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.
- Swairjo M.A., Rothschild K.J., Nappi B., Lane A. and Gold H. (1991). Infrared fiber optic sensors: New applications in biology and medicine. Applied Spectroscopy in Material Science. 1437: 60-5.
- Swairjo M.A., Seaton B.A. and Roberts M.F. (1994). Effect of vesicle composition and curvature on the dissociation of phosphatidic acid in small unilamellar vesicles - a 31P-NMR study.. Biochimica et Biophysica Acta. 1191: 354-61.
- Swairjo M.A., Roberts M.F., Campos M.-B., Dedman J.R. and Seaton B.A. (1994). 31P- and 1H-NMR studies of the interaction of annexin V with small phosphatidic acid-containing unilamellar vesicles. Biochemistry. 33: 10944-50.
- Swairjo M.A., Concha N.O., Kaetzel M.A., Dedman J.R. and Seaton B.A. (1995). Crystal structures at 1.9 Å resolution of rat annexin V in complex with glycerophosphoserine or glycerophosphoethanolamine: modes of binding to phospholipid polar moieties. Nature Structural Biology. 2: 968-74.
- Campos M.B., Mo Y.D., Mealy T.R., Li C.W., Swairjo M.A., Balch C., Head J.F., Retzinger G., Dedman J.R. and Seaton B.A. (1998). Mutational and Crystallographic Analyses of Interfacial Residues in Annexin V Suggest Direct Interactions with Phospholipid Membrane Components. Biochemistry. 22: 8004-10.
- Swairjo M.A., Towler E.M., Debouck C. and Abdel-Meguid S.S. (1998). Structural Role of the 30's Loop in Determining the Ligand Specificity of the Human Immunodeficiency Virus protease. Biochemistry. 31: 10928-36.
- Morales A.J., Swairjo M.A., and Schimmel P. (1999). Structure-Specific tRNA Binding Protein From the Extreme Thermophile Aquifex aeolicus. EMBO J. 18: 3475-83.
- Swairjo, M.A., Morales A.J., Wang C.-C., Ortiz A.R., and Schimmel P. (2000). Crystal Structure of Trbp111: a Structure-Specific tRNA Binding Protein. EMBO J. 19: 6287-98.
- Swairjo M.A., Otero F.J., Yang X.-L., Lovato M.A., et al., Schimmel P. (2004). Alanyl-tRNA synthetase crystal structure and design for acceptor-stem recognition. Molecular Cell. 13: 829-41.
- Lovato M.A., Swairjo M.A., Schimmel P. (2004). Positional recognition of a tRNA determinant dependent on a peptide insertion. Molecular Cell. 13: 843-51.
- Swairjo M.A. and Schimmel P. (2005). Breaking sieve for steric exclusion of a noncognate amino acid from active site ofa tRNA synthetase. Proc. Natl. Acad. Sci. USA. 102: 988-93.
- Van Lanen S.G., Reader J.S., Swairjo M.A., de Crécy-Lagard V., Lee B., Iwata-Reuyl D. (2005). From cyclohydrolase to oxido-reductase: Discovery of nitrile reductase activity in a common fold. Proc. Natl. Acad. Sci. USA. 102: 4264-9.
- Swairjo M.A., Reddy R.R., Lee B., Van Lanen S.G., Brown S., de Crécy-Lagard V., Iwata-Reuyl D., Schimmel P. (2005). Crystallization and preliminary X-ray characterization of the nitrile reductase QueF - a queuosine biosynthesis enzyme. Acta Crystallogr. F61: 945-8.
- Yang X.-L., Otero F.J., Ewalt K.L., Liu J., Swairjo M.A., Köhrer C., RajBhandary U.L., Skene R.J., McRee D.E., Schimmel P. (2006). Two conformations of a crystalline human tRNA synthetase-tRNA complex: implications for protein synthesis. EMBO J. 25(12): 2919-29.
- El Yacoubi B., Bonnett S., Anderson J.N., Swairjo M.A., Iwata-Reuyl D., de Crécy-Lagard V. (2006). Discovery of a new prokaryotic type I GTP cyclohydrolase family. Journal of Biological Chemistry. 281(49): 37586-93.
- El Yacoubi, B., Lyons, B., Cruz, Y., Reddy, R., Nordin, B., Agnelli, F., Williamson, J.R., Schimmel, P., Swairjo, M.A. and de Crécy-Lagard, V. (2009). The universal YrdC/Sua5 family is required for the formation of threonylcarbamoyladenosine in tRNA. Nucleic Acids Research, 37(9): 2894-2909.
- Sankaran, B., Bonnett, S., Shah, K., Gabriel, S., Reddy, R., Schimmel, P., Rodionov, D.A., de Crécy-Lagard, V., Helmann, J.D., Iwata-Reuyl, D., and Swairjo, M.A. (2009). Zinc-Independent Folate Biosynthesis: Genetic, Biochemical, and Structural Investigation Reveal New Metal Dependence for GTP Cyclohydrolase IB. J. Bacteriology. 191(22): 6936-49.
- Phillips, G., Chikwana, V.M., Maxwell, A., El-Yacoubi, B., Swairjo, M.A., Iwata-Reuyl, D., and de Crécy-Lagard, V. (2010). Discovery and characterization of an amidotransferase involved in the modification of archaeal tRNA. J. Biological Chemistry. (paper of the week), 285(17): 12706-13.
- Harris, K.A., Jones, V., Bilbille, Y., Swairjo, M.A. and Agris, P.F. (2011). YrdC exhibits properties expected of a subunit for a tRNA threonylcarbamoyl transferase. RNA, 17(9): 1678-87.
- Phillips G., Swairjo M.A., Gaston K.W., Bailly M., Limbach P.A., Iwata-Reuyl D., de Crécy-Lagard V. (2012). Diversity of archaeosine synthesis in Crenarchaeota. ACS Chemical Biology. Feb 17;7(2): 300-5.
- Elmadhoun, B.M., Swairjo, M.A., and Burczynski, F.J. (2012). Fluorescent fatty acid transfer from bovine serum albumin to phospholipid vesicles: collision or diffusion mediated uptake. J. Pharmacy and Pharmaceutical Sciences. 15(3): 420-32.
- Chikwana, V.M., Stec, B., Lee, B.W.K., de Crécy-Lagard, V., Iwata-Reuyl, D. and Swairjo, M.A. (2012). Structural basis of biological nitrile reduction. J. Biological Chemistry. 287: 30560-70.
- Hutinet, G., Swairjo, M.A., and de Crécy-Lagard, V. (2016). Deazaguanine derivatives, examples of crosstalk between RNA and DNA modification pathways. RNA Biology (online): 1-10. (10.1080/15476286.2016.1265200.)
- Mei, X., Alvarez, J., Bon Ramos, A., Samanta, U., Iwata-Reuyl, D., and Swairjo, M.A. (2017). Crystal structure of the archaeosine synthase QueF-like — Insights into amidino transfer and tRNA recognition by the tunnel fold (Cover article). Proteins 85: 103-16. (10.1002/prot.25202.)
- Paranagama, N., Bonnett, S.A, Alvarez, J., Luthra, A., Stec, B., Gustafson, A., Iwata-Reuyl, D., and Swairjo, M.A. (2017). Mechanism and catalytic strategy of the prokaryotic specific GTP cyclohydrolase IB. Biochemical J. : BCJ20161025. (10.1042/BCJ20161025.)