Walter Fast

Fast, Walter
Associate Professor of Pharmacy, Medicinal Chemistry

E-mail: waltfast@mail.utexas.edu

Website: http://www.utexas.edu/pharmacy/divisions/medicinalchem/faculty/fast.html

Main Office: BME 6.202D
Phone: (512) 232-4000

Alternate Office: BME 6.310
Phone: (512) 471-5839

Mailing Address:
The University of Texas at Austin
PHAR-MED CHEM
1 University Station C0850
Austin, TX 78712-1095

Graduate Students:

  • Linsky, Tom
  • Momb, Jessica
  • Wang, Yun

    • Post Doc Students:

  • Hong, Lin
  • Stone, Everett

    • Research Summary:
       We are interested in merging protein engineering technologies with more classical biochemical approaches in the investigation and manipulation of three enzyme systems: 1. Quorum sensing, a “language” that some bacteria use to communicate with each other. Disrupting this communication can prevent harmful infections that form biofilms. 2. Arginine modification: Arginine methylation and methyl- arginine hydrolysis are emerging as important activities in signal transduction pathways. However, little is known about the mechanism or inhibition of the enzymes that catalyze these reactions. 3. Prodrug activating enzymes: The prodrug approach seeks to limit side-effects of anticancer compounds. Protein engineering of a human protein to specifically activate prodrugs would allow for developing unique prodrug-enzyme pairs. The Fast lab uses rational & combinatorial mutagenesis, library screening & selection, small molecule synthesis, steady-state & pre-steady state kinetics, and various biophysical techniques to understand the structure & reactivity of these enzymes. These studies are then related to the larger questions of enzyme evolution and therapeutic application.
     
    Research Images:

    Dimethylarginine Dimethylaminohydrolase (DDAH) - An enzyme with a beta/alpha-propeller fold that controls nitric oxide production by hydrolyzing endogenous inhibitors of nitric oxide synthase. ( Fast Lab )

    Active-site of Dimethylarginine Dimethylaminohydrolase (DDAH) - Analysis of structure and function allow elucidation of a detailed catalytic mechanism for a guanidinohydrolase that can control nitric oxide production. ( Fast Lab )

    N-Acyl-L-Homoserinelactone Lactonase - Crystal structure of a dinculear metallohydrolase capable of disrupting bacterial quorum-sensing. ( Fast Lab )

     
    Publications:
    A click chemistry mediated in vivo activity probe for dimethylarginine dimethylaminohydrolase (2009) J Am Chem Soc, In press.
    Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxide (2009) Biochemistry 48, 8624-8635.
    Mechanism of the quorum-quenching lactonase (AiiA) from Bacillus thuringiensis. 2. Substrate modeling and active site mutations (2008) Biochemistry 47, 7715-7725.
    Promiscuous partitioning of a covalent intermediate common in the pentein superfamily (2008) Chem Biol 15, 467-475.
    Inhibition of human dimethylarginine dimethylaminohydrolase-1 by S-nitroso-L-homocysteine and hydrogen peroxide: Analysis, quantification, and implications for hyperhomocysteinemia (2007) J. Biol. Chem. 282, 34684-34692.

     
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