The origin of life is believed to have started with prebiotic molecules reacting along unidentified pathways to produce key molecules such as nucleosides. To date, a single prebiotic pathway to purine nucleosides had been proposed. It is considered to be inefficient due to missing regioselectivity and low yields. We report that the condensation of formamidopyrimidines (FaPys) with sugars provides the natural N-9 nucleosides with extreme regioselectivity and in good yields (60%). The FaPys are available from formic acid and aminopyrimidines, which are in turn available from prebiotic molecules that were also detected during the Rosetta comet mission. This nucleoside formation pathway can be fused to sugar-forming reactions to produce pentosides, providing a plausible scenario of how purine nucleosides may have formed under prebiotic conditions.

In this paper, the synthesis of a new type of intrinsically chiral, directly beta,beta'-linked, octa-meso-aryl-substituted bisporphyrins is described, by using an optimized Suzuki-Miyaura coupling procedure. This strategy leads to a broad variety of such axially chiral 'superbiaryls', differing in their metalation states and substitution patterns. On the basis of an efficient route to as-yet-unknown beta-boronic acid esters of various meso-tetraarylporphyrins (TAPs) by a two-step bromination-borylation protocol, 18 axially chiral bisporphyrin derivatives were prepared in good to excellent yields. As compared to all other directly linked dimeric porphyrin systems, the joint presence of eight bulky meso substituents and the peripheral position of the porphyrin-porphyrin linkage is unprecedented. The axial configurations and rotational barriers of the pure atropo-enantiomers were investigated by HPLC-CD experiments on a chiral phase in combination with quantum chemical CD calculations. According to the HPLC experiments and in agreement with quantum chemical calculations by applying the dispersion-corrected BLYP method, the configurational stability of the central porphyrin-porphyrin axis strongly depends on the nature of the central metals. Cyclovoltammetric studies proved the systematic influence of the meso substituents and of the metal ions on the oxidation potentials of the bisporphyrins. The novel axially chiral bis(tetrapyrrole) compounds described here are potentially useful as substrates for asymmetric catalysis, biomimetic studies on directed electron-transfer processes, for photodynamic therapy (PDT), and for chiral recognition.

8-Oxopurines (8-oxodG and 8-oxodA) and formamidopyrimidines (FaPydG and FaPydA) are major oxidative DNA lesions involved in cancer development and aging. Their mutagenicity is believed to result from a conformational shift of the N9-C1' glycosidic bonds from anti to syn, which allows the lesions to form noncanonical Hoogsteen-type base pairs with incoming triphosphates during DNA replication. Here we present biochemical data and what are to our knowledge the first crystal structures of carbocyclic FaPydA and FaPydG containing DNA in complex with a high-fidelity polymerase. Crystallographic snapshots show that the cFaPy lesions keep the anti geometry of the glycosidic bond during error-free and error-prone replication. The observed dG·dC→dT·dA transversion mutations are the result of base shifting and tautomerization.

DNA base-damage recognition in the base excision repair (BER) is a process operating on a wide variety of alkylated, oxidized and degraded bases. DNA glycosylases are the key enzymes which initiate the BER pathway by recognizing and excising the base damages guiding the damaged DNA through repair synthesis. We report here biochemical and structural evidence for the irreversible entrapment of DNA glycosylases by 5-hydroxy-5-methylhydantoin, an oxidized thymine lesion. The first crystal structure of a suicide complex between DNA glycosylase and unrepaired DNA has been solved. In this structure, the formamidopyrimidine-(Fapy) DNA glycosylase from Lactococcus lactis (LlFpg/LlMutM) is covalently bound to the hydantoin carbanucleoside-containing DNA. Coupling a structural approach by solving also the crystal structure of the non-covalent complex with site directed mutagenesis, this atypical suicide reaction mechanism was elucidated. It results from the nucleophilic attack of the catalytic N-terminal proline of LlFpg on the C5-carbon of the base moiety of the hydantoin lesion. The biological significance of this finding is discussed.

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