Some characteristics and carcinogenic classification for PAHs.
\r\n\t
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Polycyclic aromatic hydrocarbons (PAHs) comprise a large variety of organic compounds whose main characteristic is that they are formed by the fusion of benzene rings [1]. PAHs are originated mainly from incomplete pyrolysis of organic materials. Pyrolysis is the process in which organic compounds such as fuels undergo a change in the molecular structure at high temperature without sufficient oxygen concentration. These reactions are mainly dependent on temperature and concentration and are generally endothermic [2].
During combustion at high temperatures and relatively low amounts of oxygen, part of the combustible material is fragmented into small molecular masses, usually to free radicals by pyrolysis (approximately 500–800°C), which recombine to give rise to the PAHs by pyrosynthesis by decreasing the temperature. Once PAH of low molecular weight is formed, (e.g., naphthalene, 128) the pyrosynthesis process continues with “zigzag additions,” which generates high molecular weight PAH [3].
PAHs are categorized as low molecular weight (LMW) and high molecular weight (HMW) based on molecular structure. The LMW PAHs include two and three rings structure while HMW PAHs comprise four and more rings structure. The carcinogenicity of PAHs increased with increasing molecular weight [4].
PAHs are ubiquitous pollutants in the atmosphere. The behavior of PAHs in the atmosphere depends on complex physicochemical reactions, interactions with other pollutants, photochemical transformations, and dry and wet deposition. PAHs in the ambient air exist in vapor phase or adsorb into airborne particulate matter depending on the atmospheric conditions (ambient temperature, relative humidity, etc.), the nature (i.e., origin and properties) of the aerosol, and the properties of the individual PAH [5]. The physicochemical properties of PAHs make them highly mobile in the environment, allowing them to distribute across air, soil, and water bodies where their presence is ubiquitous. PAHs are widely distributed in the atmosphere. The PAHs entering the atmosphere can be transported over long distances before deposition through atmospheric precipitation onto soils, vegetation or water [5].
The adsorption of PAHs onto particulate phases can also be affected by the humidity. Moreover, PAH adsorption also depends on the types of suspended particulates (e.g., soot, dust, fly ash, pyrogenic metal oxides, pollens, etc.) and the amounts of dust in the air influence PAH concentrations in the particulate phase [5].
PAHs are known to be toxic and carcinogenic [6]. They are metabolized in the body through oxidation by P450 enzymes and may produce carcinogenic metabolites. These metabolites have been shown to induce lung and skin tumors in animals [7]. People can be exposed through polluted air from urban or industrial environments, tobacco smoke, and diet [6]. The carcinogenicity of the PAHs usually increases with increased number of aromatic rings and higher molecular weight, while low molecular weight PAHs are more acute toxic [7]. Many hundreds of PAHs exist in the environment, but the US Environmental Protection Agency (USEPA) has listed 16 as “Consent Decree” priority pollutants chosen because, because of the likelier risk to be exposed to them, the high amount of information about them, and that they are believed to be more harmful [7] (Table 1).
Some characteristics and carcinogenic classification for PAHs.
The partition of PAHs between gas and particulate phases in the atmosphere fundamentally depends on the vapor pressure, temperature, atmospheric pressure, and the concentration [8, 9]. PAHs having two rings exist in the gas phase, PAHs having three and four rings are in both phases and PAHs having five rings or more exist in the particle phase [10].
The standard methods to measure PAHs in ambient air are active samplers, and these equipment use a pump to draw the air into the sampler, through the filter and the following adsorbent.
The samplers have a sampling module which often consists of two compartments: a filter and a solid adsorbent to collect the particle associated and the gas phase pollutants, respectively. The filter, often teflon, glass or quartz fiber, is placed in the inlet of the sampler [11, 12, 13, 14, 15]. The solid adsorbent normally consists of a polyurethane foam (PUF) plug or a sorbent tube with XAD-2 or Tenax depending on the target pollutants and the capacity required; the adsorbent also retains pollutants that volatilize from the particles on the filter during sampling.
The other alternative is passive samplers, in contrast to active samplers, not in need of a pump and electricity to collect pollutants. Instead, the collection is based on a free flow of pollutants from the air to the collecting medium. Most of the existing passive samplers are designed for gas sampling of semi-volatile organic compounds and based on high capacity sampling against a linear sampling rate for long durations such as weeks or months. Polyurethane (SPMDs), XAD-resin based samplers and membrane samplers are such examples [16, 17, 18].
In conclusion, sampling equipment can be active or passive, must be compatible and consistent with the analysis method and the monitoring objectives.
Given the complexity of environmental matrices, specialized analytical procedures are required for the determination of PAHs. The analytical procedures must include different stages for extraction of compounds from complex samples, purification and detection techniques for multicomponent mixtures that consist of compounds with a wide range of molecular weights, volatilities and polarities.
The extraction of PAHs from airborne particulates is mainly done through methods based on the use of solvents [19]. Being soxleth and ultrasound techniques the most commonly used for extracting soluble organic matter [20]. Subsequently, other solvent-based methods have been developed, accelerated solvent extraction and microwave extraction, both methods have the characteristics that use less solvent and extraction time [21, 22]. Finally, solid phase microextraction (SPME) was adapted for the extraction of PAHs associated with airborne particles, specifically for those of low molecular weight (less than four rings). The main characteristic of this method is that it uses very small amounts of solvents compared to the other extraction techniques mentioned [23]. Table 2 shows a summary of the main techniques for the extraction of organic compounds from environmental matrices, some characteristics and applications.
Techniques | Characteristics | Analytes | References |
---|---|---|---|
Soxhlet | It has been so far applied for organic compound extraction from solid matrices due to its high extraction efficiency | PAHs, polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), among others | [29, 30, 31] |
Ultrasound assisted extraction (UAE) | Ultrasound energy has also been widely used for the leaching of organic and inorganic compounds from solid matrices | Pharmaceutical Endocrine disruptor compounds (EDCs), perfluorochemicals (PFCs), antibiotics, tetrabromobisphenol-A (TBBPA) PAHs, phthalate esters (PEs), PCBs, nonylphenols (NPs), nonylphenol ethoxylates (NPEOs) and pharmaceuticals and personal care products | [32, 33, 34, 35] |
Pressurized liquid extraction (PLE) | Pressure is applied to allow the use of extraction solvents or mixtures at temperatures higher than their normal boiling point. The increase on the extraction temperature can promote higher analyte solubility by increasing both solubility and mass transfer rate | Perfluorinated acids (PFAs), perfluorosulfonates (PFSs) and perfluoroctanesulfonamide PAHs | [36, 37] |
Microwave-assisted extraction (MAE) | Microwave-assisted extraction (MAE) uses microwave energy to heat the sample-solvent mixture. This technique reduces the extraction times and the extractant amount for the extraction of organic compounds from solid matrices | PAHs in airborne particles, 17-estradiol (E2), estriol (E3), 17-ethinyl estradiol (EE2) | [38, 39] |
Supercritical fluid extraction (SFE) | Supercritical fluid extraction is an alternative extraction method with the advantages of reduced solvent consumption and extraction time compared with the classical extraction techniques. Carbon dioxide is commonly used as fluid and methanol is added as organic modifier when polar compounds are extracted | PAHs in marine sediment | [40, 41] |
Solid Phase Microextraction (SPME) | It is used specifically for the extraction of low molecular weight organic compounds, from liquid, air and solid matrix | PAHs or polybrominated biphenyls (PBBs) | [42] |
Classification of the main extraction techniques, characteristics and applications.
PAHs extracts from airborne particulate matter represent a very complex matrix in trace amounts, which contain saturated hydrocarbons, nitrogen, oxygen, and sulfur heterocompounds, among others, what difficult the identification of the PAHs identification in environmental samples [24, 25, 26]. After liquid extraction, a cleanup procedure is recommended to eliminate some interferences that can affect the PAHs detection in the chromatographic analysis. The most common cleanup procedures are as follows: liquid-liquid extraction (LLE) and solid phase extraction (SPE) with silica gel and/or C18 cartridges [27, 28].
Traditionally, the analysis of PAHs in environmental samples has been carried out by gas chromatography (GC), rather than liquid chromatography (LC), and this is due to its greater selectivity, resolution and sensitivity. GC-MS is one of the most powerful analytical tools available for the chemical analysis of complex mixtures. The use of mass spectrometry enhances the capabilities of gas chromatography; the specific information provided in the mass spectrum makes the mass spectrometer a highly selective detector that can be used for qualitative analysis and structural determination.
Mass spectrometry is undoubtedly one of the most widely used for the analysis and characterization of chemical compounds due to its high sensitivity and resolution capacity. Then, when it is coupled to the chromatographic techniques, it is particularly useful in the identification and quantification of organic substances of interest, which are in trace concentrations in environmental samples, it is highly valued mainly for its high sensitivity, that is, it is feasible to quantify those substances contained in a sample quantity of the order of mg.
One of the main disadvantages of mass spectrometry is the conditions used for the generation of stable ionized species and their adequate detection. This process can be a limitation to clearly observe the molecular ion and, therefore, perform a detailed analysis of the chemical structure. In the literature, a significant number of ionization methods have been reported, which depend on the physicochemical properties of the system in question. However, ionization is not the only limitation in mass technique; there are previous problems such as the distinction of different structures when analyzing complex mixtures. Therefore, the use of chromatography as a separation technique is essential for environmental samples such as those obtained in the ambient air, while after the ionization is the analyzer that is where the ionized species are separated and detected, they are also of great importance for analysis.
The criteria considered the most relevant in mass spectrometry are as follows: sensitivity, resolution, stability and selectivity; that depending on the level we need to reach each one of these, there are several types of coupled mass spectrometry equipment arrangements, so their choice depends mainly on the different chemical systems and the scope of the analysis. In the case of air samples such as gases and respirable suspended particles, the unambiguous quantification and identification of the analyte are the main objectives; therefore, the standardization and prior validation of the method used are essential, so it is necessary to carry out several preliminary tests with specific equipment arrangements in order to achieve reliable results.
The mass spectrometer is among the most sensitive chromatographic detectors, having a detection limit below the picogram level, through the use of selected ion monitoring (SIM) mode. PAHs are easily resolved using standard GC columns without a requirement for derivatization. Most separations can be achieved in less than 30 min using capillary columns such as 30 m × 0.25 mm i.d. and 0.25 μm film thickness, 5% phenyl polysiloxane type phases. The use of a narrow bore, thin film column allows an increase in chromatographic resolving power, coupled with a reduction in analysis time.
GC-MS method has been used to all or some subset of the US Environmental Protection Agency (US-EPA) 16 priority PAHs. Single quadrupole GC-MS has offered the opportunity to increase selectivity for these analytes over that of classical detectors, such as UV and fluorescence detectors in high pressure liquid chromatography (HPLC) and electron capture detector (ECD) and flame ionization detector (FID) detectors in GC. This has allowed for limited optimization of sample preparation procedures to increase time to result [43, 44].
Quadrupole mass analyzers are widely used in many areas of environmental analysis. Although popularly referred to as quadrupole mass spectrometers, the mass-resolving properties of such devices are really much more similar to those of a tunable variable hand pass mass filter. Only ions within a narrow mass region (generally <1 amu) are allowed to pass through the device.
Quadrupole mass analyzers have several advantages such as no requirement for very high vacuum (>10–7 Torr) and their relatively fast and simple operation for high-throughput analysis. Disadvantages include low transmittance, a low m/z cutoff, and low (generally unit) resolution. Electron impact (EI) is well established and is the most common method of ionization in gas chromatography (GC) [45]. The molecules exiting the gas chromatograph are bombarded by an electron beam (70 eV), which removes an electron from the molecule resulting in a charged ion.
EI mode produces single charged molecular ions and fragment ions, which are used for structure elucidation.
The generated mass spectrum plots the signal intensity at a given m/z ratio (Figure 1).
Mass spectrum for methanol obtained by electronic impact [47].
Mass spectrometric methods are particularly suited for analysis of PAHs, because these compounds are semi-volatile and occur as complex mixtures; electron ionization (EI) and chemical ionization (CI) with quadrupole or magnetic sector mass spectrometers have been effectively used to determine PAHs. Although distinguishing between the isomeric forms of PAHs using EI is difficult because the isomers tend to produce common intermediates that give identical losses upon high-energy ionization or collisional activation [46].
For example, when trying to distinguish between compounds with the same or similar molecular weight, the GC-MS coupling is difficult, given its low resolution, Figures 2 and 3 show the separation of chrysene and triphenylene and mass spectrum respectively. The quantification of chrysene is often biased due to its coelution with triphenylene (the compounds with m/z 228 also contain fragments of m/z 226). Another case is the separation of the isomers of benzo(b, k, j)fluoranthene (252 m/z).
Examples for PAHs separations with similar molecular weight [47].
Mass spectrum for chrysene and triphenylene [47].
As seen in the previous examples, the mass spectrum with a single quadrupole is limited to distinguish among compounds that have structural isomers, since it only considers a single identification criterion, in fact they show a similar mass to charge fragmentation patterns (Figure 4). Recently, the coupling gas chromatography coupled to triple quadrupole mass spectrometry (GC-QqQ) was developed. Comparing triple quadrupole analyzer (QqQ) with single quadrupole analyzer, the product ion is more specific than the ion in the simple MS spectrum because the tandem configuration offers the only alternative of selecting the precursor ion of each compound by the first quadrupole and filtering it into the collision cell, with the consequent elimination of the remaining fragments and consequently the decrease in noise (Figure 5). Then that mass to charge pattern obtained by the second spectrometer, which is derived from the collision of the parent fragment, this usually has a unique pattern mass to charge daughter that provides invaluable structural information of the substance, which decreases the probability of false positives and facilitates the unequivocal identification of the target compound. It is clear that the coupling substantially solves the difficulties of simple couplings and can significantly improve the reliability of the determination by offering lower noise levels and additional identification criteria. Several reports show the utility of different arrays of mass spectrometers coupled to gas and liquid chromatographs used for the PAHs and their derivatives analysis. Among the most used is the triple quadrupole GC–MS/MS system, which provides detection and quantification levels equivalent to parts per trillion.
Triple quadrupole mass analyzer (QqQ) [49].
Chromatogram 14 PAHs by GC-QqQ (own authorship).
For instance, the unequivocal identification of B(b)F and B(k)F isomers (Figure 6) was successfully achieved by distinct transitions mass to charge obtained with triple quadrupolar mass spectrometer arrange (Figure 7). It means QqQ may provide more accurate quantification and confirmation in trace analysis with complex matrix [48].
Mass to charge (m/z) transitions (a) and (b).
Scheme of the gas chromatography bidimensional (GC × GC): peaks eluting from the first dimension column enter the second dimension column through the modulator [60].
For these characteristics, recently the GC-QqQ has been proposed for the quantification of the PAHs and its derivatives. Its characteristics have proved to be useful for example in the determination of nitro-PAHs in PM10 particles obtained with low sample volume (16.7 lpm). This implies a lower mass of the compound per gram of particle collected per day, and without an exhaustive treatment and sample purification need as those that are followed for particles obtained from high volume samplers (1.3 m3/h). An analytical method was recently developed for the simultaneous determination of 14 nitro-PAHs (2-nitrofluorene, 9-nitroanthracene, 9-nitrophenanthrene, 3-nitrophenanthrene, 2-nitroanthracene, 3-nitrofluoranthene, 1-nitropyrene, 2,7-dinitrofluorene, 7-nitrobenzo [a]anthracene, 6-nitrochrysene, 1,3-dinitropyrene, 1,8-dinitropyrene, 1,6-dinitropyrene, and 6-nitrobenzo[a]pyrene) in PM10 by GC-QqQ in multiple reaction monitoring (MRM) mode. The method performance evaluation showed that the technique is quite reliable, since it provides high repeatability with relative standard deviation <10% and with detection limits between 0.25 and 10 ng/mL. This was also facilitated its application to only half of the filter containing the sample, in this way the remaining part served to complement the chemical characterization of the sample [50]. In the MRM mode, as the name implies, in the first quadrupole (Q1) one or multiple precursor ions of the analyzed substance were are filtered, which react by fragmenting in the collision cell (Q2), until arriving at the second quadrupole (Q3), where the ions product of the quantification and qualification are filtered. The results of this type of analysis are highly specific and sensitive because they provide unique structural information of the molecule that leads to its identification and unambiguous distinction between other substances contained in the sample [50].
Gas chromatography with tandem mass spectrometry has also been successfully applied for the determination of precursor PAHs. Although they are found in environmental levels between one and two orders of magnitude higher than their derivatives, they are trace concentrations substances, which are similarly affected by the different interferences that may come in the samples and by the matrix effect in the extracts. Therefore, the organic extract must be purified before its analysis by GC-MS [51]. However, it was shown that when samples obtained with high volume equipment are analyzed, the extraction is sufficient, and the purification of the extract can be dispensed with before its analysis by GC-MS/MS [52].
Another coupling proposed for the analysis of the nitro-PAHs and oxy-PAHs derivatives is the ultrahigh pressure liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometer (UHPLC-(+)-APCI-MS/MS). In addition to the stated advantage of the tandem arrangement, this alternative technique aims to contribute to reducing the thermal degradation that has been consistently reported for those oxy-PAHs classified as quinones in the injection port of the GC. Thus, facilitating their simultaneous analysis with the nitro-PAHs, and taking advantage of the improvements in the sensitivity and selectivity in the determination in organic and aqueous extracts obtained from PM2.5 and PM10 particles. It has also been found that chemical ionization at atmospheric pressure (APCI), and photoionization at atmospheric pressure provides high ionization efficiency for oxy-PAHs, while electrospray ionization efficiency is usually lower [53]. In a pioneering study, it was shown that liquid chromatography atmospheric pressure chemical ionization-tandem mass spectrometer (LC-APCI-MS/MS) is feasible for the determination of oxy-PAHs and can contribute to the simplification of sample preparation by reducing it to an extraction and evaporation step [54]. Consistently, in a study of the simultaneous analysis of 5 nitro-PAHs—1-nitropyrene (1-NPYR), 2-nitrofluorene (2-NFLU), 3-nitrofluoranthene (3-NFLUANTH), 9-nitroanthracene (9-NANTH), 1,5-dinitronaphthalene (1,5-DNNAPHT)—, 3 oxy-PAHs-2-fluorenecarboxaldehyde (2-FLUCHO), and 5,12-naphthacenequinone (5,12-NAPHTONA), it showed that the LC/MS arrangement provides a high degree of sensitivity and selectivity for the determination of these substances. In fact, it was demonstrated that it allowed the feasibility of its application to real samples. However, it was only possible to reliably report environmental levels of four of eight of these substances, at atmospheric concentrations between 0.01 and 240.62 ng/m3, equivalent to 0.3 and 30 mg/g, respectively [56] (Table 3).
Location | Compounds | Equipment | Ionization mode | References |
---|---|---|---|---|
Industrial area of Taranto, Italy | Nitro-PAHs in airborne, PM10 | GC/MS triple quadrupole | EI+ | [48] |
Seoul, Korea | PAHs in PM2.5 airborne particles | GC-GC-TOFMS | ESI+, APPI+ | [55] |
Buenos Aires, Argentina | Oxy-PAHs and nitro-PAHs airborne, PM2.5 and PM10 | UHPL-MS/MS triple quadrupole | APCI+ | [53] |
Zaragoza, Spain | PAH associated to the airborne particulate matter, PM10 | GC/MS triple quadrupole | EI+ | [51] |
Application of the GC/MS coupling for the analysis of PAH and its derivatives.
The widespread use of capillary columns in the 1980s improved significantly the separation power of complex mixtures. This positioned gas chromatography as the technique of choice whenever analyzing volatile substances. However, it soon became clear that in some fields, the separation capacity offered by a single chromatographic column was not sufficient. For example, in the case of the oil industry, environmental applications or aroma analysis, whose separations are highly complex, often result in a chromatogram with a large portion of unresolved components [57]. Mass spectrometry can be used to resolve some of the complexity, but large concentration differences and structural isomers can complicate the spectral interpretation and data analysis. Some chromatographic resolution can be improved with an efficient, long, narrow bore, thin-film capillary column, but increased analysis time and decreased sample loading. This situation has been improved with the implementation of multidimensional gas chromatography (GC × GC). Multidimensional gas chromatography increases resolution by using two separate columns with two different stationary phases. One form of GC × GC is heart-cutting. After a preliminary evaluation of the sample, a portion of the unresolved GC effluent is reoriented to a different column before detection. Heart-cutting is a simple way to obtain a better separation of a complex mixture but just a portion of the one-dimensional separation can be improved with the second-dimension column. A high-frequency modulator is utilized by the comprehensive two-dimensional gas chromatography (GC × GC) for diverting the whole one-dimensional effluent onto a second-dimension column [58, 59] (Figure 7).
For instance, phenanthrene and anthracene are two important PAHs that can be used in order to assess whether material is petrogenic or pyrogenic in origin. Selecting mass 178 which is the molecular mass of the PAHs in question using the software allows isolated assessment (Figure 8).
Example of the application of the GC × GC for the separation and identification of structural isomers [61].
As seen in the GC × GC, saving time in sample preparation, instrumental analysis, has the ability to analyze an extensive range of complex samples with the simultaneous target and nontarget detection, which makes it a powerful technique for the elucidation of complex matrices; however, it is expensive.
PAHs are one of the families of organic compounds associated with the airborne particles that have generated the most concern. Currently, there is evidence of the multiple impacts that these compounds have on human health and the environment. The exposure time to which humans are exposed, the concentration levels of PAHs in the air, as well as the phase in which they occur; that is to say gas or particle, and the size of the particles with which they are associated. All these parameters must be measured and determined by the appropriate methods of sampling, extraction, and analysis. In the last 20 years, analytical methodologies and equipment development have experienced significant advances; all this has allowed the advance of more selective and less destructive extraction procedures; in the same way, the purification methods of complex samples have been improved, but perhaps where greater progress has been made, has been in the instrumental analysis by coupling online extraction procedures, use of different detectors and the implementation of specialized software.
The main feature in the evolution of sampling systems has been the reduction of artifacts, through the use of adequate adsorption materials, as well as the mechanisms of PAHs uptake for both the gaseous and particulate phases. Regarding the extraction process, the greatest progress has been made in the reduction in the amount of solvents, compared with the traditional system (Soxleth). To reduce the multiple interferences of the extracts obtained from the airborne particles and to increase the sensitivity in the detection of the PAHs, several purification schemes have been implemented based mainly on the use of solid phase extraction cartridges. Finally, the chromatographic techniques are those that have experienced the greatest advances, starting with the GC–MS coupling. However, this configuration does not allow to distinguish between compounds that have structural isomers. What caused the coupling of several quadrupoles (QqQ) in the same equipment, thus increasing the resolution. Finally, the inclusion of two-dimensional chromatography GC × GC has allowed the simultaneous identification of compounds of different polarities, placing it as a powerful technique in the characterization of complex samples such as environmental samples.
There is no doubt the advance in the technology used for the analysis of PAHs in airborne particle matter in recent years. However, these new technologies require a high initial investment, in addition to highly qualified personnel, for this reason, before making the decision to acquire any of these new technologies, many aspects must be analyzed, for example if the equipment is going to be used for routine analysis, if the analytes to be studied can be extracted and detected with a simpler system, etc.
The authors wish to thank PRODEP (Program for the Development of Teachers), for the support in the financing of this publication.
The authors declare no conflict of interest.
In eukaryotic cells, intracellular protein degradation is mainly regulated by the ubiquitin-proteasome system, where abnormal and unwanted proteins are targeted by polyubiquitin, which is produced from monoubiquitin by ubiquitin-activating enzyme (E1) and ubiquitin-conjugating enzyme (E2) [1]. The proteins that conjugated polyubiquitin by ubiquitin ligase (E3) are finally targeted to the 26S proteasome [2]. However, there is accumulating evidence that ubiquitin-independent proteasomal protein degradation pathway exists in the cells [3, 4]. Although ubiquitin-dependent proteasomal protein degradation is carried out normally by 26S proteasome, there are many reports that ubiquitin-independent proteasomal protein degradations are executed by the only 20S proteasome without the energy of ATP hydrolysis [4]. Among others, some ubiquitin-independent degradation pathways are known to be carried out using not the 20S but the 26S proteasome with the energy of ATP hydrolysis. In this chapter, we introduce ubiquitin-independent proteasomal degradation pathway mediated by polyamine regulating protein, “antizyme.”
\nPolyamines are highly charged bioactive substances presented ubiquitously in species from bacteria to human. Polyamines are necessary for cell growth and are involved in highly diversified cellular functions such as cell division, apoptosis, autophagy, oxidative stress, and ion channel activity. There are three major polyamines, putrescine, spermidine, and spermine, in the cells [5, 6]. Intracellular polyamine concentration is highly regulated by the protein “antizyme” [7, 8, 9, 10] that is widely distributed from yeast to human [11]. Antizyme (AZ) is induced in response to the increased concentration of intracellular polyamines through the polyamine-induced translational frameshifting mechanism [12]. AZ mRNA consists of two ORFs (ORF1 and ORF2). In the low polyamine concentration, translation of ORF1 is terminated at stop codon “UGA” of ORF1, and short product is produced (Figure 1). But in the increasing cellular polyamine concentration, reading frame shifts +1 direction at the end of ORF1 (Figure 1 bottom column). In this case, following ORF1, ORF2 is translated and full length active product “antizyme” is produced [12, 13]. The induced AZ protein binds to ornithine decarboxylase (ODC) monomer, a key enzyme in polyamine biosynthesis, and catalyzes the conversion from ornithine to putrescine and inhibits its activity. AZ-bound ODC is targeted to the 26S proteasome for degradation without ubiquitination (Figure 1) [14]. AZ also suppresses polyamine uptake by inhibiting membrane polyamine transporter (Figure 1) [15, 16]. Thus, AZ provides the negative feedback regulation of cellular polyamines. In addition, AZ is regulated by the protein, antizyme inhibitor (AZIN), that is homologous to ODC and can bind to AZ with higher affinity than ODC but lacking the enzymatic activity [17, 18].
\nNegative feedback regulation of cellular polyamine by antizyme. Three cis-acting elements, UGA stop codon, upstream stimulator, and pseudoknot structure, are known to be important for +1 frameshifting (bottom column). Putrescine, spermidine, and spermine are major polyamines in the mammalian cell. Putrescine synthesized from ornithine by ODC could be metabolized to spermidine and spermine in the cells. PAT is a polyamine transporter that uptakes polyamines from outside of the cells.
In mammals, cells express three members of AZ protein family, AZ1–3 (Table 1) [19]. AZ1 and AZ2 are distributed ubiquitously in most of the tissues, whereas AZ3 is testis specific [20, 21, 22]. Both AZ1 and AZ2 bind to ODC and accelerate its degradation in the cells [9, 23], but AZ3 has no activity for acceleration of ODC degradation [24]. The rate of ODC degradation by AZ1 is faster than that by AZ2 [23, 25]. Polyamine (putrescine) concentration of AZ1 knockdown cells is markedly increased, compared to that of AZ2 knockdown and control cells [26]. Therefore, it is thought that AZ1 mainly regulates cellular polyamine concentration. On the other hand, although AZ2 is highly homologous to AZ1 [25], it is considered that AZ2 is not a backup of AZ1 because of some differences between each other. AZ2 was found as one of the genes upregulated in neuronal cells by the drug that induces seizure [27]. Nucleic acid sequence of AZ2 is evolutionally conserved higher than that of AZ1 [11]. AZ2 is localized mainly in the nucleus [26] and is phosphorylated in the cells [28]. We will mention about AZ2 specific function with its interacting protein that we found very recently in this chapter.
\nCharacteristics of antizyme family.
It had been considered that ODC is the only protein degraded through AZ-mediated ubiquitin-independent proteasomal degradation system. However, recently several AZ1-interacting proteins other than ODC have been reported (Table 2). Although it has already been reported that those proteins are degraded by the ubiquitin-proteasome pathway, AZ1 could also accelerate those degradation without ubiquitination (Tables 1 and 2, Figure 1). Smad1, which is involved in bone morphogenetic protein (BMP) signaling pathway [29, 30], is the first reported protein that interacts AZ1 other than ODC [31]. In this case, newly synthesized HsN3, which is β-subunit for 20S proteasome, forms ternary complex with AZ1 and smad1. This complex may bind to 20S proteasome, and next 19S complex is docked on 20S, and then smad1 is degraded by the 26S proteasome.
\nThe proteins degraded by antizyme-mediated ubiquitin-independent proteasomal pathway.
Newman et al. reported that AZ1 has the ability to accelerate the degradation of cyclin D1, one of the cell cycle regulatory protein families [32]. Cyclin D1 interacts with cyclin-dependent kinase (CDK), and accumulation of cyclin D1-CDK complex is important for cell cycle progression [33]. This protein is already known to be degraded by ubiquitin-proteasome pathway [34]. They demonstrated that AZ1 induction by polyamine or overexpression of AZ1 accelerates cyclin D1 degradation, and knockdown of AZ1 suppresses it. Furthermore, in vitro experiment using purified cyclin D1, AZ1, and rabbit reticulocyte extracts as a source of 26S proteasome, AZ1 accelerated cyclin D1 degradation in a ATP-dependent manner. AZ1 could also degrade ubiquitin-deficient mutant of cyclin D1 in the cells [32]. In vitro size distribution analysis for binding between AZ1, cyclin D1, and ODC suggested that binding sites of AZ1 for cyclin D1 and ODC do not overlap each other, and cyclin D1 binds to the N-terminus of AZ1 and ODC binds at the C-terminus, respectively. Binding affinity of AZ1 to cyclin D1 is fourfold lower than that to ODC [35]. Although physiological significance is not clear, it showed that those three proteins form cyclin D1-AZ1-ODC ternary complex.
\nThe oncogene Aurora A encodes a protein kinase that exerts essential roles in mitotic events and is important for induction of centrosome amplification [36]. Overexpression of Aurora A in many cancers induces aneuploidy, centrosome anomaly, poor prognosis, and invasiveness [37, 38]. Aurora A is ubiquitinated by the E3 ubiquitin (Ub) ligase, anaphase-promoting complex/cyclosome (APC/C) that is activated by both cell-division cycle protein 20 (Cdc20) and Cdh1, substrate-recognition subunit of APC/C, and is degraded by the proteasome [39, 40]. However, Lim and Gopalan demonstrated that AZ1 could accelerate Aurora A degradation with ubiquitin-independent manner, where Aurora A kinase-interacting protein 1 (AURKAIP1), a negative regulator of Aurora A, enhances the binding of AZ1 to Aurora A and facilitates the recognition of Aurora A by the proteasome [41].
\nMps1 is protein kinase required for centrosome duplication in regulating the spindle assembly checkpoint [42, 43]. Accumulation of Mps1 at the centrosome causes aberrant centriole assembly [44, 45]. In fact in various tumor cells, centrosomal Mps1 pool is increased, which causes abnormal centrosome duplication [44]. Thus degradation of Mps1 is important for proper pool of Mps1 at the centrosome. Although degradation of Mps1 is known to be mediated by the proteasome, amino acid residue 420–507 of the human Mps1 that is sufficient for its degradation does not contain APC/C recognition motifs, suggesting the commitment of Mps1 to ubiquitin-independent proteasomal degradation [45]. Kasbek et al. reported that AZ1 localizes to the centrosomes and binds to Mps1 to control the levels of centrosomal Mps1 by accelerating the degradation of Mps1 [46]. Fluorescent microscopy analysis showed that centrosomal Mps1 level is dependent on AZ1 expression, overexpression of AZ1 decreases the centrosome Mps1 level, and conversely, AZ1 knockdown by siRNA increases that. Furthermore, deletion of degradation signal of Mps1 abolished the regulation of centrosomal Mps1 level by AZ1. In addition, overexpressing AZIN in the cells to trap AZ1 and inhibit its function increased centrosomal Mps1 level. Thus the balance of AZ1 and Mps1 level in the centrosome is important for the centrosome duplication process.
\nP73 is a homolog of p53 and exists as two major forms, TAp73 or Delta-N (DN) p73. TAp73 is full-length form and exerts proapoptotic function, whereas DNp73, which is amino-terminal transactivation domain lacking the form of p73, exhibits dominant-negative inhibitor activity for both p73 and p53, resulting in antiapoptotic properties [47]. Therefore, in the stress condition like DNA damage, reduction of DNp73 level is needed to execute apoptosis [48, 49, 50]. It is known that degradation of both TAp73 and DNp73 is mediated by E3-ubiquitin ligase Itch in a proteasome-dependent manner in normal condition [51]. However, in Itch-decreased condition such as DNA damage by UV irradiation, stabilization of TAp73 was observed, but DNp73 was not [51]. Therefore, it was considered that the degradation of TAp73 and DNp73 is regulated by different mechanisms. Dulloo et al. reported that reduction of DNp73 in the stress condition is due to the degradation of DNp73 by AZ1-mediated ubiquitin-independent proteasomal pathway [52]. They showed that degradation of DNp73 could be induced by genotoxic stresses such as UV irradiation and doxorubicin treatment. Inhibition of ubiquitin-activating enzyme E1 by the inhibitor PYR41 could not block DNp73 degradation, indicating that it relies on ubiquitin-independent pathway. They demonstrated that polyamine induced AZ1 to bind to DNp73 for accelerating its degradation. Interestingly, AZ1-mediated DNp73 degradation is dependent on transcription factor c-Jun that is activated by stress signals. Overexpression and knocking down of AZ1 also showed that even in the presence of c-Jun, AZ1 is necessary for genotoxic stress to induce DNp73 degradation. Although it is not clear how c-Jun operates AZ1 expression, c-Jun may act upstream of polyamine biosynthesis pathway.
\nThus, several proteins degraded by AZ1-mediated proteasome pathway are found, but AZ2-interacting protein or AZ2-mediated proteasomal degradation other than ODC has not been reported. We recently found two AZ2-interacting proteins, and one of the two was the protein that accelerated its proteasomal degradation by AZ2 without ubiquitination (see next section).
\nAs mentioned above, AZ2 also binds to ODC and accelerates its degradation in the cells [9]. However, we have considered that AZ2 has specific function other than AZ1 because of the differences such as nuclear localization [26, 28], highly gene conservation between species [20], and high expression in neuronal cells [53]. We performed comprehensive analysis of AZ2-interacting protein using two-hybrid technique. Two AZ2-interacting proteins were identified. One is ATP citrate lyase (ACLY), which is the enzyme catalyzing acetyl-CoA production in cytosol [54] and related to lipid anabolism and acetylation of cellular components [55]. We found that ACLY binds not only to AZ2 but also to AZ1 by immunoprecipitation assay [56]. Degradation assay for ACLY was performed in expectation of ubiquitin-independent proteasomal degradation. However, AZs have no ability to accelerate ACLY degradation. Surprisingly, AZ1 and AZ2 activate catalytic activity of ACLY [56]. The other is proto-oncogene c-Myc that is a transcription factor with a basic region/helix–loop–helix/leucine zipper domain and forms heterodimer with Max for DNA binding [57, 58]. c-Myc functions as a master regulator of a variety of cellular processes such as cell growth, differentiation, survival, and apoptosis [58]. In cell growth, c-Myc targets ODC gene [59] and promotes synthesis of polyamine that is important for stabilization of nucleic acids, transcription, translation, and +1 frameshifting on AZ mRNA [6].
\nIt is known that degradation of c-Myc is mediated by ubiquitin-proteasome pathway, where c-Myc is phosphorylated at Thr-58 (pT58) and Ser-62 (pS62) by extracellular signal-regulated kinase, ERK, and glycogen synthase kinase 3β, GSK-3β, respectively [60, 61]. After dephosphorylation at Ser-62 by protein phosphatase 2A, PP2A, pT58-c-Myc is ubiquitinated by E3-ubiquitin ligase Fbxw7 for proteasomal degradation [60, 62]. At first, AZ2-interacting protein identified by the comprehensive analysis mentioned above was not c-Myc but a protein that has basic region/helix–loop–helix/leucine zipper domain and interacts with c-Myc (Murai et al., manuscript in preparation). However, in the process of analyzing the interaction with AZ2, we found that AZ2 interacts with c-Myc in the cells by immunoprecipitation assay. Subcellular localization analysis of both proteins using fluorescent protein tags or antibody conjugated fluorescent probe revealed that AZ2 co-localized with c-Myc in the nucleus. Treatment of proteasome inhibitor MG132 changes the nuclear co-localization of both proteins to nucleolar co-localization [26]. Overexpression of AZ2 or addition of polyamine in the cells accelerated c-Myc degradation, and knockdown of AZ2 with siRNA suppressed it. Furthermore, E1 inhibitor PYR-41 could not suppress AZ2-mediated proteasomal c-Myc degradation [26]. These results suggest that AZ2-mediated ubiquitin-independent nucleolar c-Myc degradation pathway other than ubiquitin-dependent one exists in the cells (Figure 2).
\nAZ2-mediated c-MYC degradation in the nucleolus. Two distinct c-Myc degradation pathways exist in the cells. It is thought that AZ2 pathway functions under the stress condition (polyamine increased condition) such as glucose-free and hypoxia.
In this chapter, antizyme-mediated ubiquitin-independent proteasomal degradation has been discussed. All the proteins mentioned above are already known as the proteins degraded by ubiquitin-proteasomal pathway. It is not clear how antizyme-mediated ubiquitin-independent degradation of these proteins is physiologically significant. Normally subcellular localization of ODC is mainly in the cytoplasm and at least not in the nucleolus even in the presence of MG132. In addition, ODC is necessary for cell growth, and the affinity of interaction between antizyme and ODC is high [63]; in such condition, ODC probably occupies almost all antizymes in the cytosol, and antizymes hardly function for other antizyme-interacting proteins [64]. In this context, because subcellular localization of both AZ2 and its interacting protein c-Myc is in the nucleus or nucleolus, cytosolic protein ODC could not interact with AZ2 there. ODC is one of the c-Myc-targeting proteins, and AZ2 may function upstream of c-Myc especially under the stress condition such as glucose free and hypoxic condition [26]. Further studies are needed to elucidate the significance of antizyme-proteasome degradation pathway.
\nThis research was supported by the Jikei University Graduate Research Fund and JSPS KAKENHI Grant Number JP 19K08283.
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