A Chemist's Perspective on the Role of Phosphorus at the Origins of Life

Abstract

The central role that phosphates play in biological systems, suggests they also played an important role in the emergence of life on Earth. In recent years, numerous important advances have been made towards understanding the influence that phosphates may have had on prebiotic chemistry, and here, we highlight two important aspects of prebiotic phosphate chemistry. Firstly, we discuss prebiotic phosphorylation reactions; we specifically contrast aqueous electrophilic phosphorylation, and aqueous nucleophilic phosphorylation strategies, with dry-state phosphorylations that are mediated by dissociative phosphoryl-transfer. Secondly, we discuss the non-structural roles that phosphates can play in prebiotic chemistry. Here, we focus on the mechanisms by which phosphate has guided prebiotic reactivity through catalysis or buffering effects, to facilitating selective transformations in neutral water. Several prebiotic routes towards the synthesis of nucleotides, amino acids, and core metabolites, that have been facilitated or controlled by phosphate acting as a general acid-base catalyst, pH buffer, or a chemical buffer, are outlined. These facile and subtle mechanisms for incorporation and exploitation of phosphates to orchestrate selective, robust prebiotic chemistry, coupled with the central and universally conserved roles of phosphates in biochemistry, provide an increasingly clear message that understanding phosphate chemistry will be a key element in elucidating the origins of life on Earth.

Keywords: amino acids; general acid-base catalyst.; nucleotides; phosphate; phosphorylation; prebiotic chemistry.

Figure 1

Biologically important phosphates, exemplifying the central role phosphates play in biological information transfer, structure, and energy metabolism.

Scheme 1

An overview of suggested prebiotic routes to orthophosphate and condensed phosphates production (black arrows), phosphate interconversion (green arrows), phosphate solubilisation (red arrows), and urea-mediated phosphorylation (blue arrows). N = nucleoside, pN = nucleotide, cTMP = cyclotriphosphate.

Scheme 2

Phosphorylation of uridine (5) and ribose (7) using orthophosphate and cyanoformamide (6), cyanogen (2), or cyanamide (3), in aqueous solution.

Scheme 3

Selective and high yielding nucleoside phosphorylation by cyclotrimetaphosphate (cTMP).

Scheme 4

Ligation of glycine (Gly), alanine (Ala), and aspartic acid (Asp) to afford their corresponding dipeptides under aqueous conditions promoted by cyclotrimetaphosphate (cTMP). Serine (Ser) affords the O-phosphorylated product 12.

Scheme 5

Two-step mechanism for amino acid activation and peptide ligation mediated by cyclotrimetaphosphate (cTMP).

Scheme 6

Reaction of diglycine (GlyGly) with cTMP to yield tetraglycine (GlyGlyGlyGly). Under strongly alkaline reaction conditions, the sole product is N-triphosphate 18 and no ligation reaction occurs, whereas at neutral or slightly acidic reaction conditions O-triphosphate 17 is obtained, which can be used to ligate the tetrapeptide GlyGlyGlyGly.

Scheme 7

(a) Cyclotrimetaphosphate (cTMP) mediated phosphorylation of glyceric acid (19). (b) Ammonolysis of cyclotrimetaphosphate (cTMP) to obtain amidotriphosphate (AmTP) and diamidophosphate (DAP). (c) Proposed pathway for the synthesis of glycolaldehyde phosphate (GCP) from glycolaldehyde (GC) and AmTP. (d) Synthesis of ribose phosphates (20 and 21) by reaction of ribose (7) and AmTP.

Scheme 8

Prebiotic synthesis of glyceric acid 2-phosphate (21-2p), phosphoserine (Ser-3p) and phosphoenol pyruvate (PEP) from the phosphorylation of glycolaldehyde (GC) and glyceraldehyde (GA) with diamidophosphate (DAP).

Scheme 9

Nucleophilic phosphorylation in water. Oxirane (24) and aziridine (25) precursors of glycolaldehyde phosphate (GCP) are phosphorylated by nucleophilic attack of inorganic phosphate in water or acetonitrile, respectively.

Scheme 10

Synthesis of aminooxazoline 5’-phosphate (27) by nucleophilic phosphorylation. The reaction of glycidaldehyde (30) and 2-aminooxazole (2AO) followed by phosphorylation of 5’-activated oxirane 31 by inorganic phosphate yields aminooxazoline 5’-phosphate (27). Direct addition of phosphate to glycidaldehyde (30) affords G3P, which decomposes to methyl glyoxal (28).

Scheme 11

Proposed mechanism for urea-mediated dissociative dry-state phosphorylation.

Scheme 12

Divergent synthesis of pyrimidine ribonucleotide 35 and 8-oxo-purine ribonucleotide 36 under prebiotic conditions.

Scheme 13

Phosphorylation of long chains alcohols such as decanol (37) is selective over shorter chain alcohols due to the different volatilities of these compounds.

Scheme 14

Prebiotic synthesis of pyrimidine ribonucleotides (35), in which each step is facilitated by phosphate (Pi).

Scheme 15

Resolution and sequestration of glycolaldehyde (GC) and glyceraldehyde (GA) from aqueous solution. Phosphate acts as a general acid–base catalyst for the Lobry de Bruyn–van Ekenstein transformation during the prebiotic selection of aldose sugars from complex sugar mixtures, facilitating the resolution of aminals 45 and 46 en route to pentose aminooxazolines (41) and ribonucleotides. ppt = precipitate.

Scheme 16

Phosphate catalysed Amadori rearrangements. (a) Synthesis of azepinomycin (48) by a one-pot phosphate catalysed protocol. (b) Prebiotic synthesis of 2-aminoimidazole (2AI).