The Classification
The l‑asparaginase classification
that underpins the database is based on extensive sequence (and
structure) analyses of known and predicted
l‑asparaginases. As these enzymes
form a complex and intertwined group, sequence similarity analysis was
selected as the best primary driver of the classification, rather than
other factors like taxonomy, cellular location or enzyme kinetics,
enabling a more objective and natural classification less biased by the
order of scientific discovery. This bioinformatics-centred approach also
makes the classification more robust to future discoveries.
Asparaginase Classes
There are three fundamental classes of
l‑asparaginases, each with unique
conserved motifs and structures. No homology could be inferred between
these classes of l‑asparaginases,
as they show very low mutual sequence identity. Sequences are
categorized into Class 1 (historically bacterial-type), Class 2 (plant
type) and Class 3 (R. etli-type)
l‑asparaginases. Sequences in
these classes were clustered and aligned independently. This allowed
further division into new phylogenetic clans and families inferred from
a comprehensive phylogenetic analysis.
Prior work this classification builds on
The earlier work that the classification presented here builds upon,
listed as acknowledgment and further reading.
-
da Silva LS, Doonan LB, Pessoa A Jr, et al. Structural and
functional diversity of asparaginases: overview and
recommendations for a revised nomenclature.
Biotechnol Appl Biochem. 2022;69:503–13.
10.1002/bab.2127
-
Loch JI, Jaskolski M. Structural and biophysical aspects of
l‑asparaginases: a growing
family with amazing diversity. IUCrJ.
2021;8:514–31.
10.1107/S2052252521006011
-
Borek D, Jaskolski M. Sequence analysis of enzymes with
asparaginase activity. Acta Biochim Pol.
2001;48:893–902.
10.18388/abp.2001_3855
-
Lubkowski J, Wlodawer A. Structural and biochemical properties of
l‑asparaginase.
FEBS J. 2021;288:4183–209.
10.1111/febs.16042
To cite The Asparaginase Database itself, or to see how the classification here is different to previous ones; see the
Publication section.
What Are Asparaginases?
l‑Asparaginases are a group of
enzymes that catalyse the hydrolysis of
l‑asparagine to
l‑aspartate and ammonium, a
reaction important in nitrogen metabolism and maintaining cellular and
physiological homeostasis. This class of catalytic proteins is found in
archaea, prokaryotes, and eukaryotes, including humans, and sequences
are commonly present in several isoforms. Consequently, it emerges as a
highly diverse group, characterized by various quaternary structures
with distinct amino acid sequences, while displaying a wide spectrum of
affinities not only for
l‑asparagine but often also for
other substrates. Click the reaction scheme for more details.
Medical Applications
l‑Asparaginases play a pivotal
role in treating acute lymphoblastic leukemia and rank among the most
successful biopharmaceuticals, having served as effective anticancer
agents since 1978. They function by efficiently depleting
l‑asparagine from the bloodstream,
which is an essential nutrient that many cancer cells cannot produce
independently, while healthy cells retain the ability to synthesize
their own l‑asparagine.
Food Industry Applications
In the food industry,
l‑asparaginases are employed in
reducing the formation of acrylamide, a neurotoxic compound that
develops when l‑asparagine reacts
during the heat processing of carbohydrate-rich foods. By breaking down
l‑asparagine before thermal
processing, these enzymes effectively minimize acrylamide levels in
processed food products, thereby reducing potential health risks
associated with this toxic substance.
Current Challenges
Despite their success in cancer therapy and industry applications,
current l‑asparaginase
preparations face several significant challenges, including pronounced
immunogenicity, limited stability, and suboptimal activity or substrate
affinity.
Enzyme Diversity
l‑Asparaginases are a diverse
group of enzymes, and understanding their natural diversity and
structure-activity relationships is essential for addressing current
limitations. Related enzymes include
l‑glutaminases, mixed
asparaginases/glutaminases, β-aspartyl-peptidases, glutamyl-tRNAGln
amidotransferases, and aspartylglucosaminidases.
About the Database
The Asparaginase Database (ASNasedb) is a resource that provides
organized
l‑asparaginase sequences and
structures within their phylogenetic families along with biochemical
annotations for characterized enzymes. The database is built on a
comprehensive phylogenetically driven
l‑asparaginase classification that
integrates existing biochemical knowledge with expanding sequence data.
This system is not only free of historical ambiguities but could also
aid scientists with understanding and discovering
l‑asparaginases with improved
functional or structural properties.
The current release covers a manually curated set of 101 experimentally
studied proteins from the literature, a manually curated set of 127
sequences from Swiss-Prot and 126,085 automatically classified sequences.
