Beta-N-acetylhexosaminidase: a target for the design of antifungal agents.
This review provides biochemical, analytical, and biological background information relating to beta-N-acetylhexosaminidase (HexNAc'ase; EC 3.2.1.52) as an emerging target for the design of low-molecular-weight antifungals. The article includes the following: (1) a biochemical description of HexNAc'ase (reaction catalyzed, nomenclature, and mechanism of action) that sets it apart from other, similar enzymes; (2) an overview and a critical evaluation of methods to assay the enzyme, including in crude extracts (photo- and fluorometric procedures with model substrates; HPLC/pulsed amperometric detection of N-acetylglucosamine and chito-oligomers; end-point vs. rate measurements); (3) a summary of some general characteristics of HexNAc'ases from fungi and organisms of other types (Km values, substrate preference, and glycoconjugation); (4) an hypothesis of a specific target function of wall-associated HexNAc'ase (a component of the assembly of surface-located enzymes effecting a continuous turnover and remodelling of the wall fabric through its combined hydrolytic and transglycosylating activities, and a mediator enzyme acting in concert with chitinase and chitin synthase to provide for the controlled lysis and synthesis of chitin during growth); (5) a tabulation of the structural formulae of reaction-based HexNAc'ase inhibitors with Ki values < or = 100 microM (some of them representing transition state mimics that could serve as leads for the development of new antifungals); and (6) an outline of approaches towards the establishment of a three-dimensional model of HexNAc'ase suitable for a truly rational design of antimycotics as well as agricultural fungicides.
Horsch
M
M
Plant Biology Department, University of Zürich, Switzerland.
Mayer
C
C
Sennhauser
U
U
Rast
D M
DM
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000627:therapeutic use; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D009181:Mycoses / Q000188:drug therapy / Q000201:enzymology; D001619:beta-N-Acetylhexosaminidases / Q000032:analysis / Q000187:drug effects / Q000378:metabolism
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D001619:beta-N-Acetylhexosaminidases