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Kathryn Betty Grant

Kathryn Betty Grant Kathryn Betty Grant
Professor
Graduate Biochemistry Advisor
Biochemistry, Bioinorganic Chemistry


B.A. (1980):  New York University
B.S. (1989):  SUNY at Purchase
M.A. (1990) :  Columbia University
M.Phil. (1993) :  Columbia University
Ph.D. (1994) :  Columbia University
NIH Fellowship (1994-1997) :  California Institute of Technology

Dr. Kathryn Betty Grant
Department of Chemistry
Georgia State University
P.O. Box 3965
Atlanta, Georgia 30302-3965

Department Office Phone: 404-413-5500


Phone: 404-413-5522
Lab Phone: 404-413-5523
Fax: 404-413-5505
Office: 423 Natural Science Center
Email:  kbgrant@gsu.edu

Our research explores the chemical properties of biomolecules by an interdisciplinary approach that extends into the fields of inorganic chemistry, organic chemistry, and molecular biology.

Cleavage of Peptides and Proteins by Metal Complexes

Reagents which mediate the selective cleavage of peptides and proteins have become increasingly important to the fields of chemistry and biology for protein structural analyses. However, the extreme stability of the peptide amide bond has placed severe limits on the number of reagents available and there is a great need for new cleavage strategies. Our research is focused on the development of combinatorial methods for the rapid discovery of new metal ions and complexes for peptide cleavage. A positional scanning peptide library consisting of 8,000 discrete tripeptides within 60 sub-libraries will be synthesized by solid phase methods. Modification of cleaved peptides with a highly sensitive fluorophore will permit the rapid analysis of all 60 sub-libraries and rapid screening of a broad range of metal ions and complexes. Using positional scanning, we will identify both amino acid sequences that are cleaved by metals and optimal metal reagents for peptide cleavage. We anticipate that these studies will lead to the discovery of new and unexpected chemistry that will enable us to rationally design second generation complexes with enhanced cleavage efficiencies.

 

 

In the figure above, a positional scanning peptide library composed of eight tripeptides is screened with metal ions that promote oxidative peptide cleavage. Relative fluorescence of library samples treated with (i) vanadium(V)/light and (ii) copper(II)/ ascorbate reveals that KPG is the most reactive tripeptide motif. 
(The eight tripeptides are divided into two samples within each of three sub-libraries, based on the identity of the spatially addressed amino acid "O", which alternates between Lys and Gly in Sub-library 1, Pro and Gly in Sub-library 2, and His and Gly in Sub-library 3.)

 

 


 

 

The 5-HT Transporter in Antidepressant Drug Resistance

 

Major depression is a severe and disabling mood disorder for which there is no cure. Although tricyclic antidepressant drugs and selective serotonin reuptake inhibitors (SSRI's) which bind to or block the serotonin transporter (5-HTT, SERT) have been successful in the treatment of major depression, a subset of patients (~20% - 30%) is nonresponsive to drug therapy. The effect of poor treatment outcome contributes substantially to the morbidity and mortality associated with major depression. Unfortunately, there are no truly reliable clinical predictors of response to antidepressants and there is no clear understanding of mechanisms that underlie drug resistance. We are currently employing the polymerase chain reaction (PCR) as a screen for polymorphisms in coding and noncoding regions of the 5-HTT gene of refractory patients in order to determine if the serotonin transporter plays a pathogenic role in the phenomenon of antidepressant drug resistance. By identifying amino acid residues that are critical for drug/transporter interactions, these studies may provide structural leads for the development of potentially more effective drugs.

 

The structure of serotonin (5-HT) and a schematic model of the serotonin transporter. Antidepressants bind to 5-HTT and exert their effect by competitively blocking serotonin reuptake into presynaptic serotonergic neurons.

 


 

 

 

Professional Experience

 

2010-present Professor of Chemistry, Georgia State University
2003-2010 Associate Professor of Chemistry, Georgia State University
1997-2003 Assistant Professor, Department of Chemistry, Georgia State University.
1994-1997 NIH Postdoctoral Fellow, Department of Chemistry, California Institute of Technology, with Professor Peter B. Dervan.
Research: sequence specific cleavage of duplex DNA by major groove-binding oligonucleotide and minor groove-binding polyamide conjugates.
1990-1994 Doctoral Research, Department of Chemistry, Columbia University, with Professor Koji Nakanishi; Visiting Student at the Johns Hopkins University School of Medicine, with Professor Jeremy Nathans.
Research: vanadium-tunichrome complexation and redox chemistries; cloning and expression of goldfish opsin sequences.

 

Honors, Awards, and Grants

 

2007-2011 NSF GRANT (Georgia State)
2000-2006 NSF CAREER Award (Georgia State)
1998-2000 Petroleum Research Fund, Type G Grant (Georgia State)
1994-1997 NIH Postdoctoral Fellowship (CalTech)
1994 Pegram Award for Outstanding Research (Columbia University)
1992-1993 NIH Training Fellowship (Columbia University)
1991-1992 Eli Lilly and Company Fellowship (Columbia University)
1991 J. Malcolm Miller Award for Distinguished Teaching (Columbia University)
1989 Irene Goldring Award for Outstanding Performance in Science (SUNY at Purchase)
1989 B.S. summa cum laude in Chemistry (SUNY at Purchase)
1988-1989 Technicon Research Fellowship (SUNY at Purchase)

 

 

 

Professional Affiliations

Center for Metalloenzyme Studies, University of Georgia, Adjunct Faculty Member
M.D./Ph.D. Program, Medical College of Georgia, Adjunct Faculty Member

 

Publications

  1. Grant, K.B.,* Terry, C.A., Gude, L., Fernández, M.-J., & Lorente, A.* “Synthesis and
    DNA Photocleavage by a Pyridine-Linked Bis-Acridine Chromophore in the Presence of
    Copper(II): Ionic Strength Effects.” (2011) Bioorganic & Medicinal Chemistry Letters,
    21, 1047-1051.
  2. Kassai, M., Teopipithaporn, R., & Grant, K.B.* “Hydrolysis of Phosphatidylcholine by
    Cerium(IV) Releases Significant Amounts of Choline and Inorganic Phosphate at
    Lysosomal pH.” (2011) Journal of Inorganic Biochemistry, 105, 215-223.
  3. Wilson, B., Fernández, M.-J., Lorente, A.,* & Grant, K.B.* “Synthesis and DNA
    Interactions of a Bis-Phenothiazinium Photosensitizer.” (2008) Organic & Biomolecular
    Chemistry
    , 6, 4026 – 4035. (Selected for inclusion in the Royal Society of Chemistry
    virtual journal Chemical Biology, Issue 12, 2008.)
  4. Wilson, B., Fernández, M.-J., Lorente, A.,* & Grant, K.B.* "Syntheses and DNA Photocleavage by Mono- and Bis-phenothiazinium-piperazinexylene Intercalators" (2008) Tetrahedron, 64, 3429-3436.
  5. Cepeda, S.S., & Grant, K.B.* "Hydrolysis of Insulin Chain B Using Zirconium(IV) at Neutral pH." (2008) New Journal of Chemistry, 32, 388-391.
  6. Kassai, M., & Grant, K.B.* "Tuning Zr(IV)-Assisted Peptide Hydrolysis at Near-Neutral pH." (2008) Inorganic Chemistry Communications, 11, 521-525.
  7. Fernández, M.-J., Wilson, B., Palacios, M., Rodrigo, M.M., Grant, K.B.,* & Lorente, A.* "Copper-Activated DNA Photocleavage by a Pyridine-Linked bis-Acridine Intercalator." (2007) Bioconjugate Chemistry, 18, 121-129.
  8. Grant, K.B.* & Kassai, M. "Major Advances in the Hydrolysis of Peptides and Proteins by Metal Ions and Complexes." (2006) Current Organic Chemistry (invited review), 10, 1035-1049.
  9. Wilson, B., Gude, L., Fernández, M.-J., Lorente, A.,* & Grant, K.B.* "Tunable DNA Photocleavage by an Imidazole-Acridine Conjugate." (2005) Inorganic Chemistry, 44, 6159-6173.
  10. Gude, L., Fernández, M.-J., Grant, K.B.,* & Lorente, A.* "Syntheses and Copper(II)-Dependent DNA Photocleavage by Acridine and Anthracene 1,10-Phenanthroline Conjugate Systems." (2005) Organic and Biomolecular Chemistry, 3, 1856-1862.
  11. Kassai, M., Ravi, R.G., Shealy, S.J., & Grant, K.B.* "Unprecedented Acceleration of Zirconium(IV)-Assisted Peptide Hydrolysis at Neutral pH." (2004) Inorganic Chemistry 43, 6130-6132.
  12. De Silva, V., Woznichak, M.M., Burns, K.L., Grant, K.B., & May, S.W.* "Selenium Redox Cycling in the Protective Effects of Organoselenides against Oxidant-Induced DNA Damage." (2004) Journal of the American Chemical Society 126, 2409-2413.
  13. Espinosa, J.-F., Fernández, M.-J., Grant, K.B.,* Gude, L., Rodrigo, M.-M., & Lorente, A.* "Synthesis, DNA Intercalation and Europium(III)-triggered DNA Photocleavage by a Bis-Proflavine Succinamide Conjugate." (2004) Tetrahedron Letters 45, 4017-4020.
  14. Wilson, B., Lubin, I.M., & Grant, K.B.* "Allele-Specific Polymerase Chain Reaction-Based Genotyping of a Normal Variation in Human Color Vision." (2003) Journal of Chemical Education 80, 1289-1291.
  15. Bantan-Polak, T., & Grant, K.B.* "Selective Hydrolysis of Peptides Promoted by Metal Ions: a Positional Scanning Approach." (2002) Chemical Communications 14, 1444-1445.
  16. Gude, L., Fernández, M.-J., Grant, K.B.,* & Lorente, A.* "DNA Interaction and Photonicking Properties of DNA-Targeted Acridine (2,2'-Bipyridine)platinum(II) Complexes." (2002) Bioorganic & Medicinal Chemistry Letters 12, 3135-3139.
  17. Gude, L., Fernández, M.-J., Grant, K.B.,* & Lorente, A.* "Anthracene and Naphthalene (2,2'-Bipyridine)platinum(II) Conjugates: Synthesis and DNA Photocleavage." (2002) Tetrahedron Letters 43, 4723-4727.
  18. Yang, X., & Grant, K.B.* "Chemical Sequencing of Restriction Fragments 3'-End-Labeled with [35S]dATPαS." (2002) Journal of Biochemical and Biophysical Methods 50, 123-128.
  19. Bantan-Polak, T., Kassai, M., & Grant, K.B.* "Comparison of Fluorescamine and Naphthalene-2,3-dicarboxaldehyde Fluorogenic Reagents for Microplate-based Detection of Amino Acids." (2001) Analytical Biochemistry 297, 128-136.
  20. Fernández, M.-J., Grant, K.B.,* Herraiz, F., Yang, X., & Lorente, A.* "DNA Photocleavage by Dicationic Bisintercalants." (2001) Tetrahedron Letters 42, 5701-5704.
  21. Grant, K.B.,* & Pattabhi, S. "Use of a Fluorescence Microplate Reader for the Detection and Characterization of Metal-Assisted Peptide Hydrolysis." (2001) Analytical Biochemistry 289, 196-201.
  22. Grant, K.B., & Dervan, P.B.* "Sequence-Specific Alkylation and Cleavage of DNA Mediated by Purine Motif Triple Helix Formation." (1996) Biochemistry 35, 12313-12319.
  23. Ryan, D.E.,* Grant, K.B., Nakanishi, K., Frank, P., & Hodgson, K.O. "Reactions between Vanadium Ions and Biogenic Reductants of Tunicates: Spectroscopic Probing for Complexation and Redox Products in Vitro." (1996) Biochemistry 35, 8651-8661.
  24. Ryan, D.E.,* Grant, K.B., & Nakanishi, K. "Reactions between Tunichrome Mm-1, a Tunicate Blood Pigment, and Vanadium Ions in Acidic and Neutral Media." (1996) Biochemistry 35, 8640-8650.
  25. Johnson, R.L., Grant, K.B., Zankel, T.C., Boehm, M.F., Merbs, S.L., Nathans, J.,* & Nakanishi, K.* "Cloning and Expression of Goldfish Opsin Sequences." (1993) Biochemistry 32, 208-214.