Manal A. Swairjo
Associate Professor, Biochemistry
office: CSL 340
- B.Sc., Physics and Mathematics, Kuwait University, 1988
- Ph.D., Cellular Biophysics, Boston University, 1996
- Assistant Professor, Western University of Health Sciences, 2010-2015
- Associate Professor, San Diego State University, 2015-present
My research focuses on tRNA biogenesis processes and their links to human disease. tRNA is an ancient molecule that evolved to be the adapter between amino acids and codons, thus mediating the translation of the genetic code. The coding properties of tRNA do not reside only in its primary sequence. Post-transcriptional nucleoside modification, particularly in the anticodon-stem loop (ASL) region of tRNA, are required for cognate and/or wobble codon recognition and translocation, they enhance aminoacylation properties of tRNA, and prevent ribosomal frameshifting.
Deficiencies in tRNA modifications cause a variety of diseases, e.g. hereditary human mitochondrial disease, and modified nucleosides serve as sensitive human cancer markers. Most significantly, modifications of the anticodon-stem loop have been implicated in viral replication as several retroviruses rely on modifications of host cell tRNA for virulence or to replicate.
In the past five years, my lab focused on elucidating the biosynthesis pathways of three modified tRNA nucleosides: queuosine (Q), archaeosine (G+), and threonylcarbamoyl adenosine (t6A). Studying these pathways in model microbial systems, in which some of the genes involved are essential, has led to the discovery of several new potential antimicrobial drug targets, as well as new enzymatic mechanisms and unprecedented chemistries such as biological nitrile reduction. Our approach combines X-ray crystallographic, structural bioinformatic and biochemical analyses, complemented by collaborations with geneticists and chemists.
The crystal structure of the Queuosine biosynthesis nitrile reductase enzyme QueF is an asymmetric tunnel-fold homodecamer of two head-to-head facing pentameric subunits, harboring ten active sites at the interfaces between monomeric subunits, view the video of overall structure and perspective of interfacial catalytic site.
The binding of substrate preQ0 induces closure of the active site, as shown in this video, followed by formation of a thioimide linkage with invariant side chain Cys55. This "induced fit" mechanism of substrate binding may be considered in the re-design of the active site to accept unnatural substrates.
- "Deazaguanine derivatives, examples of crosstalk between RNA and DNA modification pathways,"
Hutinet, G., Swairjo, M.A., and de Crécy-Lagard, V.,
RNA Biology (online), 1-10 (2016). (10.1080/15476286.2016.1265200.)
- "Crystal structure of the archaeosine synthase QueF-like — Insights into amidino transfer and tRNA recognition by the tunnel fold (Cover article),"
Mei, X., Alvarez, J., Bon Ramos, A., Samanta, U., Iwata-Reuyl, D., and Swairjo, M.A.,
Proteins 85, 103-16 (2017). (10.1002/prot.25202.)
- "Mechanism and catalytic strategy of the prokaryotic specific GTP cyclohydrolase IB (Cover article),"
Paranagama, N., Bonnett, S.A, Alvarez, J., Luthra, A., Stec, B., Gustafson, A., Iwata-Reuyl, D., and Swairjo, M.A.,
Biochemical J. 474, 1017-1039 (2017). (10.1042/BCJ20161025.)
- "Protection of the queuosine biosynthesis enzyme QueF from irreversible oxidation by a conserved intramolecular disulfide,"
Mohammad, A., Bon Ramos, A., Lee, B., Cohen, S., Kiani, M. K., Iwata-Reuyl, D., Stec, B., and Swairjo, M.A.,
Biomolecules 7, 30 (2017). (10.3390/biom7010030.)
- "Structure and mechanism of a bacterial t6A biosynthesis system,"
Amit Luthra, William Swinehart, Susan Bayooz, Phuc Phan, Boguslaw Stec, Dirk Iwata-Reuyl, and Manal A. Swairjo,
Nucleic Acids Research 46, 1395-1411 (2018). (10.1093/nar/gkx1300.)