A tandem combinatorial model for the prebiogenesis of diverse tetrapyrrole macrocycles

Abstract

The extant biosynthesis of tetrapyrrole macrocycles has been considered a paradigm for the prebiotic formation of such molecules, yet only a few analogous non-enzymic reactions along the overall process have been demonstrated. In a prior study, the aqueous non-enzymic reaction of a dione and an aminoketone (d-aminolevulinic acid) afforded uroporphyrinogen, Nature's last universal precursor to all extant tetrapyrroles. Here, in one flask the non-enzymic combinatorial reaction of two diones (substituents = acetic acid and methyl) and two aminoketones (substituents = propionic acid and ethyl) yields four pyrroles, which upon subsequent combinatorial reaction afford a distribution of porphyrinogens. A software program for virtual library generation predicts 538 porphyrinogens from this [2 Â 2] reaction (owing to combinations and permutations) of which there are 25 sets of isomers based on condensed formulas of substituents. The collection spans the entire range of polarity enabled by the biosynthesis including uro-(number of carboxylic acids = 8), copro-(4), meso-( 2), and etio-porphyrinogen (0). The first two are successive intermediates in the extant biosynthesis, the latter two resemble in polarity the advanced biosynthetic products protoporphyrin and chlorophyll. Upon consideration of substituent patterns, the porphyrins (obtained by oxidation of the porphyrinogens) can be grouped into one of four polarity categories (predicted percentage): hydrophilic (0.4%), uncertain (83.6%), amphiphilic (15.6%), and hydrophobic (0.4%). HPLC and mass spectrometry data are consistent with expectations to the limit of analytical capabilities. Thus, in terms of the polarity of the tetrapyrrole macrocycles formed, an all-at-once non-enzymic combinatorial process recapitulates features of the stepwise biosynthetic pathway.

Complexity in structure-directed prebiotic chemistry. Effect of a defective competing reactant in tetrapyrrole formation

“…Tetrapyrroles have been proposed as essential for evolution if not for the origin of life. 9 The expansive number of products from such a small set of reactants stems from the incorporation of four pyrroles in each porphyrin macrocycle. Indeed, the use of reactants that bear polar and/or nonpolar substituents affords a mixture of porphyrins, the hydrophilic, amphiphilic, and hydrophobic members of which partition spontaneously in aqueous-surfactant media.…”

“…One of the classic examples of a structure-directed reaction of proposed prebiotic relevance is the conversion of hydrogen cyanide to heterocycles including adenine. [7][8][9][10][11][12][13][14] Tetrapyrrole macrocycles have been suggested as valuable photoactive constituents in the evolution if not the origin of life. 5 A more recent example concerns the formation of nucleotides from simple constituents.…”

“…One reaction pathway is shown in Scheme 1. As one example, a combinatorial reaction of two aminoketones and two diketones affords up to 538 porphyrinogens, 9 whereas a corresponding [4 Â 4] combinatorial reaction affords up to 131 464 porphyrinogens. The a-methoxymethyl group enables self-condensation of the pyrrole leading to uroporphyrinogens; the latter upon dehydrogenation afford uroporphyrins, which have been proposed as ideal prebiotic photosensitizers.…”

Primordial Oil Slick and the Formation of Hydrophobic Tetrapyrrole Macrocycles

“…Recently, we examined the three pairwise reactions of 1-AcOH + 2-PrOH, 1-Me + 2-PrOH, and 1-Me + 2-Et (one dione and one aminoketone each), as are shown in Scheme 3. Each reaction was performed in aqueous solution in the presence or absence of the surfactant sodium dodecylsulfate (Taniguchi et al, 2012). The pairwise reactions (upon chemical oxidation) give the wellknown uroporphyrin, coproporphyrin, and etioporphyrin macrocycles, respectively, which represent three different classes of polarity.…”

“…Coproporphyrins, with four hydrophilic and four hydrophobic groups, can either aggregate in water or associate with a surfactant. Etioporphyrins have no carboxylic acid substituents, are hydrophobic, and are not expected to form in water in significant yields due to aggregation/precipitation of oligopyrromethane intermediates (Taniguchi et al, 2012).…”