The structure of chitinases and prospects for structure-based drug design

Abstract

Many fungi, including pathogenic strains, require proper chitin metabolism to assure normal cell wall replication. Chitinase hydrolyzes chitin; inhibition of endogenous chitinases or application of extracellular chitinases can disrupt fungal division. It is possible that chitinase inhibitors could be used as antifungal agents. We have solved the X-ray structure of a class I1 chitinase from barley and proposed a mechanism of action. The enzyme has a structural core similar to lysozyme and probably acts in a similar catalytic manner. The enzyme structure can, in principle, be used to identify small molecules that will bind avidly to the active site and act as inhibitors. Those inhibitors that embody transition state geometry are likely to be particularly effective.Key words: chitinase, mechanism of action, drug design.RCsumk : Plusieurs champignons, incluant des souches pathogtnes, ont besoin d'un mttabolisme de la chitine approprit pour assurer une reproduction normale de la paroi cellulaire. La chitinase hydrolyse la chitine; l'inhibition des chitinases endogknes ou l'application de chitinases extracellulaires peut bloquer la division fongique. I1 est possible que des inhibiteurs de la chitinase puissent Ctre utilists comme substances antifongiques. Les auteurs ont dtchiffrt la structure, aux rayons X, d'une chitinase de classe I1 chez I'orge, et proposent un mtcanisme d'action. L'enzyme posstde une structure centrale semblable i celle du lyzozyme et agit probablement d'une fa~on catalytique comparable. La structure de l'enzyme peut, en principe, Ctre utiliste pour identifier de petites moltcules qui s'attachent fortement au site actif pour agir comme inhibiteurs. Ces inhibiteurs, qui montrent un ttat gtomttrique de transition, ont des chances d'Ctre particulikrement efficaces.

Substrate assistance in the mechanism of family 18 chitinases: theoretical studies of potential intermediates and inhibitors 1 1Edited by B. Honig

“…Allosamidin, 10 ( Figure 2B), and related natural products are pseudotrisaccharide chitinase inhibitors (Sakuda et al, 1986) isolated from the mycelium of Streptomyces sp. Although detailed inhibition and kinetics studies have not been reported, allosamidin is believed to act as a transition state analog (Van Vranken, 1992;Terwisscha van Scheltinga et al, 1995;Robertus et al, 1995). Moreover, allosamidin shows no inhibitory activity against lysozyme (Koga et al, 1987), which is consistent with the suggestion that the two enzymes have different mechanisms (and therefore unique transition states) for hydrolysis.…”

“…Moreover, allosamidin shows no inhibitory activity against lysozyme (Koga et al, 1987), which is consistent with the suggestion that the two enzymes have different mechanisms (and therefore unique transition states) for hydrolysis. It was originally proposed that the planar protonated oxazoline ring acts as an oxocarbenium ion transition state analog (Robertus et al, 1995). However, an X-ray structure of hevamine with allosamidin bound in the active site (Terwisscha van Scheltinga et al, 1995) led to the suggestion that allosamizoline (11), the aglycone portion of allosamidin, instead resembles an oxazoline ion reaction intermediate.…”

Substrate Distortion to a Boat Conformation at Subsite −1 Is Critical in the Mechanism of Family 18 Chitinases

“…4.5 Design of a New Class of Inhibitor. The inhibition of chitinases has been identified as a possible objective in the development of novel antifungal therapeutics . When considering the rational design of a family 18 chitinase inhibitor, it is useful to identify unique points along the hydrolysis pathway which may be targeted.…”

“…Chitinases have been found in a wide range of organisms including bacteria, , plants, fungi, insects, and crustaceans . For those organisms that utilize the structural properties of chitin, chitinases are critical for the normal life cycle functions of molting and cell division. , In addition, plants produce chitinases as a defense against fungal pathogens. , Because chitin is not found in vertebrates, it has been suggested that inhibition of chitinases may be used for the treatment of fungal infections and human parasitosis …”

Atomic-Level Simulation and Modeling of Biomacromolecules

“…For organisms that utilize the structural properties of chitin, chitinases are critical for the normal life-cycle functions of molting and cell division (Fukamizo andKramer 1985, Kuranda andRobbins 1991). Because chitin is not found in vertebrates, inhibition of chitinases is a promising strategy for treatment of fungal infections and human parasitosis (Robertus 1995).…”