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27º Meeting of the Israel Society for Astrobiology and the Study of the Origins 27º Meeting of the Israel Society for Astrobiology and the Study of the Origins of Life Planetary evolution and biochemical adaptations: between contingency and determinism? Antonio Lazcano Facultad de Ciencias, UNAM MEXICO E-mail: [email protected] unam. mx Weizmann Institute 2013

Our understanding of the origin of life is strongly hindered by 1. lack of Our understanding of the origin of life is strongly hindered by 1. lack of geological evidence of the prebiotic environment 2. absence of a fossil record of prebiological systems 3. all-embracing lack an of generally definition agreed of life

The heterotrophic theory of the origin of life: a contemporary reassessment DNA/RNA/protein cells RNA The heterotrophic theory of the origin of life: a contemporary reassessment DNA/RNA/protein cells RNA World synthesis & accumulation of organic compounds

Current limits of molecular phylogenies (DNA/RNA/protein cells) RNA/protein cellular systems (inferred from metabolic data) Current limits of molecular phylogenies (DNA/RNA/protein cells) RNA/protein cellular systems (inferred from metabolic data) RNA World (deduced from ribozymes) primitive soup (experimental simulations & extraterrestrial organic molecules) Adapted from Futuyma (2006) Evolutionary Biology (Sinauer, Boston)

The gene complement of the last common ancestor (cenancestor, LCA, LUCA) The gene complement of the last common ancestor (cenancestor, LCA, LUCA)

Highly conserved protein domains Delaye, Becerra & Lazcano (2005) Origins Life Evol Biosph 35: Highly conserved protein domains Delaye, Becerra & Lazcano (2005) Origins Life Evol Biosph 35: 537

RNA: no more a mere molecular go-between large nc RNA (r. RNA, t. RNA, RNA: no more a mere molecular go-between large nc RNA (r. RNA, t. RNA, primer RNA) small nc RNA (Argonaute/Piwi RNA) non-coding RNA (nc RNA) coding RNA (c RNA) RNA deoxyribonucleotides ribonucleotides ribose-P, amino acids, CO 2, NH 3 coenzymes histidine alarmones

The limits of molecular phylogenies At the time being, molecular phylogenies cannot be extrapolated The limits of molecular phylogenies At the time being, molecular phylogenies cannot be extrapolated to an evolutionary period prior to the emergence of ribosome-mediated protein synthesis. There is nothing in molecular cladistics that supports the possibility of ancestral life with replicative and metabolic abilities based solely on RNA molecules. Evidence for the RNA World comes from the catalytic versatility of ribozymes and is supported by the biological ubiquity of RNA and ribonucleotides. For instance, r. RNA-mediated peptide bond formation is a strong indication that protein synthesis first evolved in an RNA world.

RNA World Unknown prebiotic chemical processes? Evolutionary outcome of pre-RNA worlds? RNA World Unknown prebiotic chemical processes? Evolutionary outcome of pre-RNA worlds?

The Miller experiment (1953) The Miller experiment (1953)

Miller, 1953 Miller, 1953

Preliminary analyses of S. L. Miller 1953 samples Preliminary analyses of S. L. Miller 1953 samples

Note: identifications were confirmed by LC-FD/To. F-MS Representative cumulative HPLC chromatograms for: (A) classic Note: identifications were confirmed by LC-FD/To. F-MS Representative cumulative HPLC chromatograms for: (A) classic apparatus design; (B) volcanic apparatus design; (C) silent discharge apparatus design; and (D) an amino acid standard; peak identifications 1 -D, L-Asp; 2 -L, D-Glu; 3 -D, L-Ser; 4 -Gly; 5 - -Ala; 6 - ABA; 7 -D, L- -AIB; 8 -D, L-Ala; 9 D, L- -ABA; 10 - -AIB; 11 -D, L- -ABA; 12 -D, L-Isovaline; 13 -D, L-Norleucine. (* are unidentified peaks); and (E) a procedural blank.

The evidence suggests that prior to the origin of life the primitive Earth already The evidence suggests that prior to the origin of life the primitive Earth already had: v a wide array of organic compounds of biochemical significance –and not only proteinic amino acids v many inorganic & organic catalysts v many different purines & pyrimidines (the potential for template-directed polymerizations) v membrane-forming compounds

Some examples of self-organization which may be relevant to the origin of life 1. Some examples of self-organization which may be relevant to the origin of life 1. Formation of micelles, liposomes and lipid vesicles from prebiotic amphiphiles; 2. Self-assembly of nucleic acids (base-bearing polymers); 3. Fe-S catalytic clusters; 4. Mineral and organic compounds complexes (clays and bases); and 5. Autocatalytic synthetic reactions (formose reaction)

The prebiotic broth: a useful metaphor cooked with a wide range of ingredients CO The prebiotic broth: a useful metaphor cooked with a wide range of ingredients CO 2, CO, N 2, H 2 S, H 2 O, CH 4 amino acids, nucleobases, sugars, lipids, oligomers of biochemical compounds CO 2, NH 3, H 2 S, H 2 O Lazcano, Natural History (Feb/2006)

Organic compounds in the 109 years-old Murchison meteorite Deamer 2011 Organic compounds in the 109 years-old Murchison meteorite Deamer 2011

Relative abundances of amino acids in the Murchison meteorite and their synthesis in a Relative abundances of amino acids in the Murchison meteorite and their synthesis in a CH 4, NH 3, & H 2 O primordial atmosphere Parker, Cleaves, Dworkin, Glavin, Cahallan, Aubrey, Lazcano & Bada, 2011

Blue, meteoritic aa; red, Miller’s volcanic experiment (CH 4, H 2 O, NH 3, Blue, meteoritic aa; red, Miller’s volcanic experiment (CH 4, H 2 O, NH 3, H 2, ); black, spark discharge simulation (CH 4, CO 2, H 2 O, NH 3, H 2 S) Parker et al. (2011) PNAS 108: 5526

Burton et al 2013 Burton et al 2013

Moles (relative to glycine = 1) of the various amino acids detected in the Moles (relative to glycine = 1) of the various amino acids detected in the volcanic apparatus vials. Amino acids underlined have not been previously reported in spark discharge experiments.

Relative aa abundances (gly = 1) for the linear α-aa detected in the target ice sample Relative aa abundances (gly = 1) for the linear α-aa detected in the target ice sample no. 1 (grey) and target ice sample no. 2 (white) Martins et al, 2013. Nature Geoscience

Synthesis of monomers under possible prebiotic conditions produce appreciable yields under a wide range Synthesis of monomers under possible prebiotic conditions produce appreciable yields under a wide range of environmental settings* Miller & Lazcano, 2002

CH 3 O O H 3 C OH NH 2 S OH H 3 CH 3 O O H 3 C OH NH 2 S OH H 3 C Valine (Val) NH 2 Methionine (Met) O O H 3 C OH H 3 C CH 3 NH 2 Leucine (Leu) Norvaline (Nva) O H 3 C OH CH 3 OH H 3 C NH 2 Isovaline (Iva) O H 3 C OH NH 2 Isoleucine (Ile)

Why do modern organisms use a small subset of the L -amino acids which Why do modern organisms use a small subset of the L -amino acids which are structurally possible? “The absence of -amino-n-butyric acid, norvaline and norleucine is most striking and a major challenge to any attempt to account for the selection of the twenty protein amino acids. Their abundance in prebiotic experiments and carbonaceous chondrites is comparable to or greater than the hydrophobic amino acids used in proteins”. Weber & Miller (1981) Jour. Mol. Evol. 17: 273

Both norvaline (Nva) and norleucine (Nle) are incorporated in vivo in recombinant hemoglobin in Both norvaline (Nva) and norleucine (Nle) are incorporated in vivo in recombinant hemoglobin in E. coli Apostol et al. (1997) J. Biol. Chem. 272: 28980

Why are norvaline (Nva) & norleucine (Nle) incorporated into recombinant hemoglobin? 1. Leucyl-t. RNA Why are norvaline (Nva) & norleucine (Nle) incorporated into recombinant hemoglobin? 1. Leucyl-t. RNA synthase is unable to discriminate between leucine and other aliphatic amino acids (Apostol et al. , 1997) Figure 6 -59 a Molecular Biology of the Cell (© Garland Science 2008) 2. Which is the intracellular source of non-protein aliphatic amino acids like norvaline and norleucine?

Biosyntheses of protein & non-protein aliphatic amino acids pyruvate threonine isoleucine -ketoisovalerate valine -ketobutyrate Biosyntheses of protein & non-protein aliphatic amino acids pyruvate threonine isoleucine -ketoisovalerate valine -ketobutyrate -ketoisocaproate leucine -ketovalerate norvaline -ketocaproate norleucine Bogosian et al. (1989) J. Biol. Chem. 264: 531

Biosyntheses of protein & non-protein aliphatic amino acids pyruvate threonine isoleucine -ketoisovalerate valine -ketobutyrate Biosyntheses of protein & non-protein aliphatic amino acids pyruvate threonine isoleucine -ketoisovalerate valine -ketobutyrate -ketoisocaproate leucine -ketovalerate norvaline -ketocaproate norleucine Bogosian et al. (1989) J. Biol. Chem. 264: 531

Under anaerobic conditions, pyruvate production is quickly enhanced –followed by a significant increment of Under anaerobic conditions, pyruvate production is quickly enhanced –followed by a significant increment of intracellular norvaline Soini et al. (2008) Microbial Cell Factories 7: 30

Burton et al 2013 Burton et al 2013

Genetically-encoded amino acids Cleaves 2010 Genetically-encoded amino acids Cleaves 2010

Genetically-encoded amino acids Cleaves 2010 Genetically-encoded amino acids Cleaves 2010

Amino acids are abundant in chondritic meteorites and are readily formed in model prebiotic Amino acids are abundant in chondritic meteorites and are readily formed in model prebiotic reactions. This is not true of: a) arginine & lysine b) histidine

Histidine Histidine

How proteins first evolved is not known, but their active sites must be one How proteins first evolved is not known, but their active sites must be one of the oldest portions of enzymes. What do they tell us about their catalytic components?

Propensity of a residue to be catalytic in each of the six classes of Propensity of a residue to be catalytic in each of the six classes of enzymes EC 1, oxidoreductases EC 2, transferases Holliday et al (2011) FEBS J 278: 3835 EC 3, hydrolases EC 4, lyases EC 5, isomerases EC 6, ligases

Harold White’s hypothesis: is histidine an evolutionary remmant of a catalytic ribonucleotide? Harold White’s hypothesis: is histidine an evolutionary remmant of a catalytic ribonucleotide?

CONCLUSIONS…. synthetic efficiency, physical stability, chemical reactivity, self-assembly, self-organization prebiotic syntheses lipids noncanonical bases CONCLUSIONS…. synthetic efficiency, physical stability, chemical reactivity, self-assembly, self-organization prebiotic syntheses lipids noncanonical bases imidazolides racemic sugars racemic nonprotein & (some) protein amino acids natural selection catalytic RNA amino acids lipids cells with RNA, proteins & DNA time

Conclusions 1. There is very good evidence for a primitive soup, but the transition Conclusions 1. There is very good evidence for a primitive soup, but the transition from it to an RNA World remains an open question; 2. Experimental simulations of prebiotic environments, analysis of meteorites and stability arguments suggest that RNA was preceded by a complex mixture of genetic polymers with different backbones and nucleobases; 3. The presence of twenty protein amino acids in extant biology does not means that they were essential for the origin of life nor that all of them were synthesized prebiotically; and 4. The key role of imidazolides in prebiotic chemistry and in biological catalysis suggests a connection between the chemical constituents of the RNA World and the emergence of the first proteins.