My laboratory is focused on the following projects: (1) Rational design of antisickling compounds for treating sickle cell disease. The goal is to develop covalent modifiers of hemoglobin (Hb) that inhibit deoxygenated sickle Hb polymerization by preventing direct contact between the Hb molecules, while maintaining their high oxygen affinity profile.
(2) Structure-function studies of enzymes involved in vitamin B6 metabolism. Pyridoxal 5’-phosphate (PLP), the active form of vitamin B6 serves as a cofactor for over 140 vitamin B6-dependent enzymes involved in amino acid, sugar, and neurotransmitter metabolisms. The in vivo concentration of PLP is very low, and in addition PLP is very reactive and if released into the cell will react with non-B6 dependent enzymes. Therefore how PLP is regulated and transported efficiently to the numerous B6 enzymes is of profound interest. The present goal is to gain insight into the mechanism of PLP regulation in the cell and subsequent transfer of this co-factor to dozens of B6 enzymes.
(3) Elucidating the mechanism involved in staphylococcal methicillin resistance. Transcription of mecA and blaZ, the two genes involved in β-lactam inactivation in S. aureus are activated by the sensor-transducer signaling molecules, MecR1 and BlaR1 when the bacterial cell is exposed to an inducing β-lactam. Our understanding of the signal transduction at molecular level is highly limited by lack of structural information. The goal is to elucidate the structures of the multidomain integral membrane MecR1 and BlaR1 proteins, which will provide a unique insight into the relationship between the parts of the molecules that are responsible for signal reception and signal transduction in S. aureus.
Selected Publications (Articles and Books):
1. F. N. Musayev, M. L. di Salvo, T.-P. Ko, A. K. Ghandi, A. Goswami, V. Schirch, and M. K. Safo. “Crystal Structure of human pyridoxal kinase: Structural basis of M+ and M2+ activation.” Protein Sci., 2007, 16: 2184-2194.
2. Smith SC, Oxford G, Baras AS, Owens C, Havaleshko D, Brautigan DL, Safo MK, Theodorescu D. “Expression of ral GTPases, their effectors, and activators in human bladder cancer.” Clin Cancer Res. 2007 13, 3803-3813
3. M. K. Safo, F. N. Musayev, M. di Salvo, S. Hunt, and V. Schirch. “Crystal Structure of Pyridoxal Kinase from the Escherichia coli PdxK gene: Implications for the Classification of Pyridoxal Kinases.” J. Bacteriol. 2006, 4542-4552.
4. M. K. Safo and D. J. Abraham. “The Enigma of the Liganded Hemoglobin End-State: A Novel Quaternary Structure of Human Carbonmonoxy Hemoglobin.” Biochemistry, 2005, 44, 8347-8359.
5. O. Abdulmalik, M. K. Safo, N.B. Lerner, J. Ochotorena, E. Daikhin, V. Lakka, R. Santacroce, D. J. Abraham and T. Asakura. “5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells.” Br. J. Hematol. 2005,128, 552-561
6. M. K. Safo, T.-P. Ko, F. N. Musayev, Q. Zhao, H. Robinson, N. Scarsdale, A. H.-J. Wang, and G. L. Archer. “Crystal Structures of the BlaI Repressor from Staphylococcus aureus and Its Complex with DNA: Insights into Transcriptional Regulation of the bla and mec Operons.” J. Bacteriol., 2005 187, 1833-44
7. M. K. Safo, F. N. Musayev, S. Hunt, M. di Salvo, N. Scarsdale and V. Schirch. “Crystal Structure of the PdxY Protein from Escherichia coli.” J. Bacteriol. 2004, 186, 8074-8082.
8. M. K. Safo, O. Abdulmalik, R. Danso-Danquah, J. C. Burnett, S. Nokuri, G. S. Joshi, F. N. Musayev, T. Asakura and D. J. Abraham. “Structural Basis for the Potent Antisickling Effect of a Novel Class of 5-Membered Heterocyclic Aldehydic Compounds.” J. Med. Chem. 2004, 47, 4665-4676.
9. F. N. Musayev, M. L. di Salvo, T.-P. Ko, V. Schirch and M. K. Safo. “Structure and Properties of Recombinant Human Pyridoxine 5’-Phosphate Oxidase” Protein Sci. 12, 2003, 1455-1463.
10. M. K. Safo and D. J. Abraham in Ronald L. Nagel, Ed., Methods in Molecular Medicine: Hemoglobin Disorders, Molecular Methods and protocols, Vol. 82: X-ray Crystallography of Hemoglobins, Humana Press Inc, Totowa, NJ, 2003, p.1.
11. L. W. Hardy, D. J. Abraham, and M. K. Safo in D. J. Abraham, Ed., Burger’s Medicinal Chemistry and Drug Discovery, Vol. 1, Structure-based Drug Design, John Wiley and Sons, Inc., Hoboken, NJ, 2002, p.417.
12. M. L. di Salvo, T.-P. Ko, F. N. Musayev, S. Raboni, V. Schirch, and M. K. Safo. “Active Site Structure and Stereospecificity of Escherichia coli Pyridoxine 5'-phosphate Oxidase” J. Mol. Biol. 315, 2002, 385-397.
13. M. K. Safo, F.N. Musayev, M.L.Di Salvo, and V.Schirch. X-ray structure of Escherichia coli pyridoxine 5'-phosphate oxidase complexed with Pyridoxal 5'-phosphate at 2.0 Å resolution. J. Mol. Biol. 310, 2001, 817-826.
14. M. K. Safo, W. -Z. Yang, L. Corselli, S. Crampton, H. S. Yuan, and R. C. Johnson. “The Regulatory Region of the Fis Protein that Activates Site-Specific DNA Inversion Contains Extended Mobile
15. M. K. Safo, M. J. M. Nesset, F. A. Walker, P. G. Debrunner, and W. R. Scheidt. “Models of the Cytochromes. Axial Ligand Orientation and Complex Stability in Iron(II) Porphyrinates: The Case of the Non-Interacting d
16. K. -F. Chak, M. K. Safo, W. -Y. Ku, H. S. -Y Hsieh, and H. S. Yuan. "The Crystal Structure of the ImmE7 Protein Suggests a Possible Colicin Colicin-Interacting Surface". Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 6437-6442.
17. D. J. Abraham, M. K. Safo, T. Boyiri, R. E. Danso-Danquah, J. Kister, and C. Poyart "How Allosteric Effectors Can Bind to the Same Protein Residue and Produce Opposite Shifts in the Allosteric Equilibrium". Biochemistry, 1995, 34, 15006-15020.
18. M. K. Safo, F. A. Walker, P. G. Debrunner, and W. R. Scheidt. "Axial Ligand Orientation in Iron(III) Porphyrinates. Effect of Axial pi-Acceptors. Characterization of the Low-Spin Complex [Fe(TPP)(4-CNPy)2]ClO4". Journal of the American Chemical Society, 1994, 116, 7760-7770.
19. M. K. Safo, G. P. Gupta, F. A. Walker, and W. R. Scheidt. "Models of the Cytochromes b. Attempts to Control Axial Ligand Orientation with a 'Hindered' Porphyrin System". Journal of the American Chemical Society, 1991, 113, 5497-5510.
Selected Patents and Inventions:
1. M. K. Safo, R. Danso-Danquah, S. S. Nokuri, F. N. Musayev, G. S. Joshi, J. C. Burnett, and D. J. Abraham. 5-Membered Heterocyclic Antisickling Agents to Treat Sickle Cell Disease. US Patent No. 7160910, 2007
2. M. K. Safo, R. Danso-Danquah, G. S. Joshi, and D. J. Abraham. Antisickling Agents. US Patent No. 7,119,208 B2, 2006.
3. D. J. Abraham, G. S. Joshi, S. J. Hoffman, M. Grella, R. Danso-Danquah, A. Yousseff, M. K. Safo, S. Kulkarni. "Substituted Chiral Allosteric Hemoglobin Modifiers". US Patent No. 6,486,342 B1, 2002.
