Abstract
The first natural compound containing carbon-to-phosphorus bond—ciliatine was discovered 60 years ago, and for four decades, phosphonates were considered simply as a biological curiosity. Finding the importance of these compounds in biogeochemical phosphorus cycling, their role in methane production, as well as discovery of numerous phosphonates and phosphonopeptides of promising antibacterial and antifungal activities has stimulated the development of studies on this class of compounds, especially on their metabolism and biochemistry. These studies are driven by the use of 31P NMR and by a clever combination of genomics and innovative chemistry by using the method of selective labeling of metabolites. These studies revealed unusual and interesting chemistry of these compounds.
Keywords
- C—P bond
- phosphonates
- ciliatine
- phosphonopeptides
- mimetics
- antibiotics
- 31P NMR
- genome mining
1. Introduction
Phosphonates are organophosphorus compounds characterized by a stable carbon-to-phosphorus (C—P) bond, which usually resists biochemical, thermal, and photochemical decomposition. The first phosphonate (compound
2. Occurrence of carbon-to-phosphorus bond
The discovery of ciliatine stimulated intensive studies on the distribution of phosphonates in nature. Despite the fact that early studies were hampered by the lack of simple and sensitive methods for the identification of the presence of carbon-to-phosphorus bond in natural samples, it was found to exist in protozoa, bacteria, coelenterates, and mollusks [6, 7, 8, 9, 10, 11]. Presumably, the unbreakable record is held by the snail
The advent of 31P NMR for the analysis of tissue extracts, body fluids, and later—whole cells provided an effective tool for tracking the forms of phosphorus and its interchanges during organism development and growth. Quite paradoxically, the availability of 31P NMR was accompanied with a significant decrease in the number of papers dealing with distribution of phosphonates in various species. Applications of this simple technique enabled the determination of the presence of C—P bond in bacteria and bacterial communities [13, 14], cyanobacteria [15], sponges [16], higher fungi [17, 18], or even human specimens [19]. However, these studies did not explain if phosphonates are synthesized
Next, gene-based methods for assessing the abundance and identity of biological phosphonate producers were applied. This approach based on knowledge regarding C—P compound biosynthesis. Thus, with a single exception [21], all the known phosphonates are derived from phosphoenolpyruvate by isomerization to phosphonopyruvate in a reaction catalyzed by the phosphoenolpyruvate mutase, followed by its fast utilization because the reaction of formation of the C—P bond is thermodynamically unfavorable (see Figure 3). Most common, decarboxylation of phosphonopyruvate by phosphonopyruvate decarboxylase to produce phosphonoacetaldehyde is the next, irreversible step [3, 22, 23, 24]. Mining in genome databases for genes related to these two enzymes, as well as their homologs, enabled to determine that 10–15% of bacterial species are able to produce phosphonates [23, 24, 25].
Discovery that phosphonates form around 10% of dissolved and particulate phosphorus in the oceans [15, 25, 26] brought the increasing recognition of the importance of these compounds in biogeochemical phosphorus cycling and an awareness of the interdependence between the global phosphorus cycle and those of the other biologically significant elements [27, 28]. It is important because phosphorus availability has been shown to be a key determinant of marine phytoplankton productivity [15]. Phosphonates are mostly concentrated in dissolved organic phosphorus (DOP), an integral and dynamic part of the marine organic matter pool. The composition of the DOP pool is complex and largely unknown, but phosphonates account for one third of its high molecular weight fraction. Thus, they seem to be an important resource of this element for aquatic organisms; however, the understanding of their utilization by eukaryotic phytoplankton is severely limited [29, 30]. They most likely occur in a form of polysaccharides esterified with methylphosphonate (compound
Up to 4% of the methane on Earth comes from the oxygen-rich waters through the cleavage of the highly unreactive carbon-to-phosphorus bond in methyl phosphonate [32]. The production of methylphosphonic acid (MPn) by cyanobacteria or marine archaea related to
Some researchers believe that phosphonates are a form of relic of evolution. Being of slightly lower formal oxidation state, they might predominate in prebiotic reductive conditions [37]. This assumption, although debatable, finds some support by finding several phosphonic acids in Murchison meteorite [39].
3. Ciliatine (AEP, 2-aminoethylphosphonic acid)
Ciliatine (compound
Lipids containing aminophosphonates are called phosphonolipids. There are two classes of these compounds—glycerophosphonolipids and sphingophosphonolipids (representative structures are shown in Figure 2). They have been isolated from numerous organisms including humans, mammals (sheep, goats, and rats), egg yolk, fish, insects, sea anemones, sponges, numerous species of freshwater and marine mollusks, seeds of plants, protozoa, and bacteria [3, 43, 44, 45, 46]. Usually they are a small fraction of the total lipids present, and their isolation and exact identification/characterization are difficult and cumbersome.
The physiologic function of phosphonolipids is still unknown, and the suggested protecting role against predators resulting from their stability toward hydrolysis by lipases and phosphatases has not been proved so far. Moreover, the distribution and abundance of phosphonolipids among organisms vary with species, tissue, or cellular location. For example, vertebrates have sphingophosphonolipids as components of nervous tissue sphingomyelin, while invertebrates frequently contain high levels of these lipids as outer membrane components.
Whereas phosphate is a common modification of polysaccharides, there are only a few examples of polysaccharides containing phosphonate moieties. Their characterization/identification was made possible as well as substantially accelerated by the development of glycomics [47]. Ciliatine and compound
Similarly as in the case of phosphonolipids, the physiological role of phosphonoglycans is not known and thus awaits determination. This might be important in the context that the glycans are essential molecules being well known to enable adaptive response to environmental changes [55]. The speculative roles of phosphonoglycans include cell-cell signaling or their action as phosphorus reservoirs in the environments of low phosphate concentration. The second assumption might be supported by the conservation of phosphonolipids at the expense of phosphodiesters in starved conditions by the oyster
It is also important to mention that the phosphonic analog of taurocholic acid was found in the gall bladders of cows [58]; however, this finding may require additional confirmation.
4. Low-molecular phosphonates metabolically related to ciliatine
Biosynthesis of phosphonates starts from rearrangement of phosphoenolpyruvate (compound
Low-molecular antibiotics such as fosfomycin (compound
Only one of them—
The separate class is aminophosphonate antibacterial antibiotics possessing an amino group in the gamma position in relation to the phosphonic functional group, namely fosmidomycin (compound
Fosmidomycin and its homologs are potent inhibitors of 1-deoxy-d-xylulose-5-phosphate reductoisomerase, an essential enzyme of the non-mevalonate pathway of isoprenoid biosynthesis being active against a broad range of enterobacteria, but not against Gram-positive organisms or anaerobes. More importantly, they are blocking the development of isoprenoids in the parasite apicoplast, and thus, structurally modified fosmidomycin derivatives are considered as promising antimalarial agents (for representative structure, see Figure 4) [68].
Two unusual placotylene A esters [69] of ciliatine (phosphoiodyn A, compound
5. Phosphonopeptide antibiotics
Half of the century after the discovery of ciliatine witnessed a slow progress in the isolation and identification of natural compounds containing the C—P bond with most of them being antibacterials. The majority of these compounds appeared to be peptides containing C-terminal phosphonic acids and mostly differ by their
Bialaphos (compound
The antibacterial activity of bialaphos is typical for all the phosphonopeptides. Peptide parts of these antibiotics usually function as a targeting unit. Thus, the peptides are efficiently transported through bacterial (or fungal) membranes and after hydrolysis release phosphonic acid, which exerts its toxic action by inhibiting parasite vital enzymes—in this case glutamine synthetase. This mechanism of action is shown schematically in Figure 6.
The following years brought the discovery of a family of antibiotics called rhizocticins (compounds
Dehydrophos (compound
Phosphonopeptides have very limited utility in human medicine because they are readily hydrolyzed in body fluids and released aminophosphonic acids that are not able to cross bacterial or fungal cell barriers and to exert antibiotic action. Additionally, they are being readily excreted through urine.
Published in 2015 work of Metcalf and van der Donk brought a significant breakthrough in studies on naturally occurring phosphonate antibiotics. By a clever combination of the mining of the genome of 10,000 of actinomycetes and selective labeling of phosphonate metabolites, they rediscovered a large number of old phosphonates and discovered 19 new compounds [24]. This opened a genetic approach in natural phosphonate chemistry and biochemistry, especially enabling the identification of metabolic pathways leading to this class of compounds. An important and instructive example here is an activation of gene cluster from
One of the examples of rediscovered compounds is fosfazinomycins A and B (compounds
The genetic approach also enabled the isolation and characterization of novel of
A separate group of phosphonic peptidomimetics is compounds denoted as K-26, K4, and I5B2 (compounds
6. Conclusions
Natural phosphonates might be considered as simple analogs of phosphate esters and/or carboxylic acids. The inherent stability of the C—P bond causes that they often display promising activities as enzyme inhibitors and therefore might be considered as drugs or agrochemicals. Moreover, the wide use of xenobiotics containing carbon-to-phosphorus bond has led to the spread of these compounds in the environment, which may result in their incorporation into variable metabolic pathways. All of this stimulate interest in these, still somewhat exotic, compounds. The development of 31P NMR and genomics supplemented by biochemical studies resulted in the development of new detection technologies, which enormously speed out the discovery of novel naturally occurring phosphonates, identification of their metabolic pathways (both biosynthesis and degradation), and their use as lead compounds for the design of new promising medicines. With the exception of the identification of antibacterial and antifungal antibiotics, these studies are not accompanied, however, with the determination of physiologic importance of these compounds.
Acknowledgments
This work was supported by statuary grants of Wrocław University of Science and Technology and National Science Centre, Poland (grant 2016/21/B/ST5/00115).
Conflict of interest
I declare that there is no conflict of interest that might have any bearing on research reported in this work.
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