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Zachary B. Mackey, Ph.D.

Virginia Polytechnic Institute and State University (Virginia Tech.)


Department of Biochemistry 124 Engel Hall
Blacksburg, VA 24061
Phone:
(540) 231-4979
Fax: (540) 231-9070
email: mackeyzb@vt.edu
RESEARCH GOAL:
The focus of my laboratory is characterizing two proteins that are involved in DNA replication in
the protozoan parasite Trypanosoma brucei. Proliferating cell nuclear antigen is an essential
DNA replication factor that acts as a sliding clamp for eukaryotic DNA polymerases. It also
coordinates several other cellular processes including chromatin reorganization, DNA repair,
and cell cycle regulation through the plethora of protein interaction that it makes. Over 200
proteins interact with human PCNA (HsPCNA) through a conserved motif known as the PCNA
interacting peptide motif (PIP-box), many of which are essential in eukaryotic cells. Our
objective for TbPCNA is to map out the interactions it makes to regulate DNA replication.
TbERK8 is an essential mitogen-activated protein kinase that phosphorylate TbPCNA in vitro
and in vivo. Our objective for this project is to understand how phosphorylation by TbERK8
regulates TbPCNA and thereby DNA replication in T. brucei.
KEYWORDS/AREAS OF INTEREST
DNA replication, Trypanosoma brucei, proliferating cell nuclear antigen, mitogen-activated
protein kinase, flow cytometry, DNA repair, genomics, graduate education, parasitology, protein
biochemistry.
EDUCATION/WORK EXPERIENCE:
1984-1989
University of Nebraska, Lincoln

B.S.

Biology

1990-1992

Research Associate Virus Reference Laboratory, San Antonio, Texas

1992-1994

Research Assistant University of Texas Health Science Center-San Antonio

1994-2000

University of Texas Health Science Center-San Antonio

Ph.D. Mol. Medicine

PRINCIPAL POSITIONS HELD


2000-2002
University of California-San Francisco

Postdoctoral Fellow, Pharm. Chem.

2002-2003

University of California-San Francisco

Postdoctoral Fellow, Pathology

2003-2008

University of California-San Francisco

Associate Specialist, Pathology

2009-2011

University of California-San Francisco

Assistant Researcher, Pathology

2011-

Virginia Tech. University

Assistant Professor, Biochemistry

HONORS AND AWARDS


1998 Graduate Student Research Award UTHSC-SA

2002

University of California, San Francisco Science & Health Education Partnership Mentor
Award

2003

University of California, San Francisco Science & Health Education Partnership Mentor
Award

2005

Minority Trainee Research Forum Talk and Poster Presentation Award

2008

US Congressional Certificate of Special Recognition for Outstanding Community


Service

2010

UCSF Champion of Diversity

2012

Keynote Speaker UNCF-Merck Fellows Day 2012

2012

Featured in CALS Innovations

PROFESSIONAL ACTIVITIES
Service to Professional Publications
2007 Federation of European Biochemical Societies (FEBS) (ad hoc reviewer)
2009

PLoS ONE (ad hoc reviewer)

2011

PloS ONE (ad hoc reviewer)

2012

PloS NTD (ad hoc reviewer)

2013

PloS NTD (ad hoc reviewer)

2013 - Chemical Biology & Drug Design (CBDD) (ad hoc reviewer)
SERVICE
2002 Summer San Francisco Science & Health Education Partnership (Mentor)
2003

Summer San Francisco Science & Health Education Partnership (Mentor)

2004

Student Poster Reviewer for Career and Research Days sponsored by Graduate
Students Association (UCSF)

2006

Student Poster Reviewer for Career and Research Days sponsored by Graduate
Students Association (UCSF)

2007

Compact for Faculty Diversity Institute on Teaching


and Mentoring UCSF Representative

2008 Black Caucus Mentor


2008-09 UCSF Kids to Work Day Mentor

2010

UCSF Champion of Diversity

2010

UCSF Kids to Work Day Mentor

2011

UCSF Kids to Work Day Mentor

2012

VT Biochemistry non-voting member P&T committee

2013-14 VT Biochemistry Awards Committee


2013- VT Biochemistry Graduate Committee
2013- VT-PREP-Search Committee
2013- VT-IMSD-Search Committee
2014

OVPR Future Faculty Workshop

2015

VTPREP-Search Committee

2015- VT Biochemistry Faculty Senator


TEACHING AND MENTORING
2002 University of California, San Francisco School of Dentistry: Invited
Lecturer for Dental-Scientist Continuing Education Short Course:
Mammalian Systems for Expressing Recombinant Proteins
2002

Summer Mentor for University of California Science & Education Partnership 2003
Summer Mentor for University of California Science & Education Partnership

2004

Student Poster Reviewer for Career and Research Days sponsored by Graduate
Students Association (UCSF)

2006

Student Poster Reviewer for Career and Research Days sponsored by Graduate
Students Association (UCSF)

2012- Biochemistry 5124 (Virginia Tech)


COURSES TAUGHT
Summer 2008-09
Medical Parasitology Co-Instructor UC Berkeley
Spring 2011

Undergraduate Research, BCHM 4994

Fall 2012

Undergraduate Research, BCHM 4994

Fall 2012

Biochemistry for Life Sciences BCHM 5124

Fall 2013

Introduction to Biochemistry BCHM 1014

Fall 2014

Biochemistry for Life Sciences BCHM 5124

Fall 2015

Introduction to Biochemistry BCHM 1014

Fall 2015

Undergraduate Research, BCHM 4994

INVITED PRESENTATIONS
2004 Gordon Research Conference on the Biology of Host-Parasite Interactions
Salve Regina College Newport R.I. June 27-July 2, (invited talk, poster)
Exploring TbCatB as a potential drug target against Trypanosoma brucei:
2005

Merck Research Laboratories Guest Lecturer:


Exploring TbCatB as a potential drug target against Trypanosoma brucei:

2005

San Francisco General Hospital Black Womens Forum


Waking up to African Sleeping Sickness

2005

National Institutes of Health (NIH) Minority Trainee Research Forum, Bethesda, MD


Exploring TbCatB as a potential drug target against Trypanosoma brucei:

2008

UC Irvine Global Health Workshop


Development of High throughput assays to screen for inhibitors of TbCatB.

2008

SROP/PREP Invited Speaker Duke University Durham NC.


Development of High throughput assays to screen for inhibitors of TbCatB.

2009

TriTryp DB Workshop/Symposium , Philadelphia, PA.


Development of High throughput assays to screen for inhibitors of TbCatB.

2012

Keynote Speaker UNCF-Merck Fellows Day 2012


Pathways to Success in Basic Science Research

2012

VT Entomology seminar series, Blacksburg, Virginia


Examining the role of TbERK8 in DNA replication in Trypanosoma brucei

2013

Entomology Society of America Annual Meeting, James Madison University


Examining the role of TbPCNA in DNA replication in Trypanosoma brucei

2013

Case Western Reserve University, Cleveland, Ohio


Examining the role of TbERK8 in DNA replication in Trypanosoma brucei

2013

ASBMB Minority Affairs Committee, Alexandria Virginia


Examining the role of TbERK8 in DNA replication in Trypanosoma brucei

2014

ASBMB Minority Affairs Committee, Alexandria Virginia

2014

Association of Underrepresented Minority Fellows


Spring Symposium, Cleveland, Ohio

2015

Penn State Hershey Medical Center, Hershey PA


Targeting strategies for TbPCNA , the proliferating cell nuclear antigen homolog in
Trypanosoma brucei

2015

Kids Tech University (KTU) Southwest Virginia Center, Abington, VA


Are there better ways to cure those weird parasitic diseases?

2015

Kids Tech University (KTU) Virginia State University, Petersburg, VA


Are there better ways to cure those weird parasitic diseases?

GRANTS AND AWARDS:


1994-1996
(DAMD17-94-J-4147) Training Program in Molecular Basis
of Breast Cancer from the Department of the Army
1996-1997

Howard Hughes Medical Institute Enrichment Program for a


Minority Trainee Supplement.

1997-1999

UNCF-Merck Graduate Science Research Dissertation


Fellowship Award.

2000-2002

UNCF-Merck Postdoctoral Fellowship Award

2003-2006

NIAID Minority Postdoctoral Fellowship

2006-2008

NIAID K22 Career Development Award (KAI071179A)

2007-2011

NIAID 5U01AI075641 Co-Investigator

RESEARCH ARTICLES:
Wang YC. Burkhart WA. Mackey ZB. Moyer MB. Ramos W. Husain I. Chen J.
Besterman JM. Tomkinson AE. Mammalian DNA ligase II is highly homologous with vaccinia
DNA ligase. Identification of the DNA ligase II active site for enzyme-adenylate formation. J Biol
Chem. 269(50):31923-8, 1994 Dec 16.
Husain I. Tomkinson AE. Burkhart WA. Moyer MB. Ramos W. Mackey ZB.
Besterman JM. Chen J. Purification and characterization of DNA ligase III from bovine testes.
Homology with DNA ligase II and vaccinia DNA ligase. J Biol Chem. 270(16):9683-90, 1995
Apr 21.
Kamel D. Mackey ZB. Sjoblom T. Walter CA. McCarrey JR. Uitto L.
Palosaari H. Lahdetie J. Tomkinson AE. Syvaoja JE. Role of deoxyribonucleic acid
polymerase epsilon in spermatogenesis in mice. Biol Reprod. 57(6):1367-74, 1997 Dec.
Mackey ZB. Ramos W. Levin DS. Walter CA. McCarrey JR. Tomkinson AE.
An alternative splicing event, which occurs in mouse pachytene spermatocytes, generates a
form of DNA ligase III with distinct biochemical properties that may function in meiotic
recombination. Mol Cell Biol. 17(2):989-98, 1997 Feb. Tomkinson AE. Mackey ZB. Structure
and function of mammalian DNA ligases. Mutat Res. 407(1):1-9, 1998 Feb.
Chen J. Tomkinson AE. Ramos W. Mackey ZB. Danehower S. Walter CA.
Schultz RA. Besterman JM. Husain I. Mammalian DNA ligase III: molecular cloning,
chromosomal localization, and expression in spermatocytes undergoing meiotic recombination.
Mol Cell Biol. 15(10):5412-22, 1995 Oct.

Mackey ZB, Neidregang C, de Murcia JM, Leppard J, Au K, Chen J, de Murcia G,


Tomkinson AE, DNA Ligase III is recruited to DNA strand breaks by a zinc finger motif
homologous to that of poly (ADP-ribose) polymerase: Identification of two functionally distinct
DNA binding regions within DNA ligase III. J Biol Chem. 274(31):21679-21687 , 1999 July 31.
Alan E. Tomkinson, Ling Chen, Zhiwan Dong, John B. Leppard, David S. Levine, Zachary B.
Mackey and Teresa A. Motycka. Completion of Base Excision Repair by Mammalian DNA
Ligases. Progress in Nucleic Acid Research and Molecular Biology, Vol. 68: 157-164 (2000)
Li Z, Zou CB, Yao Y, Hoyt MA, McDonough S, Mackey ZB, Coffino P, Wang CC.
An easily dissociated 26 S proteasome catalyzes an essential ubiquitin-mediated protein
degradation pathway in Trypanosoma brucei. J Biol Chem. 2002 May 3;277(18):15486-98.
Leppard JB, Dong Z, Mackey ZB, Tomkinson, AE. Physical and functional interaction between
DNA Ligase III and Poly(ADP-ribose) Polymerase-1 in DNA single-strand break repair. Mol
Cell Biol. 2003 Aug;23(16):5919-27.
Greenbaum, D. C., Mackey, ZB., Hansell, E., Doyle, P., Gut, J., Caffrey, C. R., Lehrman, J.,
Rosenthal, P. J., McKerrow, J. H., and Chibale, K. (2004) J Med Chem 47, 3212-3219
Zachary B. Mackey, Theresa C. OBrien, Doron C. Greenbaum, Rebecca Blank and
James H. McKerrow A Cathepsin B-Like Protease is Required for Host Protein Degradation in
Trypanosoma brucei J Biol Chem 279 Nov.12 2004(46): 48426-33.
Fujii, N., J. P. Mallari, Mackey ZB, et al.. "Discovery of potent thiosemicarbazone inhibitors of
rhodesain and cruzain. Bioorg Med Chem Lett Jan. 3 2005 15(1): 121-3.
Rapp M, Haubrich TA, Perrault J, Mackey ZB, McKerrow JH, Chiang PK, Wnuk SF.
Antitrypanosomal Activity of 5'-Deoxy-5'-(iodomethylene)adenosine and Related 6-NCyclopropyladenosine Analogues. J Med Chem. 2006 Mar 23;49(6):2096-2102.
Garcia JJ, Kramer MJ, Mackey ZB, O'Donnell RJ, Horvai AE.
Utility of CD117 immunoreactivity in differentiating metastatic melanoma from clear cell
sarcoma. Arch Pathol Lab Med. 2006 Mar;130(3):343-8
Mackey ZB, Baca AM, Mallari JP, Apsel B, Shelat A, Hansell EJ, Chiang PK, Wolff B, Guy KR,
Williams J, McKerrow JH. Discovery of Trypanocidal Compounds by Whole Cell HTS of
Trypanosoma brucei. Chem Biol Drug Des. 2006 May;67(5):355-63.
Theresa C. OBrien, Zachary B. Mackey, Richard D. Fetter, Conor R. Caffrey, Youngchool
Choe, Charles S. Craik and James H. McKerrow. A parsite cysteine protease is key to host
protein degradation and iron acquisition. JH.J Biol Chem. 2008 Oct 24;283(43):28934-43.
Epub 2008 Aug 13.
Patricia S. Doyle, Mohammed Sajid, Thresa OBrien, Kelly Dubois, Jun C. Engel, Zachary B.
Mackey, and Sharon Reed. Drugs Targeting Parasite Lysosomes. Current Pharm. Design,
2008, 14:(9), 889-900
Maha-Hamaden Abdulla, Theresa Obrien, Zachary B. Mackey, Mohamed Sajid, Dennis J.
Grab, and James H. McKerrow. In vivo RNA interference of Trypanosoma brucei cathepsin B
and L clarifies their contribution to disease progression PLoS Negl Trop Dis. 2008 Sep
24;2(9):e298.

Liu, Chao-lin; Shen, Chia-Rui; Hsu, Fong-Fu; Chen, Jeen-Kuan; Wu, Pei-Tzu; Guo, Shang-Hsin;
Lee, Wen-Chien; Yu, Feng-Wei; Mackey, Zachary B.; Turk, John; Gross, Michael L. Isolation
and identification of two novel SDS-resistant secreted chitinases from Aeromonas schubertii
Submitted
Chen C-K, Doyle PS, Yermalitskaya LV, Mackey ZB, Ang KKH, et al. (2009) Trypanosoma cruzi
CYP51 Inhibitor Derived from a Mycobacterium tuberculosis Screen Hit. PLoS Negl Trop Dis
3(2): e372. 2009
Isolation and identification of two novel SDS-resistant secreted chitinases from Aeromonas
schubertii. Liu CL, Shen CR, Hsu FF, Chen JK, Wu PT, Guo SH, Lee WC, Yu FW, Mackey ZB,
Turk J, Gross ML. Biotechnol Prog. 2009 Jan-Feb;25(1):124-31.
Oluwafemi AJ, Okanla EO, Camps P, Muoz-Torrerob D, Mackey ZB, Chiang PK, Seville S,
Wright CW. Evaluation of cryptolepine and huperzine derivatives as lead compounds towards
new agents for the treatment of human African trypanosomiasis. Nat Prod Commun. 2009
Feb;4(2):193-8.
Kerr ID, Wu P, Marion-Tsukamaki R, Mackey ZB, Brinen LS. Crystal Structures of TbCatB and
rhodesain, potential chemotherapeutic targets and major cysteine proteases of Trypanosoma
brucei. PLoS Negl Trop Dis. 2010 Jun 8;4(6):e701.
Ang KK, Ratnam J, Gut J, Legac J, Hansell E, Mackey ZB, Skrzypczynska KM, Debnath A,
Engel JC, Rosenthal PJ, McKerrow JH, Arkin MR, Renslo AR. Mining a cathepsin inhibitor
library for new antiparasitic drug leads. PLoS Negl Trop Dis. 2011 May 3;5(5):e1023.
Mackey ZB, Koupparis K, Nishino M, McKerrow JH. High Throughput Analysis of an RNAi
Library Identifies Novel Kinase targets in Trypanosoma brucei.
Chem Biol Drug Des. Volume 78, Issue 3, pages 454463, September 2011
Lavrado J, Mackey ZB, Hansell E, McKerrow JH, Paulo A, Moreira R. Antitrypanosomal and
cysteine protease inhibitory activities of alkyldiamine cryptolepine derivatives. Bioorg Med Chem
Lett. 2012 Oct 1;22(19):6256-60. doi:10.1016/ j.bmcl.2012.07.104.
Sanchez LM, Knudsen GM, Helbig C, De Muylder G, Mascuch SM, Mackey ZB, Gerwick L,
Clayton C, McKerrow JH, Linington RG. Examination of the Mode of Action of the Almiramide
Family of Natural Products against the Kinetoplastid Parasite Trypanosoma brucei. J Nat Prod.
2013 Feb 27.
Frevert U, Movila, A, Nikolskaia O, Raper J, Mackey ZB, Abdulla M, McKerrow J and Grab DJ.
Early Invasion of Brain Parenchyma by African Trypanosomes PLoS One. 2012;7(8):e43913.
doi: 10.1371/journal.pone.0043913.
Ndao M, Nath-Chowdhury M, Sajid M, Marcus V, Mashiyama ST, Sakanari J, Chow E, Mackey
Z, Land KM, Jacobson MP, Kalyanaraman C, McKerrow JH, Arrowood MJ, Caffrey CR.
Antimicrob Agents Chemother. A Cysteine Protease Inhibitor Rescues Mice from a Lethal
Cryptosporidium parvum Infection. 2013 Dec;57(12):6063-73. doi: 10.1128/AAC.00734-13.
Epub 2013 Sep 23.
Deviating the level of proliferating cell nuclear antigen in Trypanosoma brucei elicits distinct

mechanisms for inhibiting proliferation and cell cycle progression. Valenciano AL, Ramsey AC,
Mackey ZB. Cell Cycle. 2015;14(4):674-88. doi: 10.4161/15384101.2014.987611.
Submitted
TbERK8 phosphorylates TbPCNA at the unique insertion loop in its second domain
Ana L. Valenciano1, Nicole Olson2, Giselle M. Knudsen2, Charles S. Craik2, and Zachary B.
Mackey1
In Preparation
T2AA selectively inhibits HsPCNA but not TbPCNA. Ana L. Valenciano, Hyun Kang, Naoaki
Fujii, and Zachary B. Mackey*
AZ 960, a selective inhibitor of TbERK8 that has bioactivity against Trypanosoma brucei. Ana L.
Valenciano, Aaron C. Ramseys, William P. Janzen and Zachary B. Mackey