Inhibitors of chitinases

Kd, Spindler; Spindler-Barth, Margarethe

doi:10.1007/978-3-0348-8757-1_14

Cited by 14 publications

(13 citation statements)

References 52 publications

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“…6). All family 18 chitinases are inhibited by allosamidin (13), and the activity of rCHT1 was inhibited by allosamidin (Fig. 6), indicating H. longicornis chitinase is a family 18 chitinase.…”

Section: Discussionmentioning

confidence: 92%

“…The chitinase inhibitor, allosamidin, isolated from culture broth of Streptomyces sp. (12), has been used as an important tool to elucidate several essential features of insect chitinases (13). Ticks are second only to mosquitoes as vectors of diseasecausing agents in humans and are the most important arthropod transmitting pathogens to domestic and wild animals, e.g.…”

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confidence: 99%

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Identification and Molecular Characterization of a Chitinase from the Hard Tick Haemaphysalis longicornis

You

Xuan

Tsuji

et al. 2003

Journal of Biological Chemistry

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A cDNA encoding tick chitinase was cloned from a cDNA library of mRNA from Haemaphysalis longicornis eggs and designated as CHT1 cDNA. The CHT1 cDNA contains an open reading frame of 2790 bp that codes for 930 amino acid residues with a coding capacity of 104 kDa. The deduced amino acid sequence shows a 31% amino acid homology to Aedes aegypti chitinase and a multidomain structure containing one chitin binding peritrophin A domain and two glycosyl hydrolase family 18 chitin binding domains. The endogenous chitinase of H. longicornis was identified by a two-dimensional immunoblot analysis with mouse anti-rCHT1 serum and shown to have a molecular mass of 108 kDa with a pI of 5.0. A recombinant baculovirus AcMNPV⅐CHT1-expressed rCHT1 is glycosylated and able to degrade chitin. Chitin degradation was ablated by allosamidin in a dose-dependent manner. The optimal temperature and pH for activity of the purified chitinase were 45°C and pH 5-7. The CHT1 cDNA has an ELR motif for chemokine-mediated angiogenesis and appears to be a chitinase of the chemokine family. Localization analysis using mouse anti-rCHT1 serum revealed that native chitinase is highly expressed in the epidermis and midgut of the tick. AcMNPV⅐CHT1 topically applied to H. longicornis ticks exhibited replication. This is the first report of insect baculovirus infection of ticks. The importance of AcMNPV⅐CHT1 as a novel bio-acaricide for tick control is discussed.

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Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

Identification and Molecular Characterization of a Chitinase from the Hard Tick Haemaphysalis longicornis

You

Xuan

Tsuji

et al. 2003

Journal of Biological Chemistry

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“…This makes D. melanogaster an ideal system for studying nuclear-receptor function and regulation. The 20E hormone, which is considered to be a principal determinant of developmental timing, controls diverse biological processes, including morphogenetic, apoptotic, physiological, reproductive and behavioral responses (5,6). Like vertebrate steroid hormones, 20E exerts its effects via a member of the nuclear receptor superfamily, a product of the EcR gene (7).…”

Section: Introductionmentioning

confidence: 99%

Novel DNA-binding element within the C-terminal extension of the nuclear receptor DNA-binding domain

Jakób¹,

Kolodziejczyk²,

Orłowski³

et al. 2007

Nucleic Acids Research

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The heterodimer of the ecdysone receptor (EcR) and ultraspiracle (Usp), members of the nuclear receptors superfamily, is considered as the functional receptor for ecdysteroids initiating molting and metamorphosis in insects. Here we report the 1.95 Å structure of the complex formed by the DNA-binding domains (DBDs) the EcR and the Usp, bound to the natural pseudopalindromic response element. Comparison of the structure with that obtained previously, using an idealized response element, shows how the EcRDBD, which has been previously reported to possess extraordinary flexibility, accommodates DNA-induced structural changes. Part of the C-terminal extension (CTE) of the EcRDBD folds into an α-helix whose location in the minor groove does not match any of the locations previously observed for nuclear receptors. Mutational analyses suggest that the α-helix is a component of EcR-box, a novel element indispensable for DNA-binding and located within the nuclear receptor CTE. This element seems to be a general feature of all known EcRs.

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“…Allosamidin is a chitin-like metabolite that inhibits numerous chitinase enzymes with different efficacies by binding to the active site (12). Although it is known that allosamidin does not universally inhibit chitinase enzymes (for example, S. griseus chitinase is not inhibited [10]), it was surprising to discover that PbCHT1, the ortholog of the efficiently inhibited PgCHT1, was insensitive in our assay (Fig.…”

Section: Discussionmentioning

confidence: 89%

Knockout of the Rodent Malaria Parasite Chitinase PbCHT1 Reduces Infectivity to Mosquitoes

et al. 2001

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During mosquito transmission, malaria ookinetes must cross a chitin-containing structure known as the peritrophic matrix (PM), which surrounds the infected blood meal in the mosquito midgut. In turn, ookinetes produce multiple chitinase activities presumably aimed at disrupting this physical barrier to allow ookinete invasion of the midgut epithelium. Plasmodium chitinase activities are demonstrated targets for human and avian malaria transmission blockade with the chitinase inhibitor allosamidin. Here, we identify and characterize the first chitinase gene of a rodent malaria parasite, Plasmodium berghei. We show that the gene, named PbCHT1, is a structural ortholog of PgCHT1 of the avian malaria parasite Plasmodium gallinaceum and a paralog of PfCHT1 of the human malaria parasite Plasmodium falciparum. Targeted disruption of PbCHT1 reduced parasite infectivity in Anopheles stephensi mosquitoes by up to 90%. Reductions in infectivity were also observed in ookinete feeds-an artificial situation where midgut invasion occurs before PM formationsuggesting that PbCHT1 plays a role other than PM disruption. PbCHT1 null mutants had no residual ookinete-derived chitinase activity in vitro, suggesting that P. berghei ookinetes express only one chitinase gene. Moreover, PbCHT1 activity appeared insensitive to allosamidin inhibition, an observation that raises questions about the use of allosamidin and components like it as potential malaria transmission-blocking drugs. Taken together, these findings suggest a fundamental divergence among rodent, avian, and human malaria parasite chitinases, with implications for the evolution of Plasmodium-mosquito interactions.After ingestion of infectious Plasmodium gametocytes by the mosquito, motile ookinetes develop in the midgut lumen and traverse the chitin-containing peritrophic matrix (PM), the microvillus-associated network, and the midgut epithelium to form sporozoite-producing oocysts on the hemocoel side of the midgut (11,18). After the demonstration that ookinetes secrete multiple chitinase activities (6), two distinct Plasmodium chitinase genes were isolated. The first was isolated from the human malaria parasite Plasmodium falciparum (PfCHT1) (14), while the second was found in the avian malaria parasite Plasmodium gallinaceum (PgCHT1) (15). The primary structures of these two chitinase genes are markedly different: PgCHT1 encodes putative amino-terminal proenzyme and carboxy-terminal chitin-binding domains, which are both absent in PfCHT1. P. gallinaceum secretes a second chitinase activity provisionally named PgCHT2, believed to be orthologous to that encoded by PfCHT1 based on its molecular mass and physiological properties (pH optimum and sensitivity to the chitinase inhibitor allosamidin), and it may have additional chitinase activities (15).The Streptomyces-produced molecule allosamidin is a 622-dalton pseudo-oligosaccharide that inhibits Plasmodium chitinase activities in vitro (10,14,15). Moreover, the presence of allosamidin in an infected blood meal inhibited ooc...

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Inhibitors of chitinases

Cited by 14 publications

References 52 publications

Identification and Molecular Characterization of a Chitinase from the Hard Tick Haemaphysalis longicornis

Identification and Molecular Characterization of a Chitinase from the Hard Tick Haemaphysalis longicornis

Novel DNA-binding element within the C-terminal extension of the nuclear receptor DNA-binding domain

Knockout of the Rodent Malaria Parasite Chitinase PbCHT1 Reduces Infectivity to Mosquitoes

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