Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Defensins are highly abundant and variably cationic peptides that possess antimicrobial, cytotoxic, and chemoattractant properties and equip mammalian phagocytes for participation in host defense and inflammatory processes. We studied the binding of the human defensin HNP-1 by proteins in plasma and serum and identified activated (F-form) alpha 2-macroglobulin (alpha 2M) as a principal binding protein for HNP-1. In contrast, native (S-form) alpha 2M bound little HNP-1. The binding of HNP-1 by F-form alpha 2M was resistant to salt and boiling in 2% sodium dodecyl sulfate but was ablated by dithiothreitol. Pretreatment of methylamine-activated serum or plasma by iodoacetamide substantially decreased the binding of HNP-1 to alpha 2M, suggesting that thiol groups in activated alpha 2M play a role in defensin binding, possibly by covalently trapping defensins via thiol-disulfide exchange. Western blots of conventionally collected sera showed endogenous defensins complexed with the F-form of alpha 2M, indicating that the generation of defensin-alpha 2M complexes was not limited to the in vitro model of methylamine-activated serum or plasma and radiolabeled HNP-1. Previous studies indicated that native alpha 2M can be converted to its F-form by many proteases, including those released by neutrophils and platelets, and that the F-form is recognized and internalized by specific receptors on macrophages and hepatocytes. Our findings suggest that the alpha 2M system may function as a scavenger of defensins and other peptide mediators in inflamed tissues and may constitute an important mechanism for the regulation and containment of inflammation.
Am J Respir Cell Mol Biol 1991 Aug
PMID:Activated alpha 2-macroglobulin is a principal defensin-binding protein. 171 45

The regulation of gene expression by the two-component regulatory system PhoP/PhoQ is necessary for Salmonella typhimurium survival within macrophages, defensin resistance, acid resistance, and murine typhoid fever pathogenesis. Salmonella experience multiple environments during mammalian infection and survival requires tightly regulated gene expression. After phagocytosis by macrophages, signal transduction by PhoQ results in the transcription of phoP-activated genes (pags) encoding proteins essential to bacterial survival and virulence. One such gene, pagC, encodes an envelope protein with amino acid similarity to an epithelial cell invasion protein of Yersina enterocolitica, Ail, and a bacteriophage lambda outer membrane protein, Lom. The PhoP and PhoQ proteins can also repress the synthesis of proteins, encoded by phoP repressed genes (prgs), when pags are maximally expressed. If prgs encode receptors for toxic compounds, prg repression may protect the cell within macrophages when pag expression is most necessary. At least one prg locus, prgH, is required for full S. typhimurium mouse virulence. Within the macrophage, different environments may stimulate a switch from pag to prg expression that is necessary to Salmonella survival. prg expression may also be necessary for surviving nonmacrophage environments. Study of the PhoP regulon should lead to the discovery of new virulence factors, increase knowledge of how gene regulation is essential to bacterial virulence, and perhaps lead to the development of better vaccines for typhoid fever.
Mol Microbiol 1991 Sep
PMID:PhoP/PhoQ: macrophage-specific modulators of Salmonella virulence? 176 80

Solution structures of the rabbit neutrophil defensin NP-5 have been determined by 1H nuclear magnetic resonance (n.m.r.) spectroscopy and distance geometry techniques. This 33 amino acid peptide is part of the oxygen-independent mammalian defense system against microbial infection. The structures were generated from 107 n.m.r. derived inter-residue proton-proton distance constraints. A distance geometry algorithm was then used to determine the range of structures consistent with these distance constraints. These distance geometry calculations employed an improved algorithm that allowed the chirality constraints to be relaxed on prochiral centers when it was not possible to make stereo-specific assignments of protons on these centers. This procedure gave superior results compared with standard distance geometry methods and also produced structures that were more consistent with the original n.m.r. data. Analysis of the NP-5 structures shows that the overall folding of the peptide backbone is well defined by the n.m.r. distance information but that the side-chain group conformations are generally less well defined.
J Mol Biol 1988 Jun 05
PMID:Solution structures of the rabbit neutrophil defensin NP-5. 284 52

The injection of Escherichia coli and Micrococcus luteus into the hemocoel of Aedes aegypti induces a potent antibacterial activity in the hemolymph. We have purified and fully characterized three 40-residue antibacterial peptides from the hemolymph of bacteria-challenged mosquitoes that are absent in naive mosquitoes. The peptides are potently active against Gram-positive bacteria and against one of the Gram-negative bacteria that were tested. The amino acid sequences clearly show that the three peptides are novel isoforms of the insect defensin family of antibacterial peptides. They differ from each other by one or two amino acid residues. We present here the complete amino acid sequences of the three isoforms and the activity spectrum of the predominant Aedes defensin.
Insect Biochem Mol Biol 1995 Jul
PMID:Insect immunity: isolation of three novel inducible antibacterial defensins from the vector mosquito, Aedes aegypti. 763 71

Defensins, antimicrobial and cytotoxic peptides of neutrophils, bind to and are inactivated by blood proteins. We identified defensin interactions with alpha 1-proteinase inhibitor (alpha 1-PI), alpha 1-antichymotrypsin (alpha 1-ACT), alpha 2-antiplasmin (alpha 2-AP), and antithrombin III (AT III) and examined defensin binding to alpha 1-PI and alpha 1-ACT in more detail. Defensin interactions with either alpha 1-PI or alpha 1-ACT were not affected by iodoacetamide or high salt concentration. Preincubation of alpha 1-ACT or alpha 1-PI with increasing concentrations of defensin resulted in a progressive decrease of antiprotease activity of both inhibitors against cathepsin G and antiprotease activity of alpha 1-PI against human neutrophil elastase. At higher concentrations, defensin also ablated the inhibitory effect of normal human serum on cathepsin G and human neutrophil elastase. Both alpha 1-PI and alpha 1-ACT inhibited defensin cytotoxicity toward the human lung carcinoma cell line A549, whereas the elastase inhibitor antileukoprotease did not. Complex interactions between serpins and defensin may have a role in regulating inflammatory processes.
Am J Respir Cell Mol Biol 1995 Mar
PMID:Human neutrophil defensin and serpins form complexes and inactivate each other. 787 2

Using a new, sensitive assay of bacterial growth inhibition, inducible antibacterial activity has been identified in the haemolymph of the mosquito, Aedes aegypti following inoculation with bacteria or with microfilariae of the filarial nematode Brugia pahangi, but not after inoculation with sterile culture medium. A lower level of antibacterial activity has also been observed in untreated individual mosquitoes. Following bacterial inoculation, a basic, inducible antibacterial peptide has been detected using native PAGE at pH 4, which corresponds with a 4.5 kDa peptide detected by tricine SDS-PAGE followed by silver staining. A peptide has been purified from immune haemolymph by ultrafiltration, followed by reversed-phase HPLC, yielding a single major peak with antibacterial activity. Partial amino acid sequence analysis of this fraction has revealed substantial homology with insect defensins. The data are consistent with the peptide being another member of this family, and we propose the name Aedes aegypti defensin.
Insect Biochem Mol Biol 1994 Apr
PMID:Purification of an insect defensin from the mosquito, Aedes aegypti. 802 59

Polymorphonuclear leukocytes (PMN) contribute to epithelial injury at sites of inflammation, but their mechanisms of action are incompletely understood. PMN can injure target tissues by oxidative and nonoxidative mechanisms. Included in the nonoxidative mechanisms are defensins (DEF), small (3.5 to 4.0 kD), arginine- and cysteine-rich polypeptides. DEF are bactericidal, fungicidal, viricidal, and tumoricidal, but their ability to contribute to inflammatory injury has not been extensively evaluated. One marker of inflammatory injury is disrupted epithelial barrier integrity. Using Madin-Darby canine kidney (MDCK) epithelial monolayers, we measured the effect of both human and rabbit DEF on barrier integrity using mannitol permeability (Pmann) and transepithelial electrical resistance (Rt). Human DEF (HNP1-3, 2:2:1 molar ratio) increased Pmann in a time- and concentration-dependent manner and Rt fell progressively over a 48-h period after exposure of monolayers to HNP1-3. Rabbit DEF peptide 1 (NP-1) also increased Pmann, but rabbit peptide 5 (NP-5) had no effect on Pmann. To investigate the role of charge, HNP1-3 was added to the monolayers with the polyanions heparin or sulfated dextran. Heparin and sulfated dextran only partially inhibited the increase in Pmann. Fetal bovine serum (FBS), however, completely inhibited the effect of HNP1-3, but this protection was only partially explained by the anionic protein, albumin. The FBS protection was time dependent and was present when FBS was added up to 16 h after exposure to HNP1-3. While both HNP1-3 and NP-1 increased epithelial permeability, neither were cytolytic to MDCK cells as measured by lactate dehydrogenase release.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Feb
PMID:Defensins reduce the barrier integrity of a cultured epithelial monolayer without cytotoxicity. 842 10

The human neutrophil-derived cationic peptide HP-4 exhibits corticostatic activity on adrenal cells and is an L-type calcium channel agonist at nanomolar concentrations. Complementary DNA clones encoding the HP-4 precursor have been isolated from a human bone marrow cDNA library by screening with oligonucleotide probes. The nucleotide sequence shares about 72% identity with the cDNA encoding defensin HP-1, but differs from it, and from other genes of this family characterized to date, by an extra 83-base segment. This extra segment is not adjacent to an intron and is apparently the result of a recent duplication within the coding region corresponding to most of the mature HP-4 peptide. The predicted amino acid sequence shows the HP-4 precursor structure to be typical of this family of molecules. By analysis of DNA from a pannel of hamster/human hybrid cell lines, the HP-4 gene was found to be on chromosome 8, as is the gene for human peptide HP-1. Comparison with the few sequences of other corticostatin/defensin genes available does not indicate distinct lineages of corticostatic and noncorticostatic peptides, since HP-1 and HP-4 cDNA sequences share more identity with each other than either shares with cDNAs encoding rabbit MCP-1 or MCP-2, or guinea pig GNCP-1.
Mol Endocrinol 1993 Feb
PMID:The gene encoding the human corticostatin HP-4 precursor contains a recent 86-base duplication and is located on chromosome 8. 846 33

Peptides in an extract of skin from the agnathan Petromyzon marinus (sea lamprey) were purified by reversed-phase high-performance liquid chromatography and characterized by Edman degradation. The primary structure of a cysteine- and arginine-rich peptide (termed lamprey corticostatin-related peptide [LCRP]) was established as Cys-Pro-Cys-Gly-Arg-Arg-Arg-Cys-Cys-Val-Arg-Gly-Leu-Asn-Val-Tyr-Cys-Cys- Phe. Mass spectrometry indicated that all cysteine residues are intramolecularly linked. This amino acid sequence shows structural similarity to rat corticostatin R4 and rabbit corticostatin R1. In particular, LCRP contains the polyarginine sequence at the N-terminus of the peptide that is believed to mediate both the inhibition of ACTH stimulated steroidogenesis and the antimicrobial (defensin-like) actions of the corricostatins.
Comp Biochem Physiol B Biochem Mol Biol 1996 Jun
PMID:Isolation of a peptide structurally related to mammalian corticostatins from the lamprey Petromyzon marinus. 875 87

Larvae of the mosquito vector of human malaria, Anopheles gambiae, were inoculated with bacteria and extracts were biochemically fractionated by reverse-phase HPLC. Multiple induced polypeptides and antibacterial activities were observed following bacterial infection, including a member of the insect defensin family of antibacterial proteins. A cDNA encoding An. gambiae preprodefensin was isolated using PCR primers based on phylogenetically conserved sequences. The mature peptide is highly conserved, but the signal and propeptide segments are not, relative to corresponding defensin sequences of other insects. Defensin expression is induced in response to bacterial infection, in both adult and larval stages. In contrast, pupae express defensin mRNA constitutively. Defensin expression may prove a valuable molecular marker to monitor the An. gambiae host response to infection by parasitic protozoa of medical importance.
Insect Mol Biol 1996 Aug
PMID:Inducible immune factors of the vector mosquito Anopheles gambiae: biochemical purification of a defensin antibacterial peptide and molecular cloning of preprodefensin cDNA. 879 39


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