co-evolution of the genetic code and amino acid biosynthesis anna battenhouse an hypothesis from...
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Co-Evolution ofthe Genetic Code and
Amino Acid BioSynthesis
Anna Battenhouse
An hypothesis from 1975by Jeffrey Tze-Fei Wong
Universal Phylogenetic Tree
Translation – the PlayersRibosome• large subunit: 23S rRNA,
many proteins– peptidyl transferase reaction,
tRNA sites
• small subunit: 16S rRNA, many proteins– messenger RNA (mRNA) contacts
Translation factors• EF-Tu, EF-G proteins, GTPtRNA (transfer RNA)
• acceptor arm holds amino acid• anticodon arm “reads” mRNA,
implements Genetic CodeaaRS (aminoacyl tRNA synthetase)
• “charge” tRNAs with the appropriate amino acid
22 “coded” amino acids
Chicken or Egg?
protein RNA
DNA
transcription
translation
synthesis,metabolism
excellent information storage,poor catalysis
poor information storage,excellent catalysis adequate information
storage,adequate catalysis
Simplifying Assumptions
• Ribosome proteins serve as scaffold• Small PTC RNA core with 2-fold symmetry
– A, P sites
• Translation factors not required– EF-Tu, EF-G, GTP
• “Proto-genes” were RNA molecules– copied by an RNA replicase ribozyme
• tRNA charging enzymes were ribozymes– left imprint on modern aaRSs
Science 256 (1992)
Benner, S.A., Ellington, A.D., Tauer, A., Modern metabolism as a palimpset of the RNA world PNAS 86 (1989)
The Pre-translation RNA world was metabolically complex
Diverse RNA enzymes (ribozymes), using cofactors and small random peptides
What’s Left to Explain?
What drove code evolution?
• Sterochemical interactions– Codon assignments arose from
Physical/chemical interactions between AAs and RNA
• Error minimization– Adjacency of codons minimizes potential
damage due to mutations/translation errors
• Expanding codons– Not all codon triplets used at first. Usage
expanded over time to modern 64.
• Amino acid biosynthesis– Formation/extension of AA biosynthetic
pathways
PNAS 55 (1966)
Woese et al., Microbio. Mol. Bio. Rev., 64:1 (2000)
7.5
9.1
7.5
9.1
Yarus 2009 Results
• RNA can bind wide variety of AAs specifically– polar, charged, aromatic– even aliphatic
• Several AA/RNA binding sites showed anticodon enrichment– Ile, Phe, Arg,
His, Trp, (Tyr)– However ~80% of triplets
not found
Woese, PNAS 55 (1966)
Direct RNA Template Model
Error Minimization
Amino Acid Biosynthesis Co-Evolution
Wong, J.T., Trends Bio. Sci.,
Feb. 1981
Wong, J.T., PNAS 73 (1976)
BioSynthesis Co-Evo Predictions
• AA biosynthesis is essential– phase 1 AA abundancy– phase 2 AA non-abundancy
• Biosynthetic evolutionary trace should still be discernable for precursor product pairs– codon allocation– “pre-translation” synthesis
• Set of encoded AAs is, in theory, (slightly) mutable
Not all amino acids would initially be available/abundant
Asn, Gln thermally unstable
Cys, Met, Trp, Phe, His
UV labile
Gly, Ala, Val, Leu Ile, Ser, Asp, Glu, initially most
abundant
Wong, J.T., Coevolution theory of the genetic code at age 30, BioEssays, 27.4 (2005)
Genetic Code by Biosynthetic Families
AAAA Precursor Product
Indirect Charging (“pre-translation”
biosynthesis)
Amino Acyl tRNA Synthetases (“aaRSs”) tRNA charging enzymes
AA AA
AA
AA
AA
Direct Charging
inventiveinventive biosynthesibiosynthesi
ss
Pre-translation Biosynthesis
Wong, J.T.,BioEssays 27.4 (2005)
Sep-tRNA Cys-tRNA(Sep = O-phosphoserine)
Lack of CysRS Euryarchaea
O’Donoghue et al.,PNAS 102:52 (2005)
Archaea
Archaea
Wong, J.T., Coevolution theory of the genetic code at age 30, BioEssays 27.4 (2005)
Distribution of Genes forPre-trans biosynthesis
Glu Gln Asp Asn
neither precursor nor product aaRSprecursor aaRS onlyboth precursor and product aaRS
Additional Evidence
• Phylogeny of aaRS genes– product aaRSs are often related to their
precursor aaRSs (and precursors more ancient)
• Enzyme for de novo Asn synthesis in many archaea was once an AspRS– pre-trans de novo biosynthesis via aaRS
paralog
• Natural and synthetic modifications to the Genetic code exist– pyrrolysine – 22nd amino acid– engineered AA additions in E. coli
Roy et al., and Francklyn, C., PNAS 100:17 (2003); Doring, et al., Scienece 292:501 (2001)
Pyrrolysine
• Incorporated in only a few prokaryotic proteins– has its own tRNA, (codon UAG, normally “stop”), aaRS
• Found in only a few species– Archaea
• 3 Methanosarcina• Methanococcoides
– Eubacteria• Desulfitobacterium hafniense (HGT)
• All species live off methylamine (fishy smell)– Pyl used in monomethylamine methyltransferase enzyme
Lehninger, Principles of Biochemistry, Fifth Ed.
Synthetic Code Expansion
BioSynth Co-Evo Theory Limitations
• Long on correlations, short on mechanisms• Does not address the important questions
surrounding tRNA– how did it arise? – did the anticodon arm develop independently
of the acceptor stem?– how did aaRSs come to be?
• and the Class I/Class II aaRS division
– role of the extensive AA base modifications
• What about the co-evolution of tRNAs and the 23S and 16S RNAs?– and the fascinating questions around message-
reading translocation
Blind men feeling an Elephant
Anticodon
wobble position
Acceptor stem
Transfer RNA (tRNA)
Maizels, N. et al., Biol. Bull. 196 (1999)
• Rossman fold active site• 2’ –OH attachment first• interacts with minor
groove of tRNA acceptor stem
• Beta sheet active site• 3’ –OH attachment• interacts with major
groove of tRNA acceptor stem
Schimmel et al., in The RNA World, Third Edition, Cold Spring Harbor Laboratory Press (2006)
Class I aaRSs Class II aaRSs
Giege, R. et al., Nucleic Acids Res. 26 (1998)
tRNA Identity Elements
Giege, R. et al., Nucleic Acids Res. 26 (1998)
Class I aaRS Class II aaRS
Xue, H., Tong, K., Marck, C., Grosjean, H., Wong, J.T., Transfer RNA paralogs, Gene 310 (2003)
tRNA phylogeny
Universal Phylogenetic Tree
Wobble
Watson/Crick A-U pair
Non-Watson/Crick G-U pair
I (inosine) can pair with C,U,A
Wobble Usage
Tong, K., Wong, J.T., Anticodon and wobble evolution, Gene 333 (2004)
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