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Martin K. Safo , Ph.D.
Associate Professor
Department of Medicinal Chemistry


Location:
Virginia Biotechnology Research Park, Suite 212
Virginia Commonwealth University

Mailing Address:
Virginia Biotech I
800 E. Leigh St.
P.O. Box 980540
Richmond, VA 23219-1540

Phone: (804) 828-7291
Fax: (804) 827-3664
Email: msafo@vcu.edu

Research Interests

  • My primary research interest focuses on structure-function studies of enzymes involved in vitamin B6 metabolism, regulation and utilization. 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. Pyridoxine 5’-phosphate oxidase (PNPOx) and pyridoxal kinase (PL kinase) are the two key enzymes that supply PLP to these B6 enzymes by both the salvage pathway and the conversion of nutritional sources of vitamin B6. Deficiency of PLP has been linked to several neurological symptoms, as well as a number of psychiatric disorders. Through a combination of kinetics, site-directed mutagenesis, and structural studies, we have elucidated the catalytic mechanisms of PNPOx and PL kinase. The present goal is to gain insight into the mechanism of PLP regulation and subsequent transfer to dozens of apo-B6 enzymes.
  • Another research interest involves structure-function studies of hemoglobin and rational design of antisickling agents. Sickle cell disease (SCD) is a hereditary blood disorder, affecting over 75,000 people in the United States and millions of people worldwide. In SCD, a mutation in the ß-globin protein of hemoglobin causes deoxygenated sickle hemoglobin to form insoluble polymers inside red blood cells which deform into rigid shapes or sickle red blood cells that occlude capillaries and small blood vessels. The overall goal of this project is to use structure-based drug design, including X-ray crystallography, molecular modeling, synthesis, and biological evaluation to discover hemoglobin allosteric effectors and/or covalent modifiers that may be useful for treating SCD. A second goal is to use X-ray crystallography to unravel the allosteric switch mechanism of hemoglobin.

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Publications

  • Recent Publications
    • 1.F. N. Musayev, M. Di Salvo, M. Saveedra, R. Contestabile, M. S. Ghatge, V. Schirch, M. K. Safo. “Crystal structure of human pyridoxine 5'-phosphate oxidase mutant R229W: Structural basis for reduced PNP Oxidase catalytic activity in neonatal epileptic encephalopathy disorder” J. Biol. Chem. 2009.
    • 2.A.K. Gandhi, M.S. Ghatge, F.N. Musayev, A. Sease, S.O.Aboagye, M.L. di Salvo, V. Schirch, and M. K. Safo. “Kinetic and structural studies of the role of the active site residue Asp235 of human pyridoxal kinase”. Biochem. Biophys. Res. Commun., 2009.
    • 3.J. D. Jenkins, F.N. Musayev, R. Danso-Danquah, D.J. Abraham, M. K. Safo. “Structure of relaxed-state human hemoglobin: insight into ligand uptake, transport and release.” Acta Crystallogr D. 2009, 65: 41-48.
    • 4.I. N. Nnamani, G. S. Joshi, R. Danso-Danquah, O. Abdulmalik, T. Asakura, D. J. Abraham, and M. K. Safo. “Pyridyl Derivatives of Benzaldehyde as Potential Antisickling Agents.”Chemistry & Biodiversity, 2008 5:1762-1769.
    • 5.J. Yi, M. K. Safo, and G. B. Richter-Addo. “The Nitrite Anion Binds to Human Hemoglobin via the Uncommon O-Nitrito Mode.” Biochemistry, 2008, 47: 8247-8249.
    • 6. F. N. Musayev, M. L. di Salvo, T.-P. Ko, A. K. Gandhi, 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.
    • 7. 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.
    • 8. 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.
    • 9. 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

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Virginia Commonwealth University | School of Pharmacy
410 North 12th Street | Room 500
P.O. Box 980581
Richmond, Virginia 23298-0581
Phone: (804) 828-3000 | Toll-Free Line: (800) 330-0519 | Fax: (804) 827-0002
E-mail: pharmacy@vcu.edu
Updated: 10/18/2012

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