Human Lactoferrin Binds and Removes the Hemoglobin Receptor Protein of the Periodontopathogen Porphyromonas gingivalis

Shi, Yixin; Kong, Wei; Nakayama, Koji

doi:10.1074/jbc.m001518200

Cited by 46 publications

(49 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Third, a P. gingivalis kgp rgpA hagA triple deletion mutant exhibits no detectable Hb binding in a solid-phase assay (44). Last, the bacteriostatic action of lactoferrin on P. gingivalis is associated with the removal of HA2-proteins from the cell surface (43).…”

Section: Discussionmentioning

confidence: 99%

Porphyrin-Mediated Cell Surface Heme Capture from Hemoglobin byPorphyromonas gingivalis

et al. 2003

View full text Add to dashboard Cite

The porphyrin requirements for growth recovery of Porphyromonas gingivalis in heme-depleted cultures are investigated. In addition to physiologically relevant sources of heme, growth recovery is stimulated by a number of noniron porphyrins. These data demonstrate that, as for Haemophilus influenzae, reliance on captured iron and on exogenous porphyrin is manifest as an absolute growth requirement for heme. A number of outer membrane proteins including some gingipains contain the hemoglobin receptor (HA2) domain. In cell surface extracts, polypeptides derived from HA2-containing proteins predominated in hemoglobin binding. The in vitro porphyrin-binding properties of a recombinant HA2 domain were investigated and found to be iron independent. Porphyrins that differ from protoporphyrin IX in only the vinyl aspect of the tetrapyrrole ring show comparable effects in competing with hemoglobin for HA2 and facilitate growth recovery. For some porphyrins which differ from protoporphyrin IX at both propionic acid side chains, the modification is detrimental in both these assays. Correlations of porphyrin competition and growth recovery imply that the HA2 domain acts as a high-affinity hemophore at the cell surface to capture porphyrin from hemoglobin. While some proteins involved with heme capture bind directly to the iron center, the HA2 domain of P. gingivalis recognizes heme by a mechanism that is solely porphyrin mediated.

show abstract

Section: Discussionmentioning

confidence: 99%

Porphyrin-Mediated Cell Surface Heme Capture from Hemoglobin byPorphyromonas gingivalis

et al. 2003

View full text Add to dashboard Cite

show abstract

“…This protein regulates several bacteria that are associated with periodontal disease, including Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Prevotella melaninogenica (Pm) and Actinobacillus actinomycetemcomitans (Aa). [13][14][15][16][17][18] Lactoferrin's effects on Aa, which is considered to have the strongest association with aggressive periodontitis, occurs through direct killing, as well as through inhibition of attachment to epithelial cells and the development of biofilms. 14,19,20 Studies examining the pattern of inheritance of aggressive periodontitis in families suggest a genetic basis for susceptibility.…”

mentioning

confidence: 99%

“…It may be that the polymorphism described here affects the ability of lactoferrin to bind to and/or kill different genetic variants of bacteria, including Aa, that have previously been implicated with the pathogenicity in aggressive periodontitis. 4,16,17,[28][29][30][31] …”

mentioning

confidence: 99%

A nonconservative, coding single-nucleotide polymorphism in the N-terminal region of lactoferrin is associated with aggressive periodontitis in an African-American, but not a Caucasian population

et al. 2005

View full text Add to dashboard Cite

Lactoferrin is an antimicrobial protein which plays an important role in regulating bacteria that are associated with aggressive periodontitis. Lactoferrin kills directly (via its strongly cationic N-terminal region) and indirectly, through sequestering the iron that bacteria require for growth. As aggressive periodontitis has a strong heritable component, we hypothesized that genetic variation within the lactoferrin gene may play a role in susceptibility to this condition. We have identified and examined a novel, functional, single-point A/G nucleotide mutation causing a threonine/alanine substitution at position 11 (T11A) of the secreted lactoferrin protein. In a pilot case-controlled study of aggressive periodontitis, analysis of 46 African-American patients and 78 controls showed that patients were twice as likely to express the G nucleotide (alanine) allele over controls (60.3 vs 30.4%; P ¼ 0.0007, odds ratio ¼ 2.564, 95% CI ¼ 1. 475-4.459). A Caucasian population of 77 patients and 131 controls showed no such association (P ¼ 0.5201, odds ratio ¼ 0.862, 95% CI ¼ 0.548-1.356). The data presented provide a new insight into the genetic susceptibility to aggressive periodontitis. Genes and Immunity (2005) Lactoferrin is an 80 kDa cationic protein with strong antibacterial and immunomodulatory functions. [1][2][3][4][5] The antibacterial properties were originally attributed solely to its ability to bind the iron necessary for bacterial growth. However, it has been established more recently that lactoferrin also binds to bacteria and kills through direct interactions governed by its strongly basic Nterminal region. [6][7][8][9] In addition to its ability to kill bacteria, lactoferrin can also neutralize endotoxin and inhibit the induction of NFkB in monocytes in response to LPS, resulting in lowered IL-6 and TNF-alpha production. [10][11][12] Lactoferrin is present in high concentrations in saliva and is thought to play a particularly important role in regulation of those bacteria present within the oral cavity. This protein regulates several bacteria that are associated with periodontal disease, including Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Prevotella melaninogenica (Pm) and Actinobacillus actinomycetemcomitans (Aa). [13][14][15][16][17][18] Lactoferrin's effects on Aa, which is considered to have the strongest association with aggressive periodontitis, occurs through direct killing, as well as through inhibition of attachment to epithelial cells and the development of biofilms. 14,19,20 Studies examining the pattern of inheritance of aggressive periodontitis in families suggest a genetic basis for susceptibility. 18,21 The disease is particularly common within African-American populations, being up to 15 times more prevalent than in Caucasians. 21 As lactoferrin has been shown to be active against a number of pathogenic bacteria, including Aa, we hypothesized that single-nucleotide polymorphism (SNPs) within the lactoferrin gene could play a role in the genetic susceptibility that is s...

show abstract

“…Surplus haem may be stored on the surfaces as the µ-oxo dimers, resulting in black colonial pigmentation. A body of evidence that supports this hypothetical mechanism has been accumulated (Shi et al, 1999(Shi et al, , 2000Curtis et al, 1996 ;Booth & Lehner, 1997 ;Kelly et al, 1997 ;Shibata et al, 1999), but a precise mechanism of the iron acquisition and storage system is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Construction and characterization of a nonpigmented mutant of Porphyromonas gingivalis: cell surface polysaccharide as an anchorage for gingipains The GenBank/EMBL/DDBJ accession number for the sequences reported in this paper is D64132.

et al. 2002

Self Cite

View full text Add to dashboard Cite

A nonpigmented mutant of Porphyromonas gingivalis was constructed by using transposon mutagenesis. The mutant possessed the transposon DNA at the novel gene porR. Gene targeted mutagenesis revealed that porR was responsible for pigmentation. The porR gene shared similarities with genes of the degT family, the products of which are now considered to be transaminases involved in biosynthesis of sugar portions of cell-surface polysaccharides and aminoglycosides. The porR mutant showed a pleiotropic phenotype : delayed maturation of fimbrillin, preferential presence of Rgp and Kgp proteinases in culture supernatants, and no haemagglutination. The porR mutant had altered phenol extractable polysaccharide compared to the porR M sibling strain. A mAb, 1B5, that reacts with sugar portions of P. gingivalis cell surface polysaccharide and membrane-type Rgp proteinase showed no reaction with the cell lysates of the porR mutant. These results indicate that porR is involved in biosynthesis of cell surface polysaccharide that may function as an anchorage for Rgp, Kgp, haemagglutinins and the haemoglobin receptor protein.

show abstract

Human Lactoferrin Binds and Removes the Hemoglobin Receptor Protein of the Periodontopathogen Porphyromonas gingivalis

Cited by 46 publications

References 48 publications

Porphyrin-Mediated Cell Surface Heme Capture from Hemoglobin byPorphyromonas gingivalis

Porphyrin-Mediated Cell Surface Heme Capture from Hemoglobin byPorphyromonas gingivalis

A nonconservative, coding single-nucleotide polymorphism in the N-terminal region of lactoferrin is associated with aggressive periodontitis in an African-American, but not a Caucasian population

Construction and characterization of a nonpigmented mutant of Porphyromonas gingivalis: cell surface polysaccharide as an anchorage for gingipains The GenBank/EMBL/DDBJ accession number for the sequences reported in this paper is D64132.

Contact Info

Product

Resources

About