Heterotrophic Origin

(i) Heterotrophy First vs. Autotrophy First

There are two schools of thought on whether the first cell was a heterotroph feeding on organic compounds available from environmental sources, or an autotroph using only CO2 and one-carbon compounds from the environment to synthesize all other organic compounds in-house (Fig. 1.3). Prebiotic evolution began with membranes, replicators and metabolites and proceeded to the Last Universal Common Ancestor, or LUCA, from which all extant life descended. Its analysis benefits from both the 'bottom-up' and 'top-down' approaches.40 The former starts off from building blocks and goes through supramolecular structures and self-sustaining

Figure 1.2. Replicator Amplification by Stabilization (REAS). a) Binding of IMP (I) to an aptamer Ri stabilizes Ri; b) Ri directs formation of AntiRi which mutates to AntiRg. c) The latter is transcribed to the ribozyme Rg, which catalyzes conversion of I to GMP (G).
Luca Antiri
Figure 1.3. Autrophic and heterotrophic organisms (after Nealson and Conrad39).

autopoietic organization to reach the cell.41-43 The latter identifies the nature of LUCA and retraces the trail taken to arrive at LUCA. Both approaches require knowing whether the first living cell was an autotroph or heterotroph.

The experimental abiotic synthesis of Phase 1 amino acids and nucleic acid constituents, along with the finding of meteorites as a rich source of organic compounds, have led to the suggestion of a Heterotrophic First scenario by Lazcano and Miller.44 However, important discoveries in recent years have demonstrated that a range of organic biomolecules could be derived from the hydrothermal and volcanic sources:

1. Amino acids45

2. Lipids22

3. Sugars46

4. Pyruvic acid47

5. a-Hydroxy and a-amino acids48

6. Wood-Ljungdahl type pathway for acetyl-thioester formation49

7. Fischer-Tropsch synthesis of organic compounds50 These discoveries favor the feasibility ofan autotrophic origin of life within the hydrothermal-volcanic system and lend support to a Hot Start Hypothesis that "life got its start in the scalding mineral rich waters streaming out of deep sea hydrothermal vents".51 This results in an ongoing Heterotrophy First vs Autotrophy First debate: Proponents of the organic soup theory suggest that life originated through the organization of organic molecules that were produced in the atmosphere by a Miller-Urey type reaction or were delivered to Earth from space Proponents of the surface metabolism theory, by contrast, contend that metabolism arose autotrophically Proponents of both sides have recently delivered hefty criticisms of the other without a compromise in sight.17 The likelihood of Autotrophy First is enhanced by localization of reaction products and diminished by their dilution in the oceans,52,53 but there is a priori indeterminate expectation regarding the extent of dilution. Present day organisms, which include both heterotrophs and autotrophs, are also silent on the metabolic nature of the first cell. Even the identification of an autotrophic LUCA (Section 15.2) cannot settle the debate, for the first cell and

Figure 1.4. Alternate pathways of Glu-tRNA utilization. The middle pathway shows the use of Glu-tRNA for incorporation of Glu into proteins in ribosomal protein synthesis. The top and bottom pathways represent pretran syntheses of two products from Glu-tRNA, viz. Gln-tRNA for incorporating Gln into proteins in ribosomal protein synthesis in many organisms and Glu-1-semialdehyde as precursor of tetrapyrrole in heme biosynthesis.

LUCA might not have the same type ofmetabolism. Likewise, that 'banded iron' geological formations containing ferric iron became evident only from 2.3 Gya onward only shows that oxygenic photosynthesis was not widespread earlier, without ruling out early photoautotrophy on a small scale. This unsettled debate between autotrophic and heterotrophic origins is unsettling, for it renders the metabolic nature of the first living cell uncertain.

(ii) Triple Convergence

Based on genetic co de structure, the coevolution theory ofthe genetic code proposes that at first only 10 Phase 1 amino acids available from the environment were employed for protein synthesis. Later, another 10 Phase 2 amino acids were produced by the developing amino acid biosynthetic pathways and added to the genetic code,54,55 some ofthem such as Gln via pretran synthesis (Fig. 1.4). The theory, now proven by the primordial origin ofpretran syntheses (ref. 56 and Section 14.3) indicates that the amino acids employed for protein synthesis were decided by environmental availability, which could be the case only if the cells were heterotrophic.

That the environment only provided half the 20 present day canonical amino acids is supported by the results of atmospheric amino acid synthesis: using high-energy irradiation, Kobayashi et al57-58 have obtained to date the largest number of abiotically synthesized amino acids and the products include the 10 Phase 1 amino acids and none of the Phase 2 amino acids. It is further supported by the meteoritic amino acids: the largest collection of meteoritic amino acids found so far was discovered by Pizzarello59 on Antarctica meteorite CR2, comprising again the 10 Phase 1 amino acids and no Phase 2 amino acid (Section 6.2).

The convergence of these three lines of independent evidence stemming from genetic code structure, atmospheric amino acid synthesis and meteoritic amino acids, resulting in complete accord regarding the identities ofthe amino acids readily available from the prebiotic environment (Table 1.1), provides strong confirmation

Table 1.1. Triple convergence of evidence regarding the prebiotic availability of different amino acids

Gly Ala Ser Asp Glu Val Leu Ile Pro Thr Phe Tyr Arg His Trp Asn Gln Lys Cys Met

Phase of entry 1 111 1 11 1112222222222

Irradiated synthesis + + + + + ++ ++ + 0 00 000 0 0nn Meteoritic amino acids + + + + + ++ ++ + 0 00 000 0 000

Classification of Phase 1 and Phase 2 amino acids is based on reference 54. The amino acids produced by atmospheric irradiated synthesis are described in references 57 and 58. The meteoritic amino acids are described in reference 59. Production or presence is indicated by "+" and lack of production or absence by "0". "n" indicates inapplicable on account of the absence of sulfur in the irradiated synthesis.

that environmental availability was a prerequisite to the admission of any amino acid into the earliest genetic code.

Ifthe first cell was an autotroph, it would synthesize in-house all 20 canonical amino acids as in present day blue-green algae. There could be no rational explanation for the triple convergence shown in Table 1.1. On the other hand, if the first cell was a heterotroph, the triple convergence is exactly the outcome expected because the cells, being heterotrophic, had no choice but to utilize only those amino acids available in the environment for protein synthesis, viz. the 10 Phase 1 amino acids. Later on, when the cellular amino acid biosyn-thetic pathways produced the Phase 2 amino acids, these would be utilized too to increase the chemical versatility of proteins.

On this basis, the first cell was a heterotroph.

(iii) Metabolic Expansion

For a heterotrophic origin, there had to be sufficient organic nutrients in the environment to start off evolution, but not all the metabolites eventually needed would be obtainable from the environment. For example, phosphorylated cofactors like FAD and NADH could not enter into the cell through lipoidal membranes even ifthey were available in the environment. Metabolic and biosyn-thetic pathways had to be expanded through such mechanisms as:

a. When the supply of a biomolecule from the environment is exhausted, a biosynthetic pathway for the biomolecule would be developed backwards in retrograde evolution. A catalyst is introduced that catalyzes the formation of the biomolecule from an immediate precursor. When that immediate precursor is in turn exhausted, another catalytic step would be added to transform a precursor upstream to the immediate precursor, etc.60 For instance, Ala, Asp and Glu were Phase 1 amino acids available from the environment. When their supplies in the environment were used up, synthases and transaminases were developed by retrograde evolution to transform pyruvate, oxaloacetate and a-ketoglutarate into Ala, Asp and Glu respectively.

b. In the biosynthesis of a complex pigment such as chlorophyll, for instance, it appears doubtful that the process could begin with chlorophyll from the environment and develop a biosynthetic pathway backwards. Instead, the biosynthetic pathway may grow by progressive extension in the forward direction, with each pigment intermediate in the pathway functioning as a biological pigment until it is replaced by a superior pigment derived from it through a forward extension of the pathway. In this manner the biosynthetic pathway for chlorophyll-a would extend from protopor-phyrin-9 to Mg vinyl pheoporphyrin-a5 and eventually to chlorophyll-a.61

c. The pathways for the formation ofsome secondary metabolites, alkaloids, antibiotics, etc. might represent inventive biosynthesis, where a compound comes to be synthesized as the result of random explorations by catalysts.54 Since enzymes typically do not have absolute substrate or reaction specificities, they may act on intended or unintended substrates to form unintended side products. Where a side product turns out to be useful, the reaction may be permanently adopted. For example, even though penicillin is useful to Penicillium, it is chemically too unstable to have accumulated in the environment to initiate retrograde evolution. The intermediates in its biosynthetic pathway are also not active enough as antibiotics themselves to initiate progressive extension. Thus the metabolic origin ofpenicil-lin could be a case of inventive biosynthesis. The pretran syntheses of some Phase 2 amino acids from Phase 1 amino acid-tRNA compounds, which have played important roles in the genetic coding of Phase 2 amino acids (Section 14.4), are examples of inventive biosynthesis. Figure 1.4 shows the pretran syntheses of Gln in many organisms for incorporation into proteins and ofGlu-1-semialdehyde62 to serve as precursor of5-aminolevulinic acid and heme, from Glu-tRNA. There was no Gln in the prebiotic environment (Section 9.2) and Gln is also not superior to Glu. Likewise Glu-1-semialdehyde is too unstable to accumulate in the environment and Glu cannot replace the function of heme. Accordingly neither retrograde evolution nor progressive extension can be called upon to establish these biosynthetic reactions. Instead, they are most likely the results of inventive biosynthesis.

d. For catalytic reactions involving inorganic ions, a mechanism for metabolic pathway construction that might be applicable to various metallo-enzymes is enzymatized inorganic catalysis, whereby a reaction originally catalyzed by inorganic compounds is transformed to a more efficient enzymic (or at an earlier stage, ribozymic) reaction. For example, inorganic iron has a very low catalase acivity splitting hydrogen peroxide into oxygen and water. When the iron is incorporated into a protoporphyrin ring to form heme, the activity is increased one thousand fold. When the heme is attached to the catalase protein, the activity is now one million fold.61

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