In Search of an RNA Replicase Ribozyme

McGinness, Kathleen E.; Joyce, Gerald F.

doi:10.1016/s1074-5521(03)00003-6

Cited by 65 publications

(45 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Catalytic RNAs are capable of catalyzing a wide range of chemical transformations (15)(16)(17)(18)(19)(20)(21). Because the amino acid building blocks of proteins can catalyze reactions such as aldol condensation (22, 23), it is reasonable to expect that the nucleotide building blocks of RNAs may also have catalytic abilities.…”

mentioning

confidence: 99%

A mechanism for the association of amino acids with their codons and the origin of the genetic code

Copley

Smith

Morowitz

2005

Proc. Natl. Acad. Sci. U.S.A.

119

110

View full text Add to dashboard Cite

The genetic code has certain regularities that have resisted mechanistic interpretation. These include strong correlations between the first base of codons and the precursor from which the encoded amino acid is synthesized and between the second base of codons and the hydrophobicity of the encoded amino acid. These regularities are even more striking in a projection of the modern code onto a simpler code consisting of doublet codons encoding a set of simple amino acids. These regularities can be explained if, before the emergence of macromolecules, simple amino acids were synthesized in covalent complexes of dinucleotides with ␣-keto acids originating from the reductive tricarboxylic acid cycle or reductive acetate pathway. The bases and phosphates of the dinucleotide are proposed to have enhanced the rates of synthetic reactions leading to amino acids in a small-molecule reaction network that preceded the RNA translation apparatus but created an association between amino acids and the first two bases of their codons that was retained when translation emerged later in evolution.catalysis ͉ origin of life T he genetic code has many regularities (1), of which only a subset have explanations in terms of tRNA function (2) or robustness against deleterious effects of mutation (3, 4) or errors in translation (3, 5). There is a strong correlation between the first bases of codons and the biosynthetic pathways of the amino acids they encode (1, 6). Codons beginning with C, A, and U encode amino acids synthesized from ␣-ketoglutarate (␣-KG), oxaloacetate (OAA), and pyruvate, respectively. ¶ These correlations are especially striking in light of the structural diversity of amino acids whose codons share a first base. For example, codons for Glu and Pro both begin with C, and those for Cys and Leu begin with U. Codons beginning with G encode amino acids that can be formed by direct reductive amination of a simple ␣-keto acid. These include glycine, alanine, aspartate, and glutamate, which can be formed by reductive amination of glyoxalate, pyruvate, OAA, and ␣-KG, respectively. There is also a long-recognized relationship between the hydrophobicity of the amino acid and the second base of its codon (1). Codons having U as the second base are associated with the most hydrophobic amino acids, and those having A as the second base are associated with the most hydrophilic amino acids.We suggest that both correlations can be explained if, before the emergence of macromolecules, simple amino acids were synthesized from ␣-keto acid precursors covalently attached to dinucleotides that catalyzed the reactions required to synthesize specific amino acids (see Fig. 1). This is a significant departure from previous theories attempting to explain the regularities in the genetic code (3). The ''stereochemical'' hypothesis suggests that binding interactions between amino acids and their codons or anticodons dictated the structure of the genetic code (7-10). The ''coevolution'' hypothesis (6) suggests that the original genetic code specifi...

show abstract

mentioning

confidence: 99%

A mechanism for the association of amino acids with their codons and the origin of the genetic code

Copley

Smith

Morowitz

2005

Proc. Natl. Acad. Sci. U.S.A.

119

110

View full text Add to dashboard Cite

show abstract

“…1B) could form five base pairs with an internal guide sequence (Fig. 1B) (14). A pool of 30 nucleotides with random sequence was inserted at the 5Ј and 3Ј strands in the P3a region in place of the original four nucleotides of scaffold RNA (L and R marked with purple in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…7, which is published as supporting information on the PNAS web site)]. In contrast, the previously reported ligases with the exception of class I can use only limited combinations of the two substrate nucleotides at the reaction site (14,(24)(25)(26).…”

Section: ϫ3mentioning

confidence: 99%

De novo synthesis and development of an RNA enzyme

Ikawa

Tsuda²,

Matsumura³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

117

View full text Add to dashboard Cite

Arbitrary manipulation of molecular recognition at the atomic level has many applications. However, systematic design and de novo synthesis of an artificial enzyme based on such manipulation has been a long-standing challenge in the field of chemistry and biotechnology. In this report, we developed an artificial RNA ligase by implementing a synthetic strategy that fuses a series of 3D molecular modelings based on naturally occurring RNA-RNA recognition motifs with a small-scale combinatorial synthesis of a modular catalytic unit. The resulting ligase produces a 3-5 linkage in a template-directed manner for any combinations of two nucleotides at the reaction site. The reaction rate is 10 6 -fold over that of the uncatalyzed reaction with a yield higher than those of previously reported ligase ribozymes. The strategy may be applicable to the synthesis and development of a variety of nonnatural functional RNAs with defined 3D structures. Many RNA receptors and enzymes have been selected in vitro from combinatorial libraries that consist of a long random sequence (1). Anatomies of the selected RNAs are difficult to predict because their higher-order structures were not specified before the selection. However, if a precisely designed assemblage of well established modular units is used as a scaffold for preparing such functional RNAs, redesign of the resulting selected RNAs will be facilitated. They will thus enable a variety of artificial evolutionary pathways, starting from the selected molecule.In general, molecular design of biopolymers such as RNAs or proteins is difficult at the 3D level because of their highly complicated folding process. In the 1990s, biochemical and structural analyses revealed that many functional noncoding natural RNAs are organized into modules and fold into defined 3D structures (2-5). Moreover, several commonly used RNA-RNA binding motifs in these RNAs were identified by phylogenetic comparison (6) and high-resolution structural analyses (7-10). Consequently, it has become possible to design self-folding RNAs precisely by employing such motifs and mimicking the modular organization of natural RNAs (11-13). As one such example, we have previously reported the design of a self-folding RNA consisting of standard doublestranded helices connected by the two motifs: a tetraloopreceptor interaction and consecutive base-triples ( Fig. 1 A and B) (13). Results indicated that the constructed RNA folds compactly into the designed 3D structure.In this paper, we report the synthesis and development of an artificial RNA ligase as shown in the scheme (Fig. 1 A). First, a reaction site for RNA-RNA ligation was installed into the designed RNA scaffold, and a different region of the RNA was subject in vitro selection from a small combinatorial library to provide a catalytic center. The ligation reaction was chosen as a convenient target because several RNA ligases had already been obtained from large-scale pools by in vitro selection (ref. 14 and references cited therein). Biochemical characterization a...

show abstract

“…Natural processive complexes, containing RNA (telomerases, ribosomes), contain also proteins. Some distributive (but not processive) polymerases and ligases out of nucleotides were discovered or artificially synthesized [13][14][15][16][17][18]. I suggest that processive polymerases out of nucleotides cannot exist in principle due to complementary interaction between the polymerase and its template.…”

Section: Introductionmentioning

confidence: 99%

Origin of Biological Nucleic Acids and the First Genetic System (The Progene Hypothesis)

Altstein¹

2017

Transcriptomics

View full text Add to dashboard Cite

The most accepted concept of the origin of nucleic acids and life is the RNA world hypothesis that is supported by many scientists. There are very strong objections against this hypothesis (problems of selection of compounds in prebiotic conditions, processivity of polynucleotide synthesis without protein polymerases, arising of the genetic code and translation). In order to overcome these obstacles and to explain how the first biological nucleic acid (the first gene) arises simultaneously with a specific protein (a processive polymerase) forming a bimolecular genetic system, I have proposed an alternative hypothesis (the progene hypothesis). According to this hypothesis, the bimolecular genetic system emerges not from mononucleotides and monoamino acids, but from progenes, namely, trinucleotides aminoacylated on 3'-end by a non-random amino acid (NpNpNp~pX~Aa, where N -deoxyribo-or ribonucleoside, p -phosphate, X -a bifunctional agent, for example ribose, Aa -amino acid, ~ macroerge bond). The progenes are used as the only substrates for interconnected synthesis of a polynucleotide and a polypeptide. The growth of the system "polynucleotide -polypeptide" is controlled by the enzymatic properties of the growing polypeptide, and the bimolecular genetic system emerges as an extremely rare event. The progene forming mechanism (NpNp + Np~pX~Aa) makes it possible to explain the emergence of the prebiotic physicochemical group genetic code, as well as the selection of organic compounds for the future genetic system from the racemic heterogeneous environment. The bimolecular genetic system is reproduced on a progene basis via replication-transcription-translation (the first molecular genetic process) that is similar to its modern counterparts. Nothing is required for the emergence and reproduction of the bimolecular genetic system except for progenes and conditions for their formation, including lipid vesicles and short oligonucleotides (2-6 bases).

show abstract

In Search of an RNA Replicase Ribozyme

Cited by 65 publications

References 56 publications

A mechanism for the association of amino acids with their codons and the origin of the genetic code

A mechanism for the association of amino acids with their codons and the origin of the genetic code

De novo synthesis and development of an RNA enzyme

Origin of Biological Nucleic Acids and the First Genetic System (The Progene Hypothesis)

Contact Info

Product

Resources

About