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Zachary Mackey

Professor

Education

Ph.D., Molecular Medicine, University of Texas Health Science Center, San Antonio, 2000

B.S., Biology, University of Nebraska, Lincoln, 1990

Experience

  • 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- Current: Virginia Tech. Assistant Professor, Biochemistry, Blacksburg

Courses Taught

BCHM5124: Biochemistry for Life Science Graduates

BCHM 1014: Introduction to Biochemstry

Other Teaching and Advising

  • I am currently advising two graduate students
  • I also enjoy mentoring undergraduate students

Program Focus

DNA replication and repair represent two evolutionarily conserved DNA metabolism pathways that function to maintain genomic integrity in all kingdoms. These pathways in kinetoplastid parasites are fascinating because they contain rapidly evolving genes with atypical biological and biochemical properties that contrast to properties of their mammalian host orthologs. Our long-term goal is to understand the molecular anatomy of essential genes that guard genomic integrity in BSF Trypanosoma brucei. Understanding T. brucei DNA replication and repair pathways down to the mechanistic detail has valuable implications for mutagenesis and carcinogenesis. Essential DNA replication or repair pathway members with atypical properties represent targets that can be harvested as “low hanging fruit” for parasite-specific therapies.

Current Projects

Understanding how TbERK8 regulates DNA replication in Bloodstream Form (BSF) T. brucei.

We had identified TbERK8, an essential extracellular-signal regulated kinase (ERK) family member. ERKs are serine/threonine-specific protein kinases that direct cellular responses to a diverse array of external signals. They regulate proliferation, gene expression, differentiation, mitosis, cell survival, apoptosis and are implicated in DNA damage response. We demonstrate that silencing TbERK8 in BSF T. brucei causes replication arrest, severe nuclear fragmentation and stage-specific lethality in the parasite. No lethal consequence was reported when others had silenced the ERK8 homolog in human cells. ERK8 deficient human cell show decreased levels of replication and increased levels of DNA strand breaks, indicating that the influence of ERK8 homologs on DNA replication and repair is conserved across divergent eukaryotic species. Our results demonstrate that the lethal effect of silencing TbERK8 is specific to BSF T. brucei.

Examining the DNA Ligase I mechanism in Trypanosoma brucei.

DNA ligase I represents the only replicative ligase family member T. brucei. My goal is to identify and characterize the DNA metabolism pathway(s) in BSF T. brucei that involves DNA ligase I.

Examination of the mode of action of the almiramide family of natural products against the kinetoplastid parasite Trypanosoma brucei. Sanchez LM, Knudsen GM, Helbig C, De Muylder G, Mascuch SM, Mackey ZB, Gerwick L, Clayton C, McKerrow JH, Linington RG. J Nat Prod. 2013 Apr 26;76(4):630-41. doi: 10.1021/np300834q. Epub 2013 Feb 27.

Early invasion of brain parenchyma by African trypanosomes. Frevert U, Movila A, Nikolskaia OV, Raper J, Mackey ZB, Abdulla M, McKerrow J, Grab DJ. PLoS One. 2012;7(8):e43913. doi: 10.1371/journal.pone.0043913. Epub 2012 Aug 31. Free PMC Article

Antitrypanosomal and cysteine protease inhibitory activities of alkyldiamine cryptolepine derivatives. Lavrado J, Mackey Z, Hansell E, McKerrow JH, Paulo A, Moreira R. Bioorg Med Chem Lett. 2012 Oct 1;22(19):6256-60. doi: 10.1016/j.bmcl.2012.07.104. Epub 2012 Aug 15.

High-throughput analysis of an RNAi library identifies novel kinase targets in Trypanosoma brucei. Mackey ZB, Koupparis K, Nishino M, McKerrow JH. Chem Biol Drug Des. 2011 Sep;78(3):454-63. doi: 10.1111/j.1747-0285.2011.01156.x. Epub 2011 Jul 14. Free PMC Article

Mining a cathepsin inhibitor library for new antiparasitic drug leads. 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. PLoS Negl Trop Dis. 2011 May 3;5(5):e1023. doi: 10.1371/journal.pntd.0001023. Free PMC Article

Crystal Structures of TbCatB and rhodesain, potential chemotherapeutic targets and major cysteine proteases of Trypanosoma brucei. Kerr ID, Wu P, Marion-Tsukamaki R, Mackey ZB, Brinen LS. PLoS Negl Trop Dis. 2010 Jun 8;4(6):e701. doi: 10.1371/journal.pntd.0000701.

Evaluation of cryptolepine and huperzine derivatives as lead compounds towards new agents for the treatment of human African trypanosomiasis. Oluwafemi AJ, Okanla EO, Camps P, Muñoz-Torrerob D, Mackey ZB, Chiang PK, Seville S, Wright CW. Nat Prod Commun. 2009 Feb;4(2):193-8.

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. doi: 10.1002/btpr.100. Free PMC Article

Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit. Chen CK, Doyle PS, Yermalitskaya LV, Mackey ZB, Ang KK, McKerrow JH, Podust LM. PLoS Negl Trop Dis. 2009;3(2):e372. doi: 10.1371/journal.pntd.0000372. Epub 2009 Feb 3.

RNA interference of Trypanosoma brucei cathepsin B and L affects disease progression in a mouse model. Abdulla MH, O'Brien T, Mackey ZB, Sajid M, Grab DJ, McKerrow JH. PLoS Negl Trop Dis. 2008 Sep 24;2(9):e298. doi: 10.1371/journal.pntd.0000298. Free PMC Article

A parasite cysteine protease is key to host protein degradation and iron acquisition. O'Brien TC, Mackey ZB, Fetter RD, Choe Y, O'Donoghue AJ, Zhou M, Craik CS, Caffrey CR, McKerrow JH. J Biol Chem. 2008 Oct 24;283(43):28934-43. doi: 10.1074/jbc.M805824200. Epub 2008 Aug 13. Free PMC Article

Drugs targeting parasite lysosomes. Doyle PS, Sajid M, O'Brien T, Dubois K, Engel JC, Mackey ZB, Reed S. Curr Pharm Des. 2008;14(9):889-900. Review.

1998: Graduate Student Research Award UTHSC-SA

2002: University of California, San Francisco Science & Health Education Partnership Mentor Award

2005: Minority Trainee Research Forum Talk and Poster Presentation Award