Nitrogenous Derivatives of Phosphorus and the Origins of Life: Plausible Prebiotic Phosphorylating Agents in Water

Abstract

Phosphorylation under plausible prebiotic conditions continues to be one of the defining issues for the role of phosphorus in the origins of life processes. In this review, we cover the reactions of alternative forms of phosphate, specifically the nitrogenous versions of phosphate (and other forms of reduced phosphorus species) from a prebiotic, synthetic organic and biochemistry perspective. The ease with which such amidophosphates or phosphoramidate derivatives phosphorylate a wide variety of substrates suggests that alternative forms of phosphate could have played a role in overcoming the "phosphorylation in water problem". We submit that serious consideration should be given to the search for primordial sources of nitrogenous versions of phosphate and other versions of phosphorus.

Keywords: (di)amidophosphate; nitrogen-phosphorus derivatives; origins of life; phosphoramidates; prebiotic phosphorylation.

Figure 1

Formation of amidotriphosphate (AmTP) 2 and diamidophosphate (DAP) 3 as described by Quimby and Flautt [35] and Feldman and Thilo [36] starting from trimetaphosphate (sodium salt) 1 and aqueous ammonia.

Figure 2

Phosphorylation of glycolaldehyde to yield glycolaldehyde phosphate (GAP, 7) using amidotriphosphate (AmTP, 2) as shown by Eschenmoser and co-workers [34].

Figure 3

Regioselective intramolecular phosphorylation of sugars using AmTP 2 in aqueous medium, exemplified here by the phosphorylation of ribose 8 [37].

Figure 4

DAP mediated intramolecular phosphorylation of aldoses in a regioselective manner. R = CH₂OH and (CHOH)_n–CH₂OH [37].

Figure 5

Trimetaphosphate (TMP) 1 mediated phosphorylation of α-hydroxy-n-alkylamines 16, further illustrating the utility of the P–N derivatives towards phosphorylation in aqueous medium by intramolecular phosphate transfer [38].

Figure 6

Phosphorylation of arabinose with DAP 3 in aqueous medium demonstrated by Sutherland and co-workers [39].

Figure 7

Powner’s work on regioselective α-phosphorylation of glyceraldehyde 31 with DAP 3 further leading to glycolysis intermediates [40].

Figure 8

Rabinowitz’s mechanism for the reaction of trimetaphosphate 1 or polyphosphates (sodium salts) and amino acids leading to the formation of dipeptide 41 [41,42].

Figure 9

Orgel’s mechanism for dipeptide formation via cyclic and phosphoryl-activated amino acids (CAPA) intermediate 44 involving the attack of the amino group on the trimetaphosphate 1 [44].

Figure 10

Derivatives of CAPA 44, 46 and acyclic N-alkylated phosphoryl amino acids intermediates 47, 48 and hexa-coordinated P–N intermediate 49 observed during the formation of small peptide mediated by phosphate species as explained by Yu et al [49].

Figure 11

Dual electrophilic centers (carbonyl and phosphoryl) present in α-CAPAs 51 leading to the formation of dipeptide by the attack of an amino acid 35 at the carbonyl center and the formation of (oligo) nucleotides via the attack of nucleoside 52 at the phosphoryl center 50 respectively. (5'UMP—5' uridine monophosphate; UpU—3',5'-uridyluridine; Thr–NH₂—threonine).

Figure 12

Introduction of imidazole 5'-adenosine monoamidophosphate (ImpA) 55 for the activation of amino acid residues to form longer peptides as demonstrated by Orgel et al. [52,53].

Figure 13

The condensation of an amino acid 35 and a 5'-nucleoside monophosphate 62 in a condensing buffer leading to the simultaneous formation of oligonucleotides and oligopeptides amino acid 5'-nucleoside amidophosphate [54,55,56].

Figure 14

The activation of the carboxylic acid with ATP 67 (without an enzyme) through the formation of an acetyl phosphate, trapped by hydroxylamine 68 leading to the formation of acetylhydroxamate 69 [57].

Figure 15

Formation of diglycine 75 through the condensation reaction between –NH₂ of glycine 72 with ATP 67. Imidazole 57 was required for the condensation to occur due to the formation of the amidophosphate intermediate 55 [58].

Figure 16

A summary of the different 5'-phosphoramidate (P–N) species that was pioneered by Orgel [68] and expanded to other variants by Ferris [69,70,71] and Szostak [72] (to cite a few) for non-enzymatic oligonucleotide poly(N)-template mediated replication studies. The resulting product oligonucleotide formed by those methodologies contained 2'-5' non-natural linkage and/or the natural 3'–5' phosphodiester linkage.

Figure 17

Atherton, Openshaw and Todd's pioneer works demonstrating the synthesis of phosphoramidate 82 via reaction of dialkylphosphite 79 and alkylamine 81 [77].

Figure 18

Synthesis of nucleoside-5'-diphosphates 89 with various phosphoramidate species described by Moffatt and Khorana [78].

Figure 19

Formation of adenosine 5'-diphosphate 70 by the reaction of adenosine 5'-phosphoramidates 90 with orthophosphoric acid via displacement of NH₃ as the leaving group [79].

Figure 20

Convenient method for the formation of adenosine 5'-pyrophosphate 70 on reaction of monobenzylesters of amidophosphate 91 with adenosine 5'-monophosphate 59 [80].

Figure 21

Synthesis of nucleoside tetraphosphate 95 via the formation of activated P–N compound 93 as demonstrated by Taylor and co-workers [83].

Figure 22

Synthesis of nucleoside triphosphate 96 by the activation of trimetaphosphate with DABCO [84].

Figure 23

Peptide formation reaction using preformed amidophosphate of an amino acid 97 with another N-protected amino acid 98 [85].

Figure 24

Various other types of P–N bond linkages known in the literature.

Figure 25

Phosphoramidate ProTides of (fluoro)-deoxyribose [89].

Figure 26

Protide libraries with modified nucleobases [91].

Figure 27

Herdewijn’s work on the synthesis of 5'-peptidylnucleotides which can be used as pronucleotides [92].

Figure 28

P–N bonds containing species that are used in extant biochemical pathways.

Figure 29

Monoclonal 1- and 3-phosphohistidine antibodies.

Figure 30

(Top) The generation of phosphocreatine which is a phosphoryl transfer agent and (below) Human and Escherichia coli Histidine Triad Nucleotide Binding Proteins (Hint) activated phosphoramidate pronucleotide as described by Wagner et al. [101].

Figure 31

Representative structures of different P species observed by the aqueous corrosion of Fe₃P.

Figure 32

Phosphorylation of nucleosides in urea/ammonium formate/water (UAFW) eutectic solution as demonstrated by Burcar et al. [110].

Figure 33

Plausible prebiotic nitrogenous analogues of inorganic phosphates.