Aspergillus fumigatus Chitinase
Adama Berndt '17
Aspergillus fumigatus is a highly common airborne
species of mold and the primary cause of the disease aspergillosis -
characterized by allergenic symptoms. Traditionally A. fumigatus
is considered to be an opportunistic pathogen, predominantly affecting
immunocompromised individuals, and as the numbers of immunosuppressed
individuals arise, unfortunately so too does the prevalence of
aspergillosis(Latge, 2009). When thinking of targets for anti-fungal
activity, the cell wall of microbial organisms and related processes
has proved fruitful, as in the case of Beta-lactam antibiotics(Kong
However, microbial fungi have their own unique cell wall
target in Beta(1,4)-linked N-acetylglucosamine (GlcNAc) polymer -
Chitin. Thatís why it is valuable to look at enzymes such as
Chitinase A1(ChiA), which breaks the glycosidc bonds in Chitin. It
may seem counter-intuitive to inhibit an enzyme that breaks down
cell walls in fungi, but because ChiAís function is necessary for A.
fumigatus sexual reproduction, inhibiting it rather than
promoting its natural function can disrupt and hopefully halt growth
of A. fumigatus and potentially alleviate symptoms of aspergillosis.
One study screened for inhibitors of plant chitinaseís and settled
on acetazolamide to analyze the properties of Chitinase, when
acetazolamide is bound..
II. General Structure of Chitinases
The AA sequence of Chitinases ultimately dictates an eight
distinct stranded alternating alpha/beta barrel structure also known
as a Tim Barrel
. The TIM barrel is shaped in a toroid
fashion. The TIM barrel toroid can also be thought of more simply as
a doughnut-like shape, with the alpha-helices
forming the outer surface,
and the alternating beta-sheets
forming the inner surface of the toroid. Each of the eight primary
alpha-helices is connected on either end in a beta-
III. Chitinase Active Site
The active site of AfChiA is characterized by residues
Trp312, Tyr34, Gln230, Met310, Ala205, Tyr232 and "Asp172
. The carbonyl group of Asp172 engages
in hydrogen bonding with the amide group and Tyr232
with the amino acidís carbonyl oxygen. Under normal circumstances,
it is primarily the Asp residue that
interacts directly with a chitin molecule to catalyze separation of
IV. Acetazolamide Binding
The thiadiazole ring of the inhibitor engages in stacking
interaction with Trp312. Nitrogen
groups contained in thiadiazole rings primarily hydrogen bond with amides of
residues Ala124 and through much
farther water-mediated contact in the case of Tyr125
V. Concluding Thoughts
Ultimately ChiA1 is only one of many different chitinases.
In the 5 plant chitinases, acetazolamide showed similarly strong
binding profiles, therefore similar and significant inhibibition of
all other plant-type chitinases in A. fumigatus is likely.
Further optimization of acetazolamide, via decrease in size of
functional groups, would be the next best way to explore chitinase
Branden, Carl-Ivar, and John Tooze. Introduction
to Protein Structure. New York: Garland Pub., 1991. 47-50. Web.
Gros, Ludovic, David E. Blair, Julie A.
Frearson, Daan M.f. Van Aalten, Ian H. Gilbert, and Alexander W.
Schuttelkopf. "Acetazolamide-based Fungal Chitinase Inhibitors."
Bioorganic and Medicinal Chemistry 18.23 (2010): 8334-340. Web. 3
Kong, Kok-Fai, Lisa Schneper, and Kalai
Mathee. "Beta-lactam Antibiotics: From Antibiosis to Resistance
and Bacteriology." Apmis 118.1 (2010): 1-36. Web. 3 Dec. 2016.
Latge', Jean Paul. "Aspergillus Fumigatus and
Aspergillosis." Clinical Microbiology Reviews(2009): 310-50. Web.
3 Dec. 2016.
Orikoshi, H., S. Nakayama, K. Miyamoto, C.
Hanato, M. Yasuda, Y. Inamori, and H. Tsujibo. "Roles of Four
Chitinases (ChiA, ChiB, ChiC, and ChiD) in the Chitin Degradation
System of Marine Bacterium Alteromonas Sp. Strain O-7." Applied
and Environmental Microbiology 71.4 (2005): 1811-815. Web. 3 Dec.
Robertus, Jon D., and Arthur F. Monzingo.
"The Structure and Action of Chitinases." Chitin and Chitinases
(1999): 125-35. Web. 3 Dec. 2016.
Ubhayasekera, Wimal. "Structure and Function
of Chitinases from Glycoside Hydrolase Family 19." Polymer
International 60.6 (2011): 890-96. Web. 3 Dec. 2016.
Back to Top