A heme-degradation pathway in a blood-sucking insect

Paiva-Silva, Gabriela O.; Cruz-Oliveira, Christine; Nakayasu, Ernesto; Maya‐Monteiro, Clarissa M.; Dunkov, Boris C.; Masuda, Hatisaburo; Almeida, Igor C.; Oliveira, Pedro L.

doi:10.1073/pnas.0602224103

Cited by 78 publications

(76 citation statements)

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“…We show that, in this mosquito, heme detoxification initiates by the HO reaction, followed by sequential addition of two glutamines to the biliverdin IX α produced by HO. This pathway is clearly distinct from the one identified by our group in another hematophagous insect, the hemipteran R. prolixus (18), as well as it is different from the mammalian mechanism of disposal of excess bilin. The end product of heme degradation in R. prolixus is a γ-biliverdin with two cysteine residues attached to the vinyl groups and the heme molecule is initially modified prior oxidative cleavage of the porphyrin.…”

Section: Discussionmentioning

confidence: 67%

“…It involves an initial step of modification of heme by addition of two cysteinylglycine residues prior to cleavage -at the gamma position instead of the usual alpha meso-carbon -of the porphyrin ring, followed by proteolytic trimming of these dipeptides, to produce dicysteinyl-BV IX as the main end-product (18). The present work describes the heme degradation pathway in the mosquito A. aegypti and shows that -in contrast to the R. prolixus -this involves oxidative cleavage of heme without previous modification, in the α meso-carbon.…”

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confidence: 99%

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Biglutaminyl-Biliverdin IX Alpha as a Heme Degradation Product in the Dengue Fever Insect-Vector Aedes aegypti

et al. 2007

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Hemoglobin digestion in the midgut of hematophagous animals results in the release of its prosthetic group, heme, which is a pro-oxidant molecule. Heme enzymatic degradation is a protective mechanism that has been described in several organisms, including plants, bacteria, and mammals. This reaction is catalyzed by heme oxygenase and results in formation of carbon monoxide, ferrous ion, and biliverdin IXα. During digestion, a large amount of a green pigment is produced and secreted into the intestinal lumen of A. aegypti adult females. In the case of another blood-sucking insect, the kissing-bug Rhodnius prolixus, we have recently shown that heme degradation involves a complex pathway that generates dicysteinyl-biliverdin IX gamma. The light absorption spectrum of the Aedes purified pigment was similar to biliverdin, but its mobility on a reverse-phase chromatography column suggested a compound less hydrophobic than biliverdin IXα. Structural characterization by ESI-MS revealed that the mosquito pigment is the α isomer of biliverdin bound to two glutamine residues by an amide bond. This biglutaminyl-biliverdin is formed by oxidative cleavage of the heme porphyrin ring followed by two subsequent additions of glutamine residues to the biliverdin IXα. The role of this pathway in the adaptation of this insect vector to a blood-feeding habit is discussed. Keywordsheme; heme oxygenase; biliverdin; detoxification; Aedes aegypti Dengue fever, associated with dengue hemorrhagic fever (DHF), is the most prevalent vectorborne viral disease affecting humans, transmitted mainly by the mosquito Aedes aegypti (1). The ability of A. aegypti females to transmit these viruses from one vertebrate host to another is strictly related to their hematophagous habit. Ingestion of a blood meal triggers intense protein digestion which takes place in the lumen, providing nutrients required for oogenesis (2) but also leading to the release of high amounts of free heme due to host hemoglobin proteolysis. Heme is potentially toxic due to its capacity to promote the generation of reactive oxygen species (ROS) (3). Being an amphiphilic molecule, heme can also insert itself into phospholipid bilayers, leading to destabilization of membrane structure and cell lysis (4). Blood-sucking arthropods present a complex array of heme detoxification and antioxidant mechanisms (5) that allow them to counteract free heme cytotoxicity and adapt to hematophagy. These include heme-binding proteins in the hemolymph of kissing-bugs (6) and ticks (7), high levels of antioxidant enzymes in the midgut of Rhodnius prolixus (8), and aggregation of heme in the midgut of this kissing-bug (9) and ticks (10,11). In A. aegypti, the peritrophic matrix, an extracellular layer that is secreted by the midgut cells and separates the meal from the midgut epithelium, acts as a protective mechanism by binding free heme released during digestion (12). Recently, an Aedes aegypti peritrophin -a protein component of the peritrophic matrix -has been shown to be a heme-binding ...

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Section: Discussionmentioning

confidence: 67%

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confidence: 99%

Biglutaminyl-Biliverdin IX Alpha as a Heme Degradation Product in the Dengue Fever Insect-Vector Aedes aegypti

et al. 2007

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“…When B. quintana colonizes the alimentary tract of the body louse, the bacterium is exposed to potentially toxic concentrations of hemin following the ingestion of a blood meal by the body louse (50). We therefore tested if rpoE transcription is responsive to changes in the hemin concentration.…”

Section: Resultsmentioning

confidence: 99%

The Bartonella quintana Extracytoplasmic Function Sigma Factor RpoE Has a Role in Bacterial Adaptation to the Arthropod Vector Environment

Abromaitis

Koehler

2013

J Bacteriol

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Bartonella quintana is a vector-borne bacterial pathogen that causes fatal disease in humans. During the infectious cycle, B. quintana transitions from the hemin-restricted human bloodstream to the hemin-rich body louse vector. Because extracytoplasmic function (ECF) sigma factors often regulate adaptation to environmental changes, we hypothesized that a previously unstudied B. quintana ECF sigma factor, RpoE, is involved in the transition from the human host to the body louse vector. The genomic context of B. quintana rpoE identified it as a member of the ECF15 family of sigma factors found only in alphaproteobacteria. ECF15 sigma factors are believed to be the master regulators of the general stress response in alphaproteobacteria. In this study, we examined the B. quintana RpoE response to two stressors that are encountered in the body louse vector environment, a decreased temperature and an increased hemin concentration. We determined that the expression of rpoE is significantly upregulated at the body louse (28°C) versus the human host (37°C) temperature. rpoE expression also was upregulated when B. quintana was exposed to high hemin concentrations. In vitro and in vivo analyses demonstrated that RpoE function is regulated by a mechanism involving the anti-sigma factor NepR and the response regulator PhyR. The ⌬rpoE ⌬nepR mutant strain of B. quintana established that RpoE-mediated transcription is important in mediating the tolerance of B. quintana to high hemin concentrations. We present the first analysis of an ECF15 sigma factor in a vector-borne human pathogen and conclude that RpoE has a role in the adaptation of B. quintana to the hemin-rich arthropod vector environment.

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“…Acquisition of heme in the limiting environment of the human host is pivotal to the survival and pathogenesis of B. quintana. In contrast to the human host, in the gut of blood-sucking arthropods free heme is thought to exceed toxic levels during the initial digestion of a blood meal (34). The ability of B. quintana to withstand the heme-limiting environment of the human host and the heme-replete gut of the body louse suggests that its heme acquisition systems are tightly regulated.…”

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Function, Regulation, and Transcriptional Organization of the Hemin Utilization Locus of Bartonella quintana

et al. 2009

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Bartonella quintana is a gram-negative agent of trench fever, chronic bacteremia, endocarditis, and bacillary angiomatosis in humans. B. quintana has the highest known hemin requirement among bacteria, but the mechanisms of hemin acquisition are poorly defined. Genomic analyses revealed a potential locus dedicated to hemin utilization (hut) encoding a putative hemin receptor, HutA; a TonB-like energy transducer; an ABC transport system comprised of three proteins, HutB, HutC, and HmuV; and a hemin degradation/storage enzyme, HemS. Complementation analyses with Escherichia coli hemA show that HutA functions as a hemin receptor, and complementation analyses with E. coli hemA tonB indicate that HutA is TonB dependent. Quantitative reverse transcriptase PCR analyses show that hut locus transcription is subject to heminresponsive regulation, which is mediated primarily by the iron response regulator (Irr). Irr functions as a transcriptional repressor of the hut locus at all hemin concentrations tested. Overexpression of the ferric uptake regulator (fur) represses transcription of tonB in the presence of excess hemin, whereas overexpression of the rhizobial iron regulator (rirA) has no effect on hut locus transcription. Reverse transcriptase PCR analyses show that hutA and tonB are divergently transcribed and that the remaining hut genes are expressed as a polycistronic mRNA. Examination of the promoter regions of hutA, tonB, and hemS reveals consensus sequence promoters that encompass an H-box element previously shown to interact with B. quintana Irr.

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A heme-degradation pathway in a blood-sucking insect

Cited by 78 publications

References 43 publications

Biglutaminyl-Biliverdin IX Alpha as a Heme Degradation Product in the Dengue Fever Insect-Vector Aedes aegypti

Biglutaminyl-Biliverdin IX Alpha as a Heme Degradation Product in the Dengue Fever Insect-Vector Aedes aegypti

The Bartonella quintana Extracytoplasmic Function Sigma Factor RpoE Has a Role in Bacterial Adaptation to the Arthropod Vector Environment

Function, Regulation, and Transcriptional Organization of the Hemin Utilization Locus of Bartonella quintana

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