ReviewThe interplay between iron, haem and manganese in Porphyromonas gingivalis
Introduction
Chronic periodontitis is the most common of the destructive periodontal diseases amongst adults and its prevalence and severity increase with age. The global age-standardised prevalence of severe periodontitis between 1990 and 2010 was 11%, however the exact percentage varies between and within countries [1], [2], [3]. In the USA, 38% of the adult population 30 years and older and 65% of adults 65 years and older have either severe or moderate periodontitis [4], [5]. Epidemiological surveys have shown that clinical indicators of chronic periodontal disease are associated with a greater risk of certain cancers such as squamous cell carcinoma of the head, neck, and oesophagus [6], cancer of the tongue [7] and pancreatic cancer [8], [9], [10]. There is also a relationship between chronic periodontitis and systemic diseases and disorders such as cardiovascular disease [11], preterm and underweight birth [12], systemic inflammation in solid-organ transplant recipients [13], diabetes and rheumatoid arthritis [11], [14], [15], [16].
The bacterial aetiology of chronic periodontitis is acknowledged to be polymicrobial in nature. Whilst the concepts of the roles of particular oral bacterial species in disease have changed over the past two decades, there is consensus that the anaerobic, proteolytic, amino acid fermenting species Porphyromonas gingivalis plays a significant role in either initiation or progression of disease [17], [18], [19], [20]. Based on animal model data P. gingivalis has recently been proposed to be a “keystone pathogen” that manipulates the host response to favour the proliferation of a pathogenic polymicrobial biofilm (dysbiosis) and development of disease [19]. We have previously demonstrated in a longitudinal human study that the imminent progression of chronic periodontitis could be predicted by increases in the relative levels of P. gingivalis and/or Treponema denticola in subgingival plaque [21], which is consistent with other clinical studies demonstrating that P. gingivalis levels in subgingival plaque are predictive of human disease progression [22], [23], [24]. P. gingivalis is also capable of causing periodontitis in animal models of disease [25], [26].
Section snippets
Divalent metal cations
All living cells acquire transition metal ions to meet their basic cellular needs, with iron, manganese, copper, zinc, nickel and cobalt being of greatest physiological relevance [27], [28]. It has been estimated that about one-third of all proteins require essential transition metal ions to perform catalytic, structural and regulatory functions [29], [30]. Metals such as iron, copper, chromium, manganese and cobalt are capable of redox cycling in which a single electron may be accepted or
Oxidative stress
Stepwise reduction of molecular oxygen (O2) by high-energy exposure or electron-transfer reactions leads to production of highly reactive oxygen species (ROS). The conversion of atmospheric oxygen to ROS occurs inside actively respiring aerobic or facultative bacterial cells [48]. However, few ROS are generated intracellularly by anaerobic bacteria due to the absence of molecular oxygen in their environment. Commensal and pathogenic bacteria can also be exposed to the oxidative burst of
P. gingivalis
P. gingivalis is a Gram-negative, sessile, obligate anaerobe that has an absolute requirement for iron and its growth and virulence are dependent on the availability of iron complexes such as haem [54], [55], [56], [57] or ferrous iron [58]. In addition P. gingivalis cannot synthesise protoporphyrin IX [59], a porphyrin derivative that combines with ferrous iron to form haem, a cofactor for several enzymes, which can be bound transiently [60], or remain bound to the protein permanently [61].
P.
Metal acquisition systems of P. gingivalis
P. gingivalis like most anaerobic bacteria does not produce siderophores to scavenge environmental iron or compete with transferrin or lactoferrin for ferric iron binding [70]. P. gingivalis utilises human transferrin as a source of iron and peptides via proteolytic cleavage by the cell surface Arg- and Lys-specific cysteine proteinases, RgpA/B and Kgp, collectively known as gingipains [71], [72]. In the absence of gingipains P. gingivalis cannot remove the iron from transferrin [71]. The
The polymicrobial biofilm nature of health and disease
P. gingivalis is a normal component of the human oral microbiota and is a late coloniser of polymicrobial oral biofilms, relying on complex interactions with a range of other oral bacteria including Streptococcus gordonii, Fusobacterium nucleatum, Tannerella forsythia and T. denticola [112], [113], [114]. Therefore although much has been learnt by studying P. gingivalis in isolation, its interactions with other bacterial species in the biofilm will have a considerable influence on its role as
Metalloregulatory proteins
To protect against the toxic effect of the Fenton reaction, cells must utilise, store and maintain iron concentrations with careful management of cellular free iron sequestered in high affinity protein-bound forms [125]. Intracellular concentrations of metal ions in living cells are maintained and co-ordinated through a system known as metal ion homoeostasis that involves metal ion influx across the cell membrane depending on the intracellular metal ion concentration, availability and demand.
Walking the tightrope: the nexus between haem, iron, manganese and oxygen
There is interplay between iron and manganese homoeostasis in P. gingivalis as in a FeoB mutant, which had half the cellular iron of wild-type, there was a concomitant three-fold increase in cellular manganese [58]. This increase in cellular manganese content in the P. gingivalis mutant was attributed to manganous ions binding to vacant sites of ferrous ion binding proteins thus lowering the free manganous ion concentration within the cell. Given the link between increased OxyR expression under
Conclusion
The clear interplay between iron, manganese, haem and oxidative stress protection may enable the anaerobic P. gingivalis to maintain a high level of intracellular ferrous iron to maximise growth and virulence using energy efficient iron-dependent metabolism, but to rapidly replace this potentially deadly metal with manganese for survival during oxidative stress by switching to a more protective, but much more restrictive, manganese-based physiology.
Ethical approval
Ethical approval was not required.
Conflict of interest
There are no potential conflicts of interest to be disclosed.
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Cited by (4)
Oral biosciences: The annual review 2015
2016, Journal of Oral BiosciencesLysine acetylation is a common post-translational modification of key metabolic pathway enzymes of the anaerobe Porphyromonas gingivalis
2015, Journal of ProteomicsCitation Excerpt :Other pathways, such as glycan biosynthesis [50] and metabolism, and the metabolism of terpenoids and polyketides had no detected acetylated proteins, suggesting that under the tested growth condition particular metabolic pathways had been targeted for lysine acetylation. Metabolic pathways of P. gingivalis are tightly regulated at the transcriptional level [51–53] and are likely to be highly regulated at the post-translational level as inferred by the majority of the lysine-acetylated P. gingivalis proteins we detected being metabolic enzymes. P. gingivalis relies on the complex anaerobic fermentation of amino acids, particularly aspartate and glutamate to produce energy (Fig. 3) [1].