleotides is warranted.
My summary: A single process that transfers energy as information from sunlight in the context of the physiology of reproduction links the Creation of the sun to all biophysically constrained pheromone-controlled chromosomal rearrangements and all biodiversity via the transgenerational epigenetic inheritance of all morphological and behavioral phenotypes.
Reported as: How RNA formed at the origins of life
A single process for how a group of molecules called nucleotides were made on the early Earth, before life began, has been suggested by a UCL-led team of researchers.
Nucleotides are essential to all life on Earth as they form the building blocks of DNA or RNA, and understanding how they were first made is a long-standing challenge that must be resolved to elucidate the origins of life.
In a study, published today in Nature Communications and funded by the Engineering and Physical Sciences Research Council, the Simons Foundation and the Origins of Life Challenge, researchers from UCL, Harvard University and Massachusetts General Hospital suggest a single chemical mechanism by which both classes of nucleotides—purines and pyrimidines—could have formed together.
Before now, scientists thought that the two classes of nucleotide must have been made separately and under mutually incompatible conditions. This study is the first to show that both purines and pyrimidines can be formed from a common precursor molecule that existed before life began.
“We provide a new perspective on how the original RNA molecules were made and suggest a simple chemical solution for delivering both purine and pyrimidine nucleotides at the origins of life,” explained corresponding author, Dr Matthew Powner (UCL Chemistry).
“RNA is the corner stone of all life on Earth and probably carried the first information at the outset of life, but making RNA requires both purine and pyrimidine nucleotides to be simultaneously available. A solution to this problem has remained elusive for more than 50 years.”
The team demonstrated how purines and pyrimidine nucleotides can both be assembled on the same sugar scaffold to form molecules called ribonucleotides which are used to construct RNA.
Purine and pyrimidine nucleotides are used to create the DNA and RNA. The purine and pyrimidine nucleotides bind to one another through specific molecular interactions that provide a mechanism to copy and transfer information at the molecular level, which is essential for genetics, replication and evolution. Therefore understanding the origins of nucleotides is thought to be key to understanding the origins of life itself.
The team discovered that molecules, called 8-oxo-adenosine and 8-oxo-inosine, which are purine ribonucleotides, can be formed under the same chemical conditions as the natural pyrimidine ribonucleotides. They also found that one chemical precursor can divergently yield both purine and pyrimidine ribonucleotides.
“The mechanism we’ve reported gives both classes of molecule the same stereochemistry that is universally found in the sugar scaffold of biological nucleic acids, suggesting that 8-oxo-purine ribonucleotides may have played a key role in primordial nucleic acids,” said Dr Shaun Stairs (UCL Chemistry), first author of the study.
The team now plans to further investigate mechanisms that use 8-oxo-purines to transfer information, which could help scientists better understand life’s first informational transfer systems.
See also: Passing epigenetic silence to the next generation (subtitle from the print copy: Long-term epigenetic memory requires sequence-specific recruitment of enzymes)
During development and cell differentiation, histone constituents of nucleosomes are modified by the methylation, acetylation, or phosphorylation of specific amino acids. Different modifications are associated with active or silenced genes.
Ecological adaptation requires fixation of the amino acid substitutions in supercoiled DNA. By placing fixation into the context of epigenetic silence, they obfuscate the fact that fixation is energy-dependent. There is no consideration for the energy-dependent creation of the enzymes.
In the worlds of biologically uninformed theorists, energy-dependent creation goes missing, which means that virus-driven energy theft cannot be linked to all pathology.
See for example: Assessing cooperativity in supramolecular systems
This tutorial review summarises different aspects of cooperativity in supramolecular complexes.
They boldly go where no serious scientist has ever gone before. They redefine interactions between substrates and ezymes to broaden their theromodynamic perspective and eliminate the fact that the interactions are energy-dependent and also biophysically constrained.
The interactions among binding events that involve multiple steps that must link the free energy change to each subsequent step is compared to cooperative effects in which each energy-dependent step is equal to the next one in energy. A double mutant cycle is placed into the context of equilibrium and the advantages supposedly become clear.
The report (week ending March 3, 2017 on the differences in energy of two photons in Hard Two-Photon Contribution to Elastic Lepton-Proton Scattering Determined by the OLYMPUS Experiment is not considered in the report from Thordarson’s group, which was published on March 30, 2017.
Thordarson may never learn to link the differences in the energy of two photons to amino acid substitutions in supercoiled DNA, despite this January 2, 2017 publication from his group: Cooperative Subunit Refolding of a Light-Harvesting Protein through a Self-Chaperone Mechanism (with my emphasis)
The fold of a protein is encoded by its amino acid sequence, but how complex multimeric proteins fold and assemble into functional quaternary structures remains unclear. Here we show that two structurally different phycobiliproteins refold and reassemble in a cooperative manner from their unfolded polypeptide subunits, without biological chaperones. Refolding was confirmed by ultrafast broadband transient absorption and two-dimensional electronic spectroscopy to probe internal chromophores as a marker of quaternary structure. Our results demonstrate a cooperative, self-chaperone refolding mechanism, whereby the beta-subunits independently refold, thereby templating the folding of the alpha-subunits, which then chaperone the assembly of the native complex, quantitatively returning all coherences. Our results indicate that subunit self-chaperoning is a robust mechanism for heteromeric protein folding and assembly that could also be applied in self-assembled synthetic hierarchical systems.
Thordarson’s group ignored the link from energy-dependent natural selection for codon optimality and RNA-mediated amino acid substitutions in supercoiled DNA, which protects all organized genomes from virus-driven energy theft and genomic entropy. They substituted subunit self-chaperoning is a robust mechanism for heteromeric protein folding for protein folding that must be encoded by its amino acid sequence.
See also: Magnus S. Magnusson and my attempt to discuss: Human brain networks function in connectome-specific harmonic waves
James – I work on ATP synthase and non-equilibrium chemistry amongst other things. What on earth are you trying to say above?? It doesn’t make one iota of sense to me. ATP is the main energy source of the cell – yes we know that – when known that for decades. So what? I actually don’t think you understand the articles you cite. E.g., the cell article – what does it say: “Spatially localized protein synthesis allows selective memory consolidation”. And in the conclusions: “In general, neuronal protein synthesis may constitute a powerful signal for encoding information in the nervous system because it is complementary to electrical signaling in both time and space.” The phrase “genome engineering” (whatever that means) is never uttered or even implied. The medexpress cites a recent Nature Medince paper. If you go to that it actually says that viruses cause memory loss. Yes – surprising right? No? People can die from virus infections so a virus infection damaging neural cells is not exactly rocket science. Basically the Nature Med articles seems to show that a viral infection (which can be mimicked with synthetic RNA) does havoc with the immune response, especially a pprotein called CX3CR1 which is a signalling protein (GPCR) in monocytes (white blood cells). That these white cells goes out of whack then appears to be associated with memory loss. The articles doesn’t say what the direct link is between monocyte malfunction and memory loss but it stands to reason that neural cells need a healthy immune system to do “housekeeping” in the brain just like everywhere else in the body. Again, I really don’t think you understand what you are citing. Finally the old Biochimica article. It opens with “The synthesis of RNA in isolated thymus nuclei is ATP dependent.”. This is 1964 – the real role of DNA had only been discovered 12 years earlier. So they are pointing out that the cell needs ATP for RNA synthesis. Yes, is that surprising? Nearly every complicated biosynthetic pathway in the cell is thermodynamically unfavourable. That is, it needs energy. And in most cases that is ATP (sometime it’s cousin GTP and others kick in). So what this important paper did was to prove to us (because no-one had done it yet), that it is indeed ATP that is needed for RNA synthesis. No big surprise. The fact they used thymus cell is no significance. They just probably happened to be the ones that were easily accessible and easy to work with for those groups in those days. Just like now, we mainly use E. Coli for certain experiments. It doesn’t mean it is “special” just easy to work with. I am guessing though they choose the thymus cells because they have always been popular in immunology research and maybe that was their background? But the fact is that their results – ATP is needed for RNA synthesis are of universal nature – this is the case in all cells as far as I know. So how about next time James Kohl that you actually read the articles you are citing and try to understand them before you go on a wild goose chase and make strange claims in relation to what are well-known biochemical facts (mainly – yes, we need ATP).
See also the comment from Ryan Littlefield here
Ryan S. Littlefield dropped his pants and exposed himself as co-author of A nebulin ruler does not dictate thin filament lengths
and the senior author of: A nebulin ruler does not dictate thin filament lengths Tropomodulin isoforms regulate thin filament pointed-end capping and skeletal muscle physiology
It has become perfectly clear to all serious scientists that he failed to learn that alternative splicings of pre-mRNA are food energy-dependent. That fact helped serious scientists establish the fact that virus-driven energy theft is the cause of all pathology.