Mineral Induced Formation of Pentose-2,4-Bisphosphates*

MINERAL INDUCED FORMATION OFPENTOSE-2,4-BISPHOSPHATES∗

R. KRISHNAMURTHY†, S. PITSCH‡ and G. ARRHENIUSScripps Institution of Oceanography, University of California, San Diego, La Jolla, CA

92093-0220, U.S.A.

(Received 13 April, 1998)

Abstract. Formation of rac.-pentose-2,4-bisphosphates is demonstrated, starting from glycolalde-hyde phosphate and glyceraldehyde-2-phosphate, and induced by mixed valence double layer metalhydroxide minerals. The reactions proceed from dilute aqueous reactant solutions (1.5 mM) at nearneutral pH. Conditions have been established, where ribose-2,4-bisphosphate is the major product(∼48%) among the pentose-2,4-bisphosphates, which are formed with up to 25% yield.

1. Introduction

Müller, Pitschet al. (1990) demonstrated that rac.-pentose-2,4-bisphosphates andhexose-2,4,6-trisphosphates can be formed in basic aqueous solution by aldoliza-tion of glycolaldehyde phosphate in the presence of formaldehyde with rac.-ribose-2,4-bisphosphate as the major product in the aldolization mixture. In a collabora-tive investigation of the ETH and SIO groups it was then found that the formation ofhexose-2,4,6-trisphosphates is induced in the aqueous interlayer of mixed valencedouble layer metal hydroxide minerals suspended in more dilute and less basicsolution of glycolaldehyde phosphate (Pitschet al., 1995). However in the presenceof formaldehyde under otherwise identical conditions pentose-2,4-bisphosphatesformed only in low yield (1–5%).

Starting from equimolar amounts of glycolaldehyde phosphate and rac.-glycer-aldehyde-2-phosphate under otherwise similar conditions, yields were lower than7%. Further work was therefore undertaken at SIO to clarify the conditions un-der which the yield could be improved. This report describes the result of thisinvestigation.

∗ Part of this work was presented at the ISSOL’96 meeting, July 8–13, 1996, Orleans, France.(Abstract; R. Krishnamurthyet al., 1996).

† Present address: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, LaJolla, CA 92037, U.S.A.

‡ Present address: Laboratorium für Organische Chemie, ETH-Zentrum, CH 8092, Zürich,Switzerland.

Origins of Life and Evolution of the Biosphere29: 139–152, 1999.© 1999Kluwer Academic Publishers. Printed in the Netherlands.

140 R. KRISHNAMURTHY ET AL.

2. Experimental Procedures

2.1. STARTING MATERIALS AND ANALYTICAL PROCEDURES

Glycolaldehyde phosphate was obtained by ozonolysis of allyl phosphate follow-ing the procedure of Pitsch (1993). (Rac)-glyceraldehyde-2-phosphate was pre-pared by reaction of glycolaldehyde phosphate (50 mM) and formaldehyde (1.0 M)in aqueous sodium bicarbonate buffer solution (0.2 M, pH = 10.5) at ambienttemperature for 24 hr, with subsequent purification on Dowex ion exchange resin1x8, and elution with triethylammonium bicarbonate buffer. GC-MS analysis wascarried out with a Supelco SP 2340 fused silica column (30 mm×20 mm) and aHewlett Packard HP-3390A instrument using He as a carrier gas (gradient: 50 to180 ◦C in 3 min, then 2◦C min−1. to 240◦C) and detection with a HP-mass ana-lyzer using SIM at 43 amu. The relative response factors were determined by usingcommercially available sugars from Aldrich Chemical Co. All reactions containedpentaerythritol as an internal standard.1H-NMR data were acquired on a BrukerWM600 (600 MHz) instrument with deuterium oxide as the solvent. Double layermetal hydroxide (DLH) minerals used in this study were synthesized and annealed(in their chloride form) as described by Kumaet al., 1989 and by Pitschet al., 1995.Oxidizable mineral species (mangalite) were stored under a blanket of nitrogen.Structural properties were established by powder X-ray diffraction analysis usinga modified General Electric XRD-5 diffractometer with monochromatized Cu Kα

radiation.The low temperature forms of the mixed valence double layer metal hydrox-

ide minerals used here are isostructural (space group C53v – R3m) and consist

of sheets of octahedrally coordinated hydroxyl ions surrounding the alternatingdivalent and trivalent small metal cations, normally in proportion 2:1. This hexag-onal molecular sheet arrangement, [M2+

2 M3+(OH−)6]+ leads to an excess positivecharge for each R3+ ion in the sheets which thus repel each other and stratifythe structure with alternating aqueous interlayers containing charge compensating,exchangeable anions. The anion/water ratio is at room temperature and moisturesaturation mostly around 1/4, generating a quasi two dimensional diffusive anionicsolution, bilaterally bounded by the catalytically active, positively charged metalhydroxide sheets. Divalent ion substitutions in these minerals mostly involve Mg,Fe, Co, Ni, Zn; the trivalent ion is most commonly Al, Fe or Cr; these DLHminerals occur in various sedimentary and metasomatic environments in nature.Most abundant today are the Mg2+Al3+ (hydrotalcite) and Mg2+Fe3+ (ferriaurite)species, with CO2−3 , SO2−

4 and Cl− as common interlayer anions. Under pre-oxicArchean conditions an abundance of the Fe2+Fe3+ mineral, green rust, is indicatedby the widespread occurrence in the sedimentary banded iron formations (BIF) ofmagnetite Fe2+O·Fe3+

2 O3, a low temperature alteration product of green rust.

MINERAL INDUCED FORMATION OF PENTOSE-2,4-BISPHOSPHATES 141

2.2. EXPLORATORY EXPERIMENTS USING HYDROTALCITE, [Mg2Al(OH)6][Cl·nH2O], AS SOLID PHASE

The experimental procedure followed closely the one described by Pitschet al.(1995). The mineral induced coaldolization of GAP (1.5 mM) and G2P (1.5 mM)in a total volume of 14 mL was explored with varying amounts (40–300 mg,0.14–1.1 mmol positive charges) of hydrotalcite, at different pH (7.0–10.0) and∼22 ◦C. A stock solution of a 1:1 mixture of GAP and G2P as the sodium saltswas prepared containing a known amount of pentaerythritol (PE) as an internalstandard to determine yields by GC-MS. In a typical procedure, the mineral wassuspended in the solution containing GAP and G2P under a nitrogen atmosphere,pH was adjusted to the desired value by the addition of 0.1 M aqueous NaOH andthe total volume brought to 14.0 mL. The suspension was shaken over a period of7 days under nitrogen. After 7 days, pH was measured and the reaction mixtureshaken with cation exchange resin Amberlyst IR 120 (H+ form) until the mineralhad dissolved to give a clear solution with the metal cations sorbed in the resin,which was filtered off. The sugar phosphates were then derivatized by reductionwith NaBH4 followed by enzymic dephosphorylation with alkaline phosphataseand peracetylation of the polyols. The products were analyzed by GC, followingprotocols established by Mülleret al. (1990), Pitsch (1993) and the modificationsdescribed above.

The experiments indicated that the yields of pentose phosphates at pH 7.0–8.5in the aqueous phase used in the mineral induced reactions were twice as high(∼15%) as in similarly catalyzed reactions carried out at pH 10 (∼7%; Pitschetal., 1995). The reactions run at high pH (8.5–10.0) yielded substantial amountsof tetrose-2,4-bisphosphates while in the lower pH range, only minor amounts oftetrose and hexose phosphates were formed. The proportion of ribose (ca. 25%)among the pentoses was found to be largely independent of the mineral/reactantratio. The yield (based on glycolaldehyde phosphate) was doubled by doublingthe concentration of glyceraldehyde-2-phosphate to 3.0 mM while retaining the1.5 mM concentration of glycolaldehyde phosphate. The lower yields of the pentose-2,4-bisphosphates in the earlier work (Pitschet al., 1995) could be attributed tothe fact that (1) those experiments were conducted at a high pH (∼10) where theGAP reacted faster with itself to afford tetroses and therefore was not availableto react with G2P and (2) reduced availability of G2P to react with GAP, causedby the destruction of G2P by base-catalyzed irreversible dehydration to give thecorresponding enolphosphate, which has been observed by1H-NMR in solutionreactions. The availability of G2P is further limited by the fact that the mineralpreferentially sorbs GAP over G2P by a factor of 3:1 (as deduced from competitionexperiments monitored by1H-NMR).

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Figure 1.Reaction between glycolaldehyde phosphate (GAP) and glyceraldehyde-2-phosphate (G2P) in varying proportions in the presence of mixed valencedouble layer metal hydroxide minerals with varying substitution of the divalent metal cation in the main hydroxide sheets. The interlayer water content isgenerally in the range of 4–6 molecules per anion, giving an effective anion concentration of the order of 10 M.


2.3. EXPLORATORY EXPERIMENTS WITH VARYING REACTION

TEMPERATURE, MINERAL /SUBSTRATE RATIO, AND CATION

SUBSTITUTION IN THE MOLECULAR SHEETS OF THE SOLID

Variation of temperature and of the divalent metal cations, Mg, Mn, Co and Znin the metal hydroxide structure was explored in order to optimize the yields ofpentose-2,4-bisphosphates. For each mineral a set of six reaction conditions werechosen, varying the mineral-substrate ratio (3 values) at 22◦C and 40◦C. Allreactions were carried out at near neutral pH of the suspension. The concentrationof the two aldehyde reactants was 1.5 mm each. The results are summarized inFigures 2A and B.

These experiments showed that the nature of the divalent metal cations in themain hydroxide sheets of the mineral has marked effects on the product yields anddiastereomeric ratios. In all cases the yields at 40◦C were relatively higher (5–10%) than at 22◦C, with this effect increasing in the order of Zn<Mg<Mn<Co.The optimal ratio of the mineral to substrate was shifted to higher values at 40◦C,while the ratio of ribose within the pentoses was always modestly higher (up to 5%)at 22◦C. For the magnesium mineral hydrotalcite, variation in the range of 5–20mole equivalents relative to substrate had little or no effect on total product and rel-ative pentose-2,4-bisphosphates yield. In sharp contrast, an increased total productyield (up to 12%) was obtained for the cobalt-aluminum (coalite) and manganese-aluminum (mangalite) minerals at 40◦C accompanied by a slight decrease (up to5%) in the relative yield of ribose-2,4-bisphosphate. Among the different miner-als examined, coalite gave the highest yield of pentose-2,4-bisphosphates (∼20%)while the highest ratio of ribose (∼45%) among the pentose-2,4-bisphosphates wasobtained with the manganese aluminum hydroxide mineral, mangalite. Since themangalite also yielded∼14% of the pentose-2,4-bisphosphates, it appeared as thebest candidate for effective mineral induced formation of ribose-2,4-bisphosphate.

2.4. EXPLORATORY EXPERIMENTS WITH MANGALITE, VARYING THE RATIO

GAP/G2P

Utilizing mangalite, changes in the yield of pentosebisphosphate were studied withvarying ratios of GAP/G2P. Keeping GAP constant, the amount of G2P was variedfrom 1 to 4 mole equivalents. The reaction was continued for 6 days at 40◦C andat pH 7.5 of the suspension, and with 6 mole equivalents of the mineral relativeto the sum of GAP and G2P. The results are plotted in Figure 3, showing that theoptimal production of pentose-2,4-bisphosphates is accompanied by an increasedproportion (up to 48%) of ribose-2,4-bisphosphate in this fraction. It was also notedthat under these circumstances tetrose- and hexose phosphates are produced inamounts less than 5%.

Utilizing the optimal conditions (1.5 mM GAP, 6.0 mM G2P; 40◦C, 6 daysat pH 7.5) an experiment was carried out analogously but in the absence of anymineral. An initial pH of 7.5 was attained by addition of 10 mM NaOH; after six

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Figure 2. Effect of variation of mineral cation composition and concentration and of reaction temperature (◦C; in parentheses). (A) effect on the yieldof pentose-2,4-bisphosphates and (B) on the percentage of ribose-2,4-bisphosphate among pentose-2,4-bisphosphates. All reactions were carriedout atconcentration of 1.5 mM each of glycolaldehyde phosphate (GAP) and glyceraldehyde-2-phosphate (G2P) in a total volume of 14 mL and at pH 7.5, over aperiod of 7 days. Percent yields of pentose-2,4-bisphosphates and ribose-2,4-bisphosphate were determined by GC/MS after derivatization as described inPitschet al. (1995). The highest yield of pentose-2,4-bisphosphate (18%) is obtained in the interlayer solution of the cobalt substituted mineral coalite, andthe highest proportion of ribose among pentoses (46%) in the isostructural, manganese substituted mineral mangalite, {Mn2Al(OH)6}{A −·nH2O}, whereA− is the anion sorbed in the hydrous structural interlayer in the surface active mineral.


Figure 3.Effect of the mole ratio of glyceraldehyde-2-phosphate (G2P) to glycolaldehyde phosphate(GAP) on the yield and proportion of pentose-2,4-bisphosphates. Experiments were carried out over6 days at pH≈7.5 and 40◦C in a suspension with 6 mole equivalents of mangalite per mol of(GAP+G2P). Yield based on glycolaldehyde-2-phosphate.

days it had changed to 7.4. The reaction mixture was worked up and analyzed byGC-MS, as described before. This control experiment showed no tetrose-, pentose-or hexose phosphates detectable by GC-MS (Figure 4), emphasizing the fact thatthe surface active mineral is a necessary and critical component for aldolization tooccur.

2.5. PREPARATIVE EXPERIMENT

Based on the optimal conditions established, the following preparative scale re-action was carried out. To a 100 mL stock solution 5.5 mM GAP and 22 mM ofG2P were added 440 mL of water and 10 mL of 1.0 N aqueous NaOH to adjustpH to about 7.0 and to give a total volume of 550 mL. The final concentrationsof GAP and G2P were 1 mM (0.55 mmol) and 4 mM (22 mmol) respectively. To


Figure 4.Aldol condensation to form pentose phosphate occurs, under the reaction conditions used,only by interaction with the surface active minerals. The figure shows gas chromatograms for prod-ucts from a reaction mixture of 1.5 mM GAP with 4.0 mM G2P (A) with 6 mmole equivalents ofmangalite in suspension (initially in chloride form); (B) under identical conditions except for theabsence of the mineral. Reaction conditions in both cases; 40◦C, 6 days, pH≈7.5.


this solution was added 5.7 g (16.5 mmol, 6 equiv. with respect to GAP + G2P) ofmangalite, [Mn2Al(OH)6] [Cl ·nH2O] under nitrogen; the reaction mixture was keptat 40◦C and shaken for a few minutes 5–6 times daily. After 6 days the suspen-sion was centrifuged and the colorless supernatant was separated from the solidphase. The solution was treated with 20 mL of cation exchange resin AmberlystIR 120, H+ form; the resin was filtered off and washed and the combined filtrateand washings concentrated to a volume of about 50 mL. A portion was convertedto the sodium salt by treatment with cation exchange resin Dowex 50 Wx4, Na+form and lyophilized, giving a faintly yellowish white powder.1H-NMR analysisshowed traces of GAP; G2P was present in about 30% of the original amount;in addition there were less than 10% of unidentified side products. As expectedfrom the fact that the aldolization products are formed and retained in the mineral,GC-MS analysis after derivatization indicated no products (tetroses, pentoses orhexoses) in the supernatant, its chromatogram was found to be closely similar tothat obtained after the reaction conducted without any mineral, but under otherwiseanalogous conditions (Figure 4B).

The separated solid mangalite-aldol phosphate complex was suspended in400 mL water and treated with 150 mL of cation exchange resin Amberlyst IR120 H+ form, shaken until a clear solution resulted, filtered, washed and con-centrated to a volume of 150 mL. This solution was subjected to anion exchangechromatography on Dowex 1x8 resin (HCO−3 form; 2×10 cm column), eluted witha gradient of 0–1 M of HNEt3·HCO−3 buffer (500 mL fractions) and the individualfractions analyzed by tlc (Rf = 0.31, n-BuOH/H2O/AcOH, 5:3:2, staining withanisaldehyde/H2SO4/AcOH /EtOH, 5:5:1:90). The fractions corresponding to thepentose-2,4-bisphosphates were collected and concentrated in vacuum; water wasadded and the solution again concentrated by vacuum evaporation to remove theexcess buffer. The solution was then treated with 50 mL of IR 120 resin (H+form), further reduced in volume to 20 mL, treated with 10 mL of 50Wx4 resin(Na+ form) and lyophilized to give 46 mg of the sodium salts of pentose-2,4-bisphosphates about 95% pure by1H-NMR. This yield determined by GC withpentaerythritol as an internal standard, corresponds to 25% based on the reactantGAP.

The individual pentose-2,4-bisphosphates in the reaction product mixture wereidentified by the1H-NMR spectral data and by comparison with spectra fromauthentic samples obtained by the procedures described by Pitsch (1993).

Dephosphorylation of the pentose-2,4-bisphosphates obtained in the above re-action was carried out with alkaline phosphatase at room temperature overnightas described by Pitschet al. (1995). After treatment with 10 mL of IR 120 (H+form) followed by Amberlyst A 27 (OH− form) the solution was filtered andlyophilized, giving 7.9 mg (65% based on the pentose-2,4-bisphosphates) as acolorless syrup.1H-NMR spectra of the syrup confirmed the identity of the de-phosphorylated sugars by comparison with spectra from commercially availablesamples.


Figure 5. Gas chromatogram for the mineral induced preparative reaction product mixture afterion-exchange purification, reduction, dephosphorylation, and acetylation and with pentaerythritol asinternal standard. The reaction involved 1.0 mM GAP with 4.0 mM G2P and 6.0 mmole equivalentsof mangalite in suspension, and was run at 40◦C and pH = 7.5 for 6 days. The yield was 25%; theproportional distribution of products is shown in Table I.

TABLE I

Percentage proportions of pentose phosphates formed by the mineral induced aldolization of GAPand G2P under the preparative reaction conditions referred to in the text. GC ratios are determinedafter reduction, dephosphorylation and acetylation. In GC, arabinose + lyxose appear as a singlesignal. The yield of pentose-2,4-bisphosphates after purification is 27% (25% by GC). See furtherFigures 5 and 6

Product mixture Isolated pentose diphosphates

(reaction crude) (after ion exchange chromatography)

based on based on

GC 1H-NMR GC

Ribose- 46.0 48.0 48.0

Arabinose-∗ 16.042.0 43.0

Lyxose- 25.0

Xylose- 12.0 11.0 9.0

Total 100.0 100.0 100.0

}


Figure 6.(A) 1H-NMR (in D2O): Anomeric proton region of the pentose-2,4-bisphosphates formedin the mineral induced reaction. The products were isolated by DEAE ion-exchange chromatographyfrom the reaction mixture as outlined in Pitsch (1993). (B) The dephosphorylated pentoses, obtainedby treatment of the pentose-2,4-bisphosphates with alkaline phosphatase.

The stability of the pentose-2,4-bisphosphates in the mangalite interlayer so-lution was studied by extending the reaction in time. In a second preparative ex-periment 50 mg aliquots of the solid mineral phase were periodically removedfrom the suspension and subjected to the above mentioned worked up by ion ex-change, derivatization (reduction, dephosphorylation and acetylation) and analysisby GC/MS. The results show that after three months about 90% of the pentose-2,4-bisphosphates remained unaltered in the mineral interlayer solution.


Figure 7.Stability of pentose-2,4-bisphosphates as a function of time in the aqueous interlayer solu-tion in mangalite (manganese aluminum hydroxide). The mineral, initially with chloride as interlayeranion, was suspended in a solution of GAP and G2P, 1.5 mM each, at 22◦C and with pH 7.5; thealdehyde phosphate ions replace the chloride ion in the interlayer solution practically completelywithin 3 hr, initiating the aldol condensation reaction. The reaction products in the mineral interlayerat the end of the 3 month exposure experiment were determined by GC/MS after derivatization asdescribed in Pitschet al. (1995).

3. Discussion

The observation of mineral induced ribose-2,4-bisphosphate formation from dilute,(1.5 mM) neutral reactant solution contributes an experimental fact to the ongoingdiscussion of natural availability of sugar phosphates in the context of molecularevolution. The preferred formation of rac.-pentose-2,4-bisphosphates illustrates thecapacity of the host mineral in inducing the aldol condensation process, while theformation of ribose-2,4-bisphosphate as a major product illustrates the capacity ofthe divalent cation in the host mineral to direct the aldol reaction. The efficiencyof the observed reactions despite the low concentrations in solution depends onthe affinity of the anionic reactants for the positively charged molecular sheets ofthe catalytically active minerals, resulting in a concentration factor of 104 fromthe initial dilute reactant solution to the order of 10 M in the reactive interlayersolution. The stability, under the reaction conditions, of the product pentose-2,4-bisphosphates sorbed in the mineral interlayer is in line with the expectations from


the demonstrated stability of hexose phosphates under the same conditions (Pitschet al., 1995).

The pentose phosphate reaction, although efficient, is less so than the mineralinduced formation of hexosetrisphosphates starting from glycolaldehyde phosphatealone (Pitschet al., 1995). This can be attributed to two plausible causes. First, theside reaction of dehydration of glyceraldehyde-2-phosphate to the correspondingenolphosphate and its subsequent reactions may reduce the availability of G2P.Second, from equimolar solutions of G2P and GAP the latter is preferentiallysorbed by the mineral by a factor of 3:1. This preference in turn can be understoodin terms of the favorable charge to size ratio for GAP over G2P.

These experiments show an effective way for achieving condensation of glyco-laldehyde phosphate with glyceraldehyde phosphate under laboratory conditionswhich can serve as a simplified metaphor for natural conditions in an abiotic hy-drosphere. Associated questions of interest in biopoesis concern possible sourcesof glycolaldehyde in nature and plausible means for its phosphorylation, the latterbeing a step that appears necessary for subsequent concentration to reactive levels.In the literature reference is often made in this context to the formose reaction as ameans for overcoming the energy barrier from C1 to C2 aldehydes but experimentsat near-neutral pH, and expected low concentrations suggest that it would not havebeen an efficient process (Reid and Orgel, 1967).

Another pathway, which would also include phosphorylation has been demon-strated in orthophosphate induced ring opening of aziridine-2-carbonitrile (Wagneret al., 1990) and preferably oxiranecarbonitrile (Pitschet al., 1994). The latter hasbeen considered to possibly form in the interstellar cloud medium, in comets orin the Earth’s primitive ionosphere, but an initial interstellar search by microwavespectroscopy has as yet failed to detect this molecule (Dickenset al., 1995).

Another source for glycolaldehyde, forming as a byproduct together with majoramounts of formaldehyde and formic acid was demonstrated in the classical exper-iments by Löb (1906, 1913), using silent electric discharge reactions in a carbondioxide-monoxide-water vapor-hydrogen atmosphere.

These experiments coupled with the above observations again raise the questionhow, in a natural environment, phosphorylation of glycolaldehyde can be achieved,since it as an uncharged molecule and presents a problem of effective concentra-tion. Any phosphorylation reaction proposed would thus need to be effective also indilute solution, and without being able to draw on the anion concentration power ofsurface active minerals. Pathways by which glycolaldehyde phosphate could havebeen formed thus continue to be the subject of current studies.

Acknowledgments

The authors wish to acknowledge support from NASA grant NAGW 1031 andfrom NASA’s NSCORT Exobiology Program, providing postdoctoral fellowships


for R.K. and S.P. We also thank Professor A. Eschenmoser for his constructivecriticism and advice in conducting the investigation.

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602.Löb, W.: 1906,Z. f. Elektroch.15, 282–312.Löb, W.: 1913,Ber. d. Deutschen Chem. Ges.46, 684–697.Müller, D., Pitsch, S., Kittaka, A., Wagner, E., Wintner, C. and Eschenmoser, A.: 1990,Helv. Chim.

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Pitsch, S., Eschenmoser, A., Gedulin, B., Hui, S. and Arrhenius, G.: 1995,Origins Life Evol.Biosphere25, 294–334.

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Mineral Induced Formation of Pentose-2,4-Bisphosphates*