Editing RNA world (section)

=== RNA as an enzyme ===
{{Further|Ribozyme}}

In the 1980s, RNA structures capable of self-processing were discovered,<ref>{{Cite journal |last1=Kruger |first1=Kelly |last2=Grabowski |first2=Paula J. |last3=Zaug |first3=Arthur J. |last4=Sands |first4=Julie |last5=Gottschling |first5=Daniel E. |last6=Cech |first6=Thomas R. |date=November 1982 |title=Self-splicing RNA: Autoexcision and autocyclization of the ribosomal RNA intervening sequence of tetrahymena |url=http://dx.doi.org/10.1016/0092-8674(82)90414-7 |journal=Cell |volume=31 |issue=1 |pages=147–157 |doi=10.1016/0092-8674(82)90414-7 |pmid=6297745 |s2cid=14787080 |issn=0092-8674}}</ref> with the RNA [[Moiety (chemistry)|moiety]] of [[ribonuclease P]] acting as its catalytic subunit.<ref>{{Cite journal |last1=Guerrier-Takada |first1=Cecilia |last2=Gardiner |first2=Katheleen |last3=Marsh |first3=Terry |last4=Pace |first4=Norman |last5=Altman |first5=Sidney |date=December 1983 |title=The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme |url=http://dx.doi.org/10.1016/0092-8674(83)90117-4 |journal=Cell |volume=35 |issue=3 |pages=849–857 |doi=10.1016/0092-8674(83)90117-4 |pmid=6197186 |s2cid=39111511 |issn=0092-8674}}</ref> These catalytic RNAs – referred to as [[Ribozyme|RNA enzymes]], or ribozymes – are found in today's DNA-based life and could be examples of [[living fossil]]s. Ribozymes play vital roles, such as that of the [[ribosome]]. The large subunit of the ribosome includes an [[Ribosomal RNA|rRNA]] responsible for the peptide bond-forming [[peptidyl transferase]] activity of protein synthesis. Many other ribozyme activities exist; for example, the [[hammerhead ribozyme]] performs self-cleavage<ref>{{cite journal | vauthors = Forster AC, Symons RH | title = Self-cleavage of plus and minus RNAs of a virusoid and a structural model for the active sites | journal = Cell | volume = 49 | issue = 2 | pages = 211–220 | date = April 1987 | pmid = 2436805 | doi = 10.1016/0092-8674(87)90562-9 | s2cid = 33415709 }}</ref> and an [[RNA-dependent RNA polymerase|RNA polymerase]] ribozyme can synthesize a short RNA strand from a primed RNA template.<ref>{{cite journal | vauthors = Johnston WK, Unrau PJ, Lawrence MS, Glasner ME, Bartel DP | title = RNA-catalyzed RNA polymerization: accurate and general RNA-templated primer extension | journal = Science | volume = 292 | issue = 5520 | pages = 1319–1325 | date = May 2001 | pmid = 11358999 | doi = 10.1126/science.1060786 | url = http://web.wi.mit.edu/bartel/pub/publication_reprints/Johnston_Science01.pdf | url-status = live | s2cid = 14174984 | citeseerx = 10.1.1.70.5439 | bibcode = 2001Sci...292.1319J | archive-url = https://web.archive.org/web/20120227163451/http://web.wi.mit.edu/bartel/pub/publication_reprints/Johnston_Science01.pdf | archive-date = 2012-02-27 }}</ref>

Among the enzymatic properties important for the beginning of life are:
;Self-replication
:The ability to [[self-replication|self-replicate]] or synthesize other RNA molecules; relatively short RNA molecules that can synthesize others have been artificially produced in the lab. The shortest was 165 bases long, though it has been estimated that only part of the molecule was crucial for this function. One version, 189 bases long, had an error rate of just 1.1% per nucleotide when synthesizing an 11-nucleotide long RNA strand from primed template strands.<ref>{{cite journal | vauthors = Johnston WK, Unrau PJ, Lawrence MS, Glasner ME, Bartel DP | title = RNA-catalyzed RNA polymerization: accurate and general RNA-templated primer extension | journal = Science | volume = 292 | issue = 5520 | pages = 1319–1325 | date = May 2001 | pmid = 11358999 | doi = 10.1126/science.1060786 | s2cid = 14174984 | citeseerx = 10.1.1.70.5439 | bibcode = 2001Sci...292.1319J }}</ref> This 189-base pair ribozyme could polymerize a template of at most 14 nucleotides in length, which is too short for self-replication, but is a potential lead for further investigation. The longest [[primer extension]] performed by a ribozyme polymerase was 20 bases.<ref name="pmid17586759">{{cite journal | vauthors = Zaher HS, Unrau PJ | title = Selection of an improved RNA polymerase ribozyme with superior extension and fidelity | journal = RNA | location = New York, N.Y. | volume = 13 | issue = 7 | pages = 1017–26 | date = July 2007 | pmid = 17586759 | pmc = 1894930 | doi = 10.1261/rna.548807 }}</ref> In 2016, researchers reported the use of in vitro evolution to improve dramatically the activity and generality of an RNA polymerase ribozyme by selecting variants that can synthesize functional RNA molecules from an RNA template.<ref name="Horning-2016" /> Each RNA polymerase ribozyme was engineered to remain linked to its new, synthesized RNA strand; this allowed the team to isolate successful polymerases. The isolated RNA polymerases were again used for another round of evolution. After several rounds of evolution, they obtained one RNA polymerase ribozyme called 24-3 that was able to copy almost any other RNA, from small catalysts to long RNA-based enzymes. Particular RNAs were amplified up to 10,000 times, a first RNA version of the [[polymerase chain reaction]] (PCR).<ref name="Horning-2016">{{cite journal | vauthors = Horning DP, Joyce GF | title = Amplification of RNA by an RNA polymerase ribozyme | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 35 | pages = 9786–9791 | date = August 2016 | pmid = 27528667 | pmc = 5024611 | doi = 10.1073/pnas.1610103113 | bibcode = 2016PNAS..113.9786H | doi-access = free }}</ref>

:[[Life]] is thought to have emerged from inanimate matter more than 3.5 billion years ago when a rudimentary [[abiogenesis]] process gradually evolved into an [[autocatalysis|autocatalytic process]] capable of template-based replication.<ref name = Paavlinova2023>{{cite journal |vauthors=Pavlinova P, Lambert CN, Malaterre C, Nghe P |title=Abiogenesis through gradual evolution of autocatalysis into template-based replication |journal=FEBS Lett |volume=597 |issue=3 |pages=344–379 |date=February 2023 |pmid=36203246 |doi=10.1002/1873-3468.14507 |url=|doi-access=free }}</ref>  It was proposed on the basis of experimentally feasible [[RNA]] reactions catalyzed by a [[ribozyme]], that the emergence of life was likely a gradual process involving the evolutionary properties of [[genetic variation|variation]], [[heredity]] and [[reproduction]], ultimately allowing for [[Darwinism|Darwinian evolution]].<ref name = Paavlinova2023/>  Recent efforts have been directed at trying to demonstrate [[RNA]] replication under conditions that assume the presence during early evolution of plausible [[nucleotide]] intermediates and plausible environmental conditions that could favor strand replication alternating with strand separation.  One such effort was the demonstration of high fidelity RNA copying using 2’,3’-cyclic phosphate ligation to allow [[polynucleotide]] synthesis under conditions also compatible with strand separation.<ref>{{cite journal |vauthors=Calaça Serrão A, Wunnava S, Dass AV, Ufer L, Schwintek P, Mast CB, Braun D |title=High-Fidelity RNA Copying via 2',3'-Cyclic Phosphate Ligation |journal=J Am Chem Soc |volume=146 |issue=13 |pages=8887–8894 |date=April 2024 |pmid=38503430 |doi=10.1021/jacs.3c10813 |url=|pmc=10995993 }}</ref>  In another study, it was shown that in a model oscillating [[Hadean]] environment likely to have been abundant during early evolution, that ribozyme-mediated RNA synthesis and replication can occur.<ref>{{cite journal |vauthors=Salditt A, Karr L, Salibi E, Le Vay K, Braun D, Mutschler H |title=Ribozyme-mediated RNA synthesis and replication in a model Hadean microenvironment |journal=Nat Commun |volume=14 |issue=1 |pages=1495 |date=March 2023 |pmid=36932102 |doi=10.1038/s41467-023-37206-4 |url=|pmc=10023712 }}</ref> 
;Catalysis
:The ability to [[Catalysis|catalyze]] simple chemical reactions—which would enhance creation of molecules that are building blocks of RNA molecules (i.e., a strand of RNA that would make creating more strands of RNA easier). Relatively short RNA molecules with such abilities have been artificially formed in the lab.<ref name="pmid9831528">{{cite journal | vauthors = Huang F, Yang Z, Yarus M |authorlink3=Michael Yarus| title = RNA enzymes with two small-molecule substrates | journal = Chemistry & Biology | volume = 5 | issue = 11 | pages = 669–678 | date = November 1998 | pmid = 9831528 | doi = 10.1016/s1074-5521(98)90294-0 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Unrau PJ, Bartel DP | title = RNA-catalysed nucleotide synthesis | journal = Nature | volume = 395 | issue = 6699 | pages = 260–263 | date = September 1998 | pmid = 9751052 | doi = 10.1038/26193 | s2cid = 9734076 | bibcode = 1998Natur.395..260U }}</ref> A recent study showed that almost any nucleic acid can evolve into a catalytic sequence under appropriate selection. For instance, an arbitrarily chosen 50-nucleotide DNA fragment encoding for the ''[[Taurine cattle|Bos taurus]]'' (cattle) [[albumin]] mRNA was subjected to test-tube evolution to derive a catalytic DNA (a [[deoxyribozyme]], also called a DNAzyme) with RNA-cleavage activity. After only a few weeks, a DNAzyme with significant catalytic activity had evolved.<ref name="Gysbers">{{cite journal | vauthors = Gysbers R, Tram K, Gu J, Li Y | title = Evolution of an Enzyme from a Noncatalytic Nucleic Acid Sequence | journal = Scientific Reports | volume = 5 | pages = 11405 | date = June 2015 | pmid = 26091540 | pmc = 4473686 | doi = 10.1038/srep11405 | bibcode = 2015NatSR...511405G }}</ref> In general, DNA is much more chemically inert than RNA and hence much more resistant to obtaining catalytic properties. If in vitro evolution works for DNA it will happen much more easily with RNA. In 2022, Nick Lane and coauthors showed in a computational simulation that short RNA sequences could have been capable of catalyzing {{CO2}} fixation which supported protocell replication and growth.<ref>{{cite journal | vauthors = Nunes Palmeira R, Colnaghi M, Harrison SA, Pomiankowski A, Lane N | title = The limits of metabolic heredity in protocells | journal = Proceedings. Biological Sciences | volume = 289 | issue = 1986 | pages = 20221469 | date = November 2022 | pmid = 36350219 | pmc = 9653231 | doi = 10.1098/rspb.2022.1469 }}</ref>
;Amino acid-RNA ligation
:The ability to conjugate an amino acid to the 3'-end of an RNA in order to use its chemical groups or provide a long-branched [[aliphatic]] sidechain.<ref name="pmid21779963">{{cite journal | vauthors = Erives A | title = A model of proto-anti-codon RNA enzymes requiring L-amino acid homochirality | journal = Journal of Molecular Evolution | volume = 73 | issue = 1–2 | pages = 10–22 | date = August 2011 | pmid = 21779963 | pmc = 3223571 | doi = 10.1007/s00239-011-9453-4 | bibcode = 2011JMolE..73...10E }}</ref>
;Peptide bond formation
:The ability to catalyse the formation of [[peptide bonds]] between amino acids to produce short [[peptide]]s or longer [[protein]]s. This is done in modern cells by ribosomes, a complex of several RNA molecules known as [[rRNA]] together with many proteins. The rRNA molecules are thought responsible for its enzymatic activity, as no amino-acid residues lie within 18[[Ångström|Å]] of the enzyme's [[active site]],<ref name="Atk06" /> and, when the majority of the amino-acid residues in the ribosome were stringently removed, the resulting ribosome retained its full [[peptidyl transferase]] activity, fully able to catalyze the formation of peptide bonds between amino acids.<ref name="pmid1604315">{{cite journal | vauthors = Noller HF, Hoffarth V, Zimniak L | title = Unusual resistance of peptidyl transferase to protein extraction procedures | journal = Science | volume = 256 | issue = 5062 | pages = 1416–1419 | date = June 1992 | pmid = 1604315 | doi = 10.1126/science.1604315 | bibcode = 1992Sci...256.1416N }}</ref> A pseudo 2 fold symmetry of the region surrounding the peptidyl transferase center led to the hypothesis of the Proto-Ribosome, that a vestige of an ancient dimeric molecule from the RNA world is functioning within the ribosome.<ref name="pmid21930590">{{cite journal | vauthors = Krupkin M, Matzov D, Tang H, Metz M, Kalaora R, Belousoff MJ, Zimmerman E, Bashan A, Yonath A | display-authors = 6 | title = A vestige of a prebiotic bonding machine is functioning within the contemporary ribosome | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 366 | issue = 1580 | pages = 2972–2978 | date = October 2011 | pmid = 21930590 | pmc = 3158926 | doi = 10.1098/rstb.2011.0146 | doi-access = free }}</ref> An RNA molecule with the ribosomal RNA sequence has been synthesized in the lab to test the Proto-ribosome hypothesis and was able to dimerize and to form peptide bonds.<ref name="pmid35137169">{{cite journal | vauthors = Bose T, Fridkin G, Davidovich C, Krupkin M, Dinger N, Falkovich AH, Peleg Y, Agmon I, Bashan A, Yonath A | display-authors = 6 | title = Origin of life: protoribosome forms peptide bonds and links RNA and protein dominated worlds | journal = Nucleic Acids Research | volume = 50 | issue = 4 | pages = 1815–1828 | date = February 2022 | pmid = 35137169 | pmc = 8886871 | doi = 10.1093/nar/gkac052 | doi-access = free }}</ref> A much shorter RNA molecule has been synthesized in the laboratory with the ability to form [[peptide bonds]], and it has been suggested that rRNA has evolved from a similar molecule.<ref>{{cite journal | vauthors = Zhang B, Cech TR | title = Peptide bond formation by in vitro selected ribozymes | journal = Nature | volume = 390 | issue = 6655 | pages = 96–100 | date = November 1997 | pmid = 9363898 | doi = 10.1038/36375 | s2cid = 4398830 | bibcode = 1997Natur.390...96Z }}</ref> It has also been suggested that amino acids may have initially been involved with RNA molecules as cofactors enhancing or diversifying their enzymatic capabilities, before evolving into more complex peptides. Similarly, [[tRNA]] is suggested to have evolved from RNA molecules that began to catalyze amino acid transfer.<ref>{{cite journal | vauthors = Szathmáry E | title = The origin of the genetic code: amino acids as cofactors in an RNA world | journal = Trends in Genetics | volume = 15 | issue = 6 | pages = 223–229 | date = June 1999 | pmid = 10354582 | doi = 10.1016/S0168-9525(99)01730-8 }}</ref>

==== Cofactors ====
:Protein enzymes catalyze various chemical reactions, but over half of them incorporate cofactors to facilitate and diversify their catalytic activities.<ref>{{Cite journal |last=Decker |first=Karl |date=2006-01-17 |title=The Pyridine Nucleotide Coenzymes. Herausgegeben von J. Everse, B. Anderson und K.-S. You. Academic Press, New York 1982. XXXV, 389 S., geb. $ 46.00 |url=http://dx.doi.org/10.1002/ange.19830951241 |journal=Angewandte Chemie |volume=95 |issue=12 |pages=1033–1034 |doi=10.1002/ange.19830951241 |issn=0044-8249}}</ref> Cofactors are essential in biology, as they are based largely on nucleotides rather than amino acids. Ribozymes use nucleotide cofactors to create metabolism, with two basic choices: non-covalent binding or covalent attachment. Both approaches have been demonstrated using directed evolution to reinvent RNA dupes of protein-catalyzed processes. Lorsch and Szostak <ref>{{Cite journal |last1=Ekland |first1=Eric H. |last2=Szostak |first2=Jack W. |last3=Bartel |first3=David P. |date=1995-07-21 |title=Structurally Complex and Highly Active RNA Ligases Derived from Random RNA Sequences |url=http://dx.doi.org/10.1126/science.7618102 |journal=Science |volume=269 |issue=5222 |pages=364–370 |doi=10.1126/science.7618102 |pmid=7618102 |bibcode=1995Sci...269..364E |s2cid=40795082 |issn=0036-8075}}</ref> investigated ribozymes that could phosphorylate themselves and use [[Adenosine triphosphate#ATP analogues|ATP-γS]] as a substrate. However, only one of the seven classes of selected ribozymes had detectable ATP affinity, indicating that the ability to bind ATP was compromised. NAD<sup>+</sup>- dependent redox ribozymes were also evaluated.<ref>{{Cite journal |last1=Tsukiji |first1=Shinya |last2=Pattnaik |first2=Swetansu B |last3=Suga |first3=Hiroaki |date=2003-08-10 |title=An alcohol dehydrogenase ribozyme |url=http://dx.doi.org/10.1038/nsb964 |journal=Nature Structural & Molecular Biology |volume=10 |issue=9 |pages=713–717 |doi=10.1038/nsb964 |pmid=12910259 |s2cid=41081956 |issn=1545-9993}}</ref> The select ribozyme had a rate of enhancement of more than 10<sup>7</sup> fold and was proven to catalyze the reverse reaction - benzaldehyde reduction by NADH.<ref>{{Cite journal |last1=Tsukiji |first1=Shinya |last2=Pattnaik |first2=Swetansu B. |last3=Suga |first3=Hiroaki |date=2004-04-06 |title=Reduction of an Aldehyde by a NADH/Zn<sup>2+</sup>-Dependent Redox Active Ribozyme |url=http://dx.doi.org/10.1021/ja0495213 |journal=Journal of the American Chemical Society |volume=126 |issue=16 |pages=5044–5045 |doi=10.1021/ja0495213 |pmid=15099068 |issn=0002-7863}}</ref> Since the usage of adenosine as a cofactor is prevalent in current metabolism and is likely to have been common in the RNA world, these discoveries are essential for the evolution of metabolism in the RNA world.