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Kathryn Betty Grant Associate Professor, Biochemistry Ph.D., Columbia University (1994) Dr. Kathryn Grant Department of Chemistry Georgia State University P.O. Box 4098 Atlanta, Georgia 30302-4098
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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.
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In the figure to the right, 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.) |
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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.
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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
| 2003-present | 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
| 2007-2010 | 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
- 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.
- 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.
- Kassai, M., & Grant, K.B.*
"Tuning Zr(IV)-Assisted Peptide Hydrolysis at Near-Neutral pH." (2008) Inorganic Chemistry Communications, 11, 521-525.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Bantan-Polak, T., & Grant,
K.B.* "Selective Hydrolysis of Peptides
Promoted by Metal Ions: a Positional Scanning Approach."
(2002) Chemical Communications 14,
1444-1445.
- 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.
- 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.
- 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.
- 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.
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Fernández, M.-J., Grant,
K.B.,* Herraiz, F., Yang, X., & Lorente, A.*
"DNA Photocleavage by Dicationic Bisintercalants." (2001)
Tetrahedron Letters 42, 5701-5704.
- 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.
- 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.
- 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.
- 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.
- 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.
Postdoctoral Position Immediately Available
Work will focus on the application of combinatorial
chemistry toward the discovery of new metal complexes for
protein structural studies. Experience/training in coordination
chemistry, solid phase synthesis, and/or combinatorial
chemistry is desirable. If interested, please e-mail CV with a
publication list, summary of research experience, and
professional references to Prof. Kathy Grant at kbgrant@gsu.edu