Mailing Address:
Molecular Biophysics & Biochemistry Dept.
Yale University
266 Whitney Avenue
P.O. Box 208114
New Haven, CT 06520-8114
Phone: (203)432-6200
Fax: (203)432-6202
E-mail: [email protected]
Campus address: 238A BASS
Ph.D. (Chemistry) Technische Hochschule,
Stuttgart, Germany, 1962; Postdoctoral Fellow, University of Wisconsin,
Madison, 1962-1965; joined Yale faculty in 1967. Guggenheim Fellow, 1972 and
1989. Alexander von Humboldt Senior Scientist Award, 1988; Fellow, American
Association for the Advancement of Science, 1990; Member, National Academy of
Sciences, 1997; Fellow, American Academy of Microbiology, 1997.
Functional
Genomics and Aminoacyl-tRNA Synthesis.
Accurate aminoacylation of transfer RNA (tRNA) by aminoacyl-tRNA synthetases
(AARSs) is a crucial step in the faithful translation of messenger RNA. Each
AARS acylates only its cognate amino acid to the terminal adenosine of the
corresponding tRNA. It is commonly accepted that each cell contains twenty such
enzymes, one for each canonical amino acid. This was supported by the
description of twenty minoacyl-tRNA synthetases found some bacteria (e.g.,
Escherichia coli) and in the eukaryotic cytoplasm. However, recent discoveries
arising from functional genomics studies in bacteria and archaea have
overturned this concept and revealed that most organisms do not use a full
complement of twenty canonical AARSs (1). For example, the genome sequences of
the euryarchaeotes Methanococcus jannaschii and Methanobacterium
thermoautotrophicum do not contain open reading frames encoding homologs of the
canonical asparaginyl-(AsnRS), cysteinyl-(CysRS), glutaminyl-(GlnRS) and
lysyl-tRNA synthetases (LysRS). The use of indirect aminoacylation pathways for
the formation of Asn-tRNA and Gln-tRNA in most organisms circumvents the need
for AsnRS and GlnRS, which catalyze direct formation of these molecules (2,3).
Characterization of these pathways identified different enzymes for this
function in bacteria and archaea; thus the three domains of life diverged in
the production of amide aminoacyl-tRNAs (4). Several archaea and bacteria
contain a functional class I LysRS with no resemblance to canonical class II
lysyl-tRNA synthetases, explaining the apparent absence of the latter from some
genomes (5,6). Most surprisingly, where CysRS is absent, Cys-tRNA is instead
synthesized by a bi-functional prolyl-tRNA synthetase (ProCysRS), which in
addition to Pro-tRNA forms Cys-tRNA (7). Taken together, all these results
indicate that a reduced number of canonical AARSs (the minimal known complement
is 16) can work in tandem with a variety of novel enzymes and pathways to
provide the full complement of aminoacyl-tRNAs required for protein synthesis.
These findings provide novel insights into the possible origins of protein
synthesis and the genetic code (8), provide the basis for the investigation of
novel proteins and provide targets for the development of conceptually novel
antibiotics (6).
Publications
1. Ibba, M., Becker, H.D., Stathopoulos, C. Tumbula, D.L. and Söll, D. (2000) The Adaptor Hypothesis revisited. Trends
Biochem. Sci. 25, 311-316.
2. Curnow, A., Ibba, M. and Söll, D. (1996)
tRNA-dependent asparagine formation. Nature 382, 589-590.
3. Curnow, A.W., Hong, K.W., Yuan, R., Kim, S.I., Martins, O., Winkler, W.,
Henkin, T.M. and Söll, D. (1997) Glu-tRNAGln
amidotransferase: a novel heterotrimeric enzyme required for correct decoding
of glutamine codons during translation. Proc. Natl. Acad. Sci. USA 94,
11819-11826. .
4. Tumbula, D.L., Becker, H.D., Chang, W-Z. and Söll,
D. (2000) Domain-specific recruitment of amide amino acids for protein
synthesis. Nature, 407, 106-110.
5. Ibba, M., Morgan, S., Curnow, A.W., Pridmore, D.R., Vothknecht, U.C.,
Gardner, W., Lin, W., Woese, C.R. and Söll,
D. (1997) A euryarchaeal lysyl-tRNA synthetase: resemblance to class I
synthetases. Science 278, 1119-1122.
6. Ibba, M., Bono, J.L., Rosa, P.A. and Söll,
D. (1997) Archaeal-type lysyl-tRNA synthetase in the Lyme disease spirochete
Borrelia burgdorferi. Proc. Natl. Acad. Sci. USA 94, 14383-14388.
7. Stathopoulos, C., Li, T., Longman, R., Vothknecht, U.C., Becker, H., Ibba,
M. and Söll, D. (2000) One polypeptide with two
aminoacyl-tRNA synthetase activities. Science 287, 479-482.
8. Woese, C.R., Olsen, G., Ibba, M. and Söll,
D. (2000) Aminoacyl-tRNA synthetases, the genetic code, and the evolutionary
process. Microbiol. Mol. Biol. Rev. 64, 202-236.