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The Hypothesis that the Genetic Code Originated in Coupled Synthesis of Proteins and the Evolutionary Predecessors of Nucleic Acids in Primitive Cells.

Francis BR - Life (Basel) (2015)

Bottom Line: A primitive cell capable of supporting electron transport, thioester synthesis, reduction reactions, and synthesis of polyesters and polypeptides is proposed.As the synthesis of nucleic acids evolved from β-linked polyesters, the singlet coding system for replication evolved into a four nucleotide/four amino acid process (AMP = aspartic acid, GMP = glycine, UMP = valine, CMP = alanine) and then into the triplet ribosomal process that permitted multiple copies of protein to be synthesized independent of replication.This hypothesis reconciles the "genetics first" and "metabolism first" approaches to the origin of life and explains why there are four bases in the genetic alphabet.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, University of Wyoming, Laramie, WY 82071, USA. brianrf@uwyo.edu.

ABSTRACT
Although analysis of the genetic code has allowed explanations for its evolution to be proposed, little evidence exists in biochemistry and molecular biology to offer an explanation for the origin of the genetic code. In particular, two features of biology make the origin of the genetic code difficult to understand. First, nucleic acids are highly complicated polymers requiring numerous enzymes for biosynthesis. Secondly, proteins have a simple backbone with a set of 20 different amino acid side chains synthesized by a highly complicated ribosomal process in which mRNA sequences are read in triplets. Apparently, both nucleic acid and protein syntheses have extensive evolutionary histories. Supporting these processes is a complex metabolism and at the hub of metabolism are the carboxylic acid cycles. This paper advances the hypothesis that the earliest predecessor of the nucleic acids was a β-linked polyester made from malic acid, a highly conserved metabolite in the carboxylic acid cycles. In the β-linked polyester, the side chains are carboxylic acid groups capable of forming interstrand double hydrogen bonds. Evolution of the nucleic acids involved changes to the backbone and side chain of poly(β-d-malic acid). Conversion of the side chain carboxylic acid into a carboxamide or a longer side chain bearing a carboxamide group, allowed information polymers to form amide pairs between polyester chains. Aminoacylation of the hydroxyl groups of malic acid and its derivatives with simple amino acids such as glycine and alanine allowed coupling of polyester synthesis and protein synthesis. Use of polypeptides containing glycine and l-alanine for activation of two different monomers with either glycine or l-alanine allowed simple coded autocatalytic synthesis of polyesters and polypeptides and established the first genetic code. A primitive cell capable of supporting electron transport, thioester synthesis, reduction reactions, and synthesis of polyesters and polypeptides is proposed. The cell consists of an iron-sulfide particle enclosed by tholin, a heterogeneous organic material that is produced by Miller-Urey type experiments that simulate conditions on the early Earth. As the synthesis of nucleic acids evolved from β-linked polyesters, the singlet coding system for replication evolved into a four nucleotide/four amino acid process (AMP = aspartic acid, GMP = glycine, UMP = valine, CMP = alanine) and then into the triplet ribosomal process that permitted multiple copies of protein to be synthesized independent of replication. This hypothesis reconciles the "genetics first" and "metabolism first" approaches to the origin of life and explains why there are four bases in the genetic alphabet.

No MeSH data available.


Related in: MedlinePlus

Evolution of purines and pyrimidines. Arrows show directions of possible hydrogen bonds. (A–D) Structures of the malamide side chain extended with β-alaninamide in “cis”- and “trans”-like conformations relative to the two CH2 groups. Blue arrows indicate rotations producing different conformations. Nitrogen and carbon atoms in the extended side chain are highlighted in red; (E–H) Structures of ribonucleic acid bases in RNA, (uracil, cytosine, guanine, and adenine) showing their relationships to the “cis”- and “trans”-like structures shown in A–D; (I,J) Epimers of tetrahydroorotate, a possible intermediate in pyrimidine evolution formed by reaction of Asn with formaldehyde; (K,L) Tetrahydroorotate epimers linked to the backbone of nucleic acid predecessors; (M) A pyrimidine derivative, formed by crosslinking of Asn using formylation, lacking the N–H bond at position 3 needed for double hydrogen bonding; (N) Dihydroorotate intermediate in uracil synthesis; (O) 4-Aminodihydroorotate, a proposed evolutionary predecessor of cytosine; (P) 4-carboxamido-5-aminoimidazole ribonucleotide intermediate in purine synthesis; (Q) Inosine, the first purine ring synthesized in the biochemical pathway to adenine and guanine; (R,S) Proposed intermediates in the evolution of the six-membered ring of purines lacking the imidazole ring. The carbonyl group of malonamide (R) is converted to an amino group (S) using the same reactions used in inosine biosynthesis; (T) Proposed predecessor of inosine. Six-membered pyrimidine ring is linked through a 6 amino group to the nucleic acid backbone. The amino and amido nitrogen atoms of S are linked via formylation; (U) Proposed predecessor of adenine. T is converted into an amino derivative similar to the conversion of inosine into adenine.
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life-05-00467-f006: Evolution of purines and pyrimidines. Arrows show directions of possible hydrogen bonds. (A–D) Structures of the malamide side chain extended with β-alaninamide in “cis”- and “trans”-like conformations relative to the two CH2 groups. Blue arrows indicate rotations producing different conformations. Nitrogen and carbon atoms in the extended side chain are highlighted in red; (E–H) Structures of ribonucleic acid bases in RNA, (uracil, cytosine, guanine, and adenine) showing their relationships to the “cis”- and “trans”-like structures shown in A–D; (I,J) Epimers of tetrahydroorotate, a possible intermediate in pyrimidine evolution formed by reaction of Asn with formaldehyde; (K,L) Tetrahydroorotate epimers linked to the backbone of nucleic acid predecessors; (M) A pyrimidine derivative, formed by crosslinking of Asn using formylation, lacking the N–H bond at position 3 needed for double hydrogen bonding; (N) Dihydroorotate intermediate in uracil synthesis; (O) 4-Aminodihydroorotate, a proposed evolutionary predecessor of cytosine; (P) 4-carboxamido-5-aminoimidazole ribonucleotide intermediate in purine synthesis; (Q) Inosine, the first purine ring synthesized in the biochemical pathway to adenine and guanine; (R,S) Proposed intermediates in the evolution of the six-membered ring of purines lacking the imidazole ring. The carbonyl group of malonamide (R) is converted to an amino group (S) using the same reactions used in inosine biosynthesis; (T) Proposed predecessor of inosine. Six-membered pyrimidine ring is linked through a 6 amino group to the nucleic acid backbone. The amino and amido nitrogen atoms of S are linked via formylation; (U) Proposed predecessor of adenine. T is converted into an amino derivative similar to the conversion of inosine into adenine.

Mentions: Evolutionary pathway proposed for the RNA backbone. (A) A malamide monomer in poly(β-d-malamide). C2, C3, and C4 carbon atoms are highlighted in blue; (B) Reduction of the 4-carboxyl group of malamide to a hydroxymethyl group forms d-2,4-dihydroxybutyramide allowing phosphodiester linking of monomers; (C) Reduction of the carboxamido carbonyl group of d-2,4-dihydroxybutyramide to a methylene group produces a d-3-deoxyerythritol backbone that forms phosphodiester links and binds to amines or heterocyclic bases through C1; (D) Replacement of the d-3-deoxyerythritol backbone by 3'-5' phosphodiester linked d-ribose. Conservation of the C2, C3, and C4 atoms of malamide as the 3', 4', and 5' carbon atoms of ribose is shown in blue. Evolution of the polymer side chains into pyrimidines and purines is discussed in Section 18 in relation to Figure 5A,B and Figure 6. * indicates chiral carbon atom.


The Hypothesis that the Genetic Code Originated in Coupled Synthesis of Proteins and the Evolutionary Predecessors of Nucleic Acids in Primitive Cells.

Francis BR - Life (Basel) (2015)

Evolution of purines and pyrimidines. Arrows show directions of possible hydrogen bonds. (A–D) Structures of the malamide side chain extended with β-alaninamide in “cis”- and “trans”-like conformations relative to the two CH2 groups. Blue arrows indicate rotations producing different conformations. Nitrogen and carbon atoms in the extended side chain are highlighted in red; (E–H) Structures of ribonucleic acid bases in RNA, (uracil, cytosine, guanine, and adenine) showing their relationships to the “cis”- and “trans”-like structures shown in A–D; (I,J) Epimers of tetrahydroorotate, a possible intermediate in pyrimidine evolution formed by reaction of Asn with formaldehyde; (K,L) Tetrahydroorotate epimers linked to the backbone of nucleic acid predecessors; (M) A pyrimidine derivative, formed by crosslinking of Asn using formylation, lacking the N–H bond at position 3 needed for double hydrogen bonding; (N) Dihydroorotate intermediate in uracil synthesis; (O) 4-Aminodihydroorotate, a proposed evolutionary predecessor of cytosine; (P) 4-carboxamido-5-aminoimidazole ribonucleotide intermediate in purine synthesis; (Q) Inosine, the first purine ring synthesized in the biochemical pathway to adenine and guanine; (R,S) Proposed intermediates in the evolution of the six-membered ring of purines lacking the imidazole ring. The carbonyl group of malonamide (R) is converted to an amino group (S) using the same reactions used in inosine biosynthesis; (T) Proposed predecessor of inosine. Six-membered pyrimidine ring is linked through a 6 amino group to the nucleic acid backbone. The amino and amido nitrogen atoms of S are linked via formylation; (U) Proposed predecessor of adenine. T is converted into an amino derivative similar to the conversion of inosine into adenine.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390864&req=5

life-05-00467-f006: Evolution of purines and pyrimidines. Arrows show directions of possible hydrogen bonds. (A–D) Structures of the malamide side chain extended with β-alaninamide in “cis”- and “trans”-like conformations relative to the two CH2 groups. Blue arrows indicate rotations producing different conformations. Nitrogen and carbon atoms in the extended side chain are highlighted in red; (E–H) Structures of ribonucleic acid bases in RNA, (uracil, cytosine, guanine, and adenine) showing their relationships to the “cis”- and “trans”-like structures shown in A–D; (I,J) Epimers of tetrahydroorotate, a possible intermediate in pyrimidine evolution formed by reaction of Asn with formaldehyde; (K,L) Tetrahydroorotate epimers linked to the backbone of nucleic acid predecessors; (M) A pyrimidine derivative, formed by crosslinking of Asn using formylation, lacking the N–H bond at position 3 needed for double hydrogen bonding; (N) Dihydroorotate intermediate in uracil synthesis; (O) 4-Aminodihydroorotate, a proposed evolutionary predecessor of cytosine; (P) 4-carboxamido-5-aminoimidazole ribonucleotide intermediate in purine synthesis; (Q) Inosine, the first purine ring synthesized in the biochemical pathway to adenine and guanine; (R,S) Proposed intermediates in the evolution of the six-membered ring of purines lacking the imidazole ring. The carbonyl group of malonamide (R) is converted to an amino group (S) using the same reactions used in inosine biosynthesis; (T) Proposed predecessor of inosine. Six-membered pyrimidine ring is linked through a 6 amino group to the nucleic acid backbone. The amino and amido nitrogen atoms of S are linked via formylation; (U) Proposed predecessor of adenine. T is converted into an amino derivative similar to the conversion of inosine into adenine.
Mentions: Evolutionary pathway proposed for the RNA backbone. (A) A malamide monomer in poly(β-d-malamide). C2, C3, and C4 carbon atoms are highlighted in blue; (B) Reduction of the 4-carboxyl group of malamide to a hydroxymethyl group forms d-2,4-dihydroxybutyramide allowing phosphodiester linking of monomers; (C) Reduction of the carboxamido carbonyl group of d-2,4-dihydroxybutyramide to a methylene group produces a d-3-deoxyerythritol backbone that forms phosphodiester links and binds to amines or heterocyclic bases through C1; (D) Replacement of the d-3-deoxyerythritol backbone by 3'-5' phosphodiester linked d-ribose. Conservation of the C2, C3, and C4 atoms of malamide as the 3', 4', and 5' carbon atoms of ribose is shown in blue. Evolution of the polymer side chains into pyrimidines and purines is discussed in Section 18 in relation to Figure 5A,B and Figure 6. * indicates chiral carbon atom.

Bottom Line: A primitive cell capable of supporting electron transport, thioester synthesis, reduction reactions, and synthesis of polyesters and polypeptides is proposed.As the synthesis of nucleic acids evolved from β-linked polyesters, the singlet coding system for replication evolved into a four nucleotide/four amino acid process (AMP = aspartic acid, GMP = glycine, UMP = valine, CMP = alanine) and then into the triplet ribosomal process that permitted multiple copies of protein to be synthesized independent of replication.This hypothesis reconciles the "genetics first" and "metabolism first" approaches to the origin of life and explains why there are four bases in the genetic alphabet.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, University of Wyoming, Laramie, WY 82071, USA. brianrf@uwyo.edu.

ABSTRACT
Although analysis of the genetic code has allowed explanations for its evolution to be proposed, little evidence exists in biochemistry and molecular biology to offer an explanation for the origin of the genetic code. In particular, two features of biology make the origin of the genetic code difficult to understand. First, nucleic acids are highly complicated polymers requiring numerous enzymes for biosynthesis. Secondly, proteins have a simple backbone with a set of 20 different amino acid side chains synthesized by a highly complicated ribosomal process in which mRNA sequences are read in triplets. Apparently, both nucleic acid and protein syntheses have extensive evolutionary histories. Supporting these processes is a complex metabolism and at the hub of metabolism are the carboxylic acid cycles. This paper advances the hypothesis that the earliest predecessor of the nucleic acids was a β-linked polyester made from malic acid, a highly conserved metabolite in the carboxylic acid cycles. In the β-linked polyester, the side chains are carboxylic acid groups capable of forming interstrand double hydrogen bonds. Evolution of the nucleic acids involved changes to the backbone and side chain of poly(β-d-malic acid). Conversion of the side chain carboxylic acid into a carboxamide or a longer side chain bearing a carboxamide group, allowed information polymers to form amide pairs between polyester chains. Aminoacylation of the hydroxyl groups of malic acid and its derivatives with simple amino acids such as glycine and alanine allowed coupling of polyester synthesis and protein synthesis. Use of polypeptides containing glycine and l-alanine for activation of two different monomers with either glycine or l-alanine allowed simple coded autocatalytic synthesis of polyesters and polypeptides and established the first genetic code. A primitive cell capable of supporting electron transport, thioester synthesis, reduction reactions, and synthesis of polyesters and polypeptides is proposed. The cell consists of an iron-sulfide particle enclosed by tholin, a heterogeneous organic material that is produced by Miller-Urey type experiments that simulate conditions on the early Earth. As the synthesis of nucleic acids evolved from β-linked polyesters, the singlet coding system for replication evolved into a four nucleotide/four amino acid process (AMP = aspartic acid, GMP = glycine, UMP = valine, CMP = alanine) and then into the triplet ribosomal process that permitted multiple copies of protein to be synthesized independent of replication. This hypothesis reconciles the "genetics first" and "metabolism first" approaches to the origin of life and explains why there are four bases in the genetic alphabet.

No MeSH data available.


Related in: MedlinePlus