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CHEMICAL ORIGIN OF LIFE

Protocells realize their potential

Saidul Islam and Matthew W. Powner

E
volutionary biology suggests that the The iron–sulfur motifs embedded within Nutrient
last universal common ancestor of life these metalloproteins are so pervasive
on Earth was a highly sophisticated that they may be an ancient remnant of a
cell that contained a suite of biochemical by-gone biological (or prebiotic) era. But if
(transcriptional and translational) the structural complexity of the genetically
machinery to orchestrate its metabolism encoded protein framework that adorns
through sequence-specific nucleic acid the iron–sulfur cores were stripped away, NAD++ H+ 2 Fe(II)Ln H2O2
coded protein synthesis. Although there would the residual structure still elicit the
is no accurate record of the composition functional properties required to establish
of simpler organisms on Earth, the core of a proton gradient within a localized
life’s metabolic network is extraordinarily environment? If so, and if this core could
similar across all extant organisms1. This self-assemble de novo, it would imply that NADH 2 Fe(III)Ln 2 OH–
may indicate metabolic organization arose life could (initially) dispense with the need
early during life’s evolution. Crucially, three for large polymeric (enzyme) catalysts that
common energy currencies are exploited are difficult to construct, select and copy,
by life; proton gradients, sodium gradients and alleviate the pressures placed upon
and ATP (adenosine triphosphate)2. These sequence-specific polymers (for example,
gradients drive essential anabolic reactions proteins or RNAs) to fulfil phenotypic Efflux
that replenish a cell’s nutrients; for example, differentiation in protocells.
membrane-bound ATP synthase harnesses Writing in Nature Catalysis, Mansy Fig. 1 | Prebiotic iron–sulfur peptides generate a
an electrochemical gradient to fuel cell and colleagues demonstrate that simple pH gradient across vesicle membranes. Fe(III)-
survival and prevent the onset of equilibria. iron–sulfur peptides catalyse electron- peptides catalyse the oxidation of membrane-
It is clear, however, that modern translation, transfer reactions (Fig. 1)3. Although simple bound NADH. The resultant Fe(II)-peptide is
transcription and ATP synthase did not aqueous ferric (Fe(iii)) ions oxidize NADH, oxidized back to the active ferric state by H2O2
all arise in a single chemical step at the the resulting acidic solution destroys the (bold arrows). The net formation of hydroxide
onset of biology; some form of metabolism NAD+ that forms. Increasing the pH would (OH–) generates a pH gradient. Ideally, NADH
must have supported the earlier stages of prevent NAD+ degradation, but this leads to would be regenerated by a stoichiometric
evolution. So, what did the first metabolic precipitation of inactive oxo–hydroxo iron prebiotic reductant supplied to the protocell in
network look like? How was it organized? complexes. Building on their recent work the form of a membrane-permeable nutrient (red
What were its constituent parts, and what in which UV-light was shown to promote dots). The resulting oxidation product (blue dots)
dynamic interactions were essential among iron–sulfur cluster formation starting from can feed into other anabolic pathways to provide
its constituents? a range of short cysteine peptide ligands the protocell with building blocks required, or be
Extant metabolism is a complex under anoxic conditions4, the present eliminated from the protocell (dashed arrows). L
protein-regulated network, and the plexus study reveals that simple cysteine peptides =​cysteinyl peptide ligand; n =​ 1–4.
of modern metabolic enzymes is far too stabilize and solubilize Fe(iii) at higher pH
complex to have self-assembled de novo whilst maintaining redox activity. Fe(iii)-
prior to genetically encoded protein l-glutathione was observed to furnish the
synthesis. However, metabolism is organized most effective iron–sulfur catalysts, clearly electrochemical gradients found across
into chains and cycles of redox reactions accelerating the oxidation of NADH with biological membranes3.
to capture energy. For example, electrons respect to the uncatalysed background Establishing a trans-membrane
transferred from the breakdown of nutrients reaction. The reduced iron–sulfur catalyst electrochemical gradient by membrane-
— the catabolic phase of metabolism (for can then be oxidized to regenerate Fe(iii) localized redox catalysts lays the foundations
example, glycolysis) — are shuttled through by a terminal electron acceptor, hydrogen to develop simple systems that exploit
protein-associated nucleotide and metal peroxide, or an intermediate electron these gradients to drive anabolic reactions.
cofactors, leading to an ion gradient across carrier, ubiquinone. When these iron–sulfur However, maintaining an electrochemical
a biological membrane. Detailed analysis of catalysts are encapsulated in POPC (model gradient requires, in addition to a competent
the enzymes involved in the citrate cycle and protocell) membranes with 0.5 mM NADH, catalyst, feedstock reagents (nutrients) and
electron transport chains reveal that iron– stoichiometric hydrogen peroxide reduction a well-tuned semi-permeable membrane.
sulfur proteins are critical to maintaining establishes a trans-membrane pH-gradient Simpler (fatty acid) membranes could
ion gradients across biological membranes. (40 mV), with a similar magnitude to not harness this gradient3, outlining the
Nature Catalysis | VOL 1 | AUGUST 2018 | 569–570 | www.nature.com/natcatal 569
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need to simultaneously develop dynamic reactivity of thiols and sulfides in prebiotic Nevertheless, in a broader sense, the work
interactions amongst the constituent chemistry suggests an effective synthesis of Bonfio et al.3,4 suggests that the activity
molecules of life from the outset. Functions awaits elucidation6,8. Furthermore, even if of simple iron–sulfur peptides could have
must be balanced, and sealing a membrane short peptides, rather than long polymers, helped to couple catabolism with anabolism
to an ion gradient could, in principle, block are key to function during the transition during early evolution, and exemplifies
essential nutrients (or reagents) accessing from prebiotic chemistry to metabolism, value accrued by uniting catalysis with
the cell. A complex charged dinucleotide an effective synthesis of (short) peptides compartmentalization. ❐
such as NADH might not be passively that tolerates a high degree of side-chain
transported across a charge-impermeable functionality is urgently needed. The low Saidul Islam and Matthew W. Powner*
membrane. This opens up several interesting information content required to code and Department of Chemistry, University College
questions, the first of which is whether the manipulate small (information-poor) London, London, UK.
current system could be rendered catalytic catalysts make these the obvious target *e-mail: matthew.powner@ucl.ac.uk
in (membrane impermeable) NADH/ at the onset of metabolic organization
Published online: 10 August 2018
NAD+ by a second redox couple with other and only later, once life became
https://doi.org/10.1038/s41929-018-0131-4
(proto)metabolic processes (Fig. 1). For dependent on such catalytic function,
example, could iron–sulfur redox cycling be would competitive fine-tuning of References
1. Jeong, H., Tombor, B., Albert, R., Oltvai, Z. N. & Barabási, A.-L.
coupled to (prebiotic) triose glycolysis5, and catalytic function drive information-rich Nature 407, 651–654 (2000).
synthesis of phosphenol pyruvate — nature’s polymer selection. However, current 2. Skulachev, V. P. FEBS J. 208, 203–209 (1992).
highest energy phosphate — to provide a methods for (short) prebiotic peptide 3. Bonfio, C. et al. Nat. Catal. https://doi.org/10.1038/s41929-018-
proto-metabolic link between redox and synthesis remain ineffective for amino 0116-3 (2018).
4. Bonfio, C. et al. Nat. Chem. 9, 1229–1234 (2017).
phosphorylation potential? The prebiotic acids with functional side chains such as 5. Coggins, A. J. & Powner, M. W. Nat. Chem. 9, 310–317 (2017).
plausibility of the essential peptide ligand cysteine and serine, and the pronounced 6. Patel, B. H., Percivalle, C., Ritson, D. J., Duffy, C. D. & Sutherland,
also needs to be addressed. Although a nucleophilicity of thiols renders cysteine J. D. Nat. Chem. 7, 301–307 (2015).
7. Parker, E. T. et al. Proc. Natl Acad. Sci. USA 92, 719–723 (2011).
convincing prebiotic cysteine synthesis has incompatible with current methods for 8. Islam, S., Bučar, D.-K. & Powner, M. W. Nat. Chem. 9, 584–589
yet to be found6,7, the remarkable value and electrophilic activation of amino acids. (2017).

570 Nature Catalysis | VOL 1 | AUGUST 2018 | 569–570 | www.nature.com/natcatal