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Free-radical and biochemical reactions involving polar part of glycerophospholipids
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Review Article
Free-radical and biochemical reactions involving polar part of glycerophospholipids Oleg Shadyroa,b,∗, Svetlana Samovicha,b, Irina Edimechevab a b
Department of Chemistry of the Belarusian State University, Nezavisimosti av., 4, 220030, Minsk, Belarus Research Institute for Physical and Chemical Problems of the Belarusian State University, Leningradskaya st., 14, 220050, Minsk, Belarus
ARTICLE INFO
ABSTRACT
Keywords: Glycerophospholipids Free-radical fragmentation Phospholipases Inhibitors
The review summarizes and critically discusses data on biochemical and free-radical transformations of glycerophospholipids. The results presented therein demonstrate that hydroxyl-containing glycerophospholipids, such as cardiolipin, lyso-lipids and others, can undergo fragmentation upon interaction with radical agents forming the biologically active products. Hydrolysis of glycerophospholipids catalyzed by different phospholipases was shown to yield compounds, which can be involved in the free-radical fragmentation leading to significant changes in structures of original lipids.
1. Introduction Glycerophospholipids (GPL) have a multitude of functions in living systems [1–3]. As major components of biological membranes, GPL have a strong influence on membrane stability and permeability [4]. Furthermore, they play an important role in signal induction, ion transport and substances trafficking [5]. Such variety of biological functions support constant scientific interest towards investigating the properties of lipids and their functions on molecular, cellular and organismal level, shared by researchers from virtually all life sciences, including medicine. Each category of researchers has its own approach to studying lipid properties in both model systems and in organisms functioning under various conditions. In many cases, the data obtained using such methods are mutually complementary and provide a significant insights into lipid-mediated processes. GPL are amphiphilic substances, with a polar component consisting of a glycerol and a phosphate moiety [1–3]. The lipophilic part contains residues of unsaturated carboxylic acids, which are perfect substrates for free-radical oxidation due to the presence of double C]C bonds. Lipid peroxidation (LPO) reactions can be initiated by both internal and external factors [1,6,7]. As a rule, the role of initiator is played by reactive oxygen species (ROS). The primary oxidation products include various hydroperoxides being formed according to scheme 1. If ROS mediating the process (1) are formed in the course of biochemical reactions catalyzed by various oxidases, such lipid oxidation is considered to be of a biochemical type. Chemical (non-enzymatic) oxidation of lipids is initiated by external (e.g., UV-, γ-irradiation) or
∗
internal (e.g., Fenton-like reactions) initiators. However, both mechanisms share the same reaction steps, although the probabilities of their realization might be different. Besides the process (1) hydroperoxides are also formed in reactions catalyzed by lipoxygenases. The substrates for these reactions are generally unsaturated carboxylic acids, for instance, arachidonic acid [8]. The hydroperoxide group may be formed at various positions, as it is indicated in scheme (2). It has been shown that lipoxygenases can also catalyze oxidation of GPL [9]. Along with hydroperoxides, the oxidation processes of GPL are accompanied by accumulation of endo-peroxides (cyclic peroxides), which upon decomposition, form products of oxidative destruction, such as low-molecular species, the malonic dialdehyde and some others [1,10,11]. The oxidation of unsaturated acids with more than two double bounds catalyzed by cyclooxygenase results in formation of cyclic peroxides, which can generate a variety of oxidized products containing five-member ring (e.g. eicosanoids). Both biochemical and non-enzymatic reactions of lipids oxidation require oxygen. The oxygen level varies in different organs, cells and their organelles [12] that affects the oxidation processes. Intriguingly, molecular oxygen is one of the most important variables in modern cell culture systems. Fluctuations in its concentration affect culture growth, differentiation, signaling, and free-radical production [13]. Regarding the polar component of lipids, the biochemistry of its hydrolytic cleavage has been explored by numerous studies [14–20], with the principal role assigned to phospholipase-catalyzed reactions leading to cleavage of various ester bonds according to Fig. 1:
Corresponding author. Department of Chemistry of the Belarusian State University, Nezavisimosti av., 4, 220030, Minsk, Belarus. E-mail address: [email protected] (O. Shadyro).
https://doi.org/10.1016/j.freeradbiomed.2019.02.033 Received 27 December 2018; Received in revised form 20 February 2019; Accepted 28 February 2019 0891-5849/ © 2019 Elsevier Inc. All rights reserved.
Please cite this article as: Oleg Shadyro, Svetlana Samovich and Irina Edimecheva, Free Radical Biology and Medicine, https://doi.org/10.1016/j.freeradbiomed.2019.02.033
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Scheme 1. Free-radical lipid peroxidation.
Scheme 2. Lipoxygenase-catalyzed lipid peroxidation.
Fig. 1. Biochemical hydrolysis of phospholipids.
Such phospholipase-mediated reactions result in a number of products containing hydroxyl group(s) crucial for further free-radical driven fragmentation (see further in the text). Interaction of ROS with polar components of phospholipids was the subject of our studies for the past 25 years. We have found that the polar part of completely esterified lipids, such as phosphatidylcholine (PC), phosphatidylehanolamine (PE) or phosphatidylserine (PS), are relatively stable towards the action of radical agents [21–23], while hydroxyl-containing GPL (phosphatidylglycerol (PG), phosphatidylinositol (PI), lyso-lipids and cardiolipin (CL)) undergo •OH-induced decomposition accompanied by formation of various molecular products without oxygen involvement [21–26]. This review is summarizing the interrelations between biochemical and free-radical reactions of GPL polar components.
including several cytosolic and secreted PLA2 isoforms. Here, we will not discuss specific features of different PLA2 types, although they are certainly very interesting and important for the consequences of the reactions they catalyze. Reviews on PLA2 enzymes can be found elsewhere [14,15,18,27–29]. We will rather address the principal issue of this paper, which is PLA2-dependent formation of lyso-lipids, as shown in scheme (3): The major substrate for PLA2 is PC, which is cleaved in the reaction (3) to give unsaturated acids and lyso-phosphatidylcholine (lyso-PC). If arachidonic acid is released during these processes, it is subsequently involved in an important cycle of reactions leading to formation of eicosanoids [15,30]. Another product of the PLA2 hydrolysis is lyso-PC, the lipid with a variety of biological activity [31–33]. Lyso-phospholipids have negative effects on the stability of biomembranes. At low concentrations, they induce membrane fusion and regulate activity of certain membrane proteins. At high concentrations, they can act as detergents, damaging membrane proteins and lipids organization. The properties of lyso-lipids are described in details elsewhere [34,35]. Our studies [21,22] have shown that the interaction of ROS with
2. Free-radical fragmentation of products formed in phospholipase A2 and phospholipase A1 catalyzed reactions Phospholipase A2 (PLA2) represents a large family of enzymes 2
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Scheme 3. PLA2-dependent formation of lyso-lipids.
Scheme 4. Free-radical fragmentation of lyso-lipids forming in PLA2-catalyzed reactions.
lyso-lipids can cause their fragmentation leading to the accumulation of phosphocholine and 2-oxopropyl palmitate according to scheme (4). The yield of phosphocholine was shown to be higher than that of 2oxopropyl palmitate, apparently because the latter is initially formed as a radical product (reaction 4) which could be consumed in various reactions [21,22]. To prove the mechanism of the reaction (4), special precursors of lyso-lipids C-2 radicals were synthesized, enabling selective generation of the named intermediates and studying their properties [36]. Using this approach, it was found that the C-2-radicals of lyso-PC were unstable and underwent fragmentation. The reaction involving precursors of the glyceride C-2 radicals occurred as shown in scheme (5): A detailed study of lyso-PC C-2 radical properties was presented in paper [36]. The fragmentation of lyso-PC C-2 radicals was shown to proceed via a cyclic transition state with a high rate constant of ∼107 s−1. Thus, PLA2 is a significant enzyme for biochemistry of phospholipids. It catalyzes the formation of lyso-phospholipids, which are substrates in the ROS-induced free-radical fragmentation reaction. The physiological significance of these two processes is yet to be elucidated.
The data presented above demonstrate that lyso-lipids are capable of undergoing fragmentation according to a free-radical mechanism, with 2-oxopropyl palmitate being one of the main products (5). It's hard to think of other way to form these compounds. Such reaction could occur with other lyso-lipids containing various fatty acid residues, leading to formation of 2-oxopropyl fatty acids derivates. Taking into account the fact that the PLA2-catalyzed reaction mainly results in the accumulation of lyso-lipids, whereas our data demonstrated the freeradical formation of 2-oxopropyl palmitate from lyso-PC, the interrelation between the activity of PLA2 and the content of 2-oxopropyl fatty acids derivates in a biological system can be proposed. Hence, 2oxopropyl fatty acids derivates could potentially serve as biomarkers for the activity of PLA2. The role of Ca2+ cations in biochemical reactions catalyzed by PLA2 is of special interest. Calcium ions are critical factors activating PLA2 [29,37]. On the other hand, cytocolic Ca2+ is the most important second messenger regulating virtually all cell functions in eukaryotes [38–40]. Increase in cytosolic concentration of free Ca2+ lead to ROS production via activation of NADPH oxidase, a major ROS generating enzyme in different animal and plant systems [41]. In our studies, we
Scheme 5. Free-radical fragmentation of lyso-PC precursor. 3
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Scheme 6. PLA1-dependent formation of lyso-lipids.
have shown that calcium ions can inhibit the fragmentation of hydroxyl-containing lipids due to the interaction with negatively charged phosphate groups, inhibiting formation of the cyclic transition state necessary for decomposition of C-2 radicals [42]. The phospholipase A1 (PLA1) catalyzed reactions of phospholipids also give hydroxyl-containing products according to scheme (6): PLA1 is an active component of snake venom having hemolytic effects and plays an important role in lipid exchange in living organisms [15,20,43]. While studying free-radical transformations of α-diol esters, the possibility of realization of the following reaction has been demonstrated [44] (scheme (7)). Elimination of acids according to (7) occurred very effectively, since the rate constant for decomposition of HOC%HCH2OCOR was measured to be ∼105 s−1 [44]. This indirectly points to the possibility for the PLA1-catalyzed reaction products to undergo the fragmentation according to a free-radical mechanism, as shown in scheme (8): In reaction (8) the abstraction of fatty acid occurs from the second position in glycerol backbone of PC, which is usually occupied by unsaturated fatty acids [1,3]. Therefore, the reaction (8) could be an additional source of unsaturated fatty acids formed from GPL.
4. Phospholipase D and free-radical transformations of glycerophospholipids Phospholipase D (PLD) catalyzes hydrolysis of PC to phosphatidic acid (PA) [15,16,19,52]. PLD can use other lipids as substrates, including cardiolipin (CL) [52]. The reaction of such type proceeds according to scheme (11): Other PLD activities have been described, including catalysis of trans-phosphorylation reactions, in which short chain primary alcohols are transferred on GPL polar groups to generate phosphatidylalcohols. For example, the addition of ethanol to cell cultures led to the formation of phosphatidylethanol [53]. Still PA remains the main metabolite of biochemical reactions catalyzed by PLD. PA is a critical metabolite for heart membrane phospholipid biosynthesis [54]. PA also serves as a critical lipid second messenger both in animals and plants regulating several proteins implicated in the control of cell cycle progression and cell growth [55,56]. We have discovered a free-radical pathway for PA formation [21,22,24,57–59]. It has been found that interaction of ROS with PG results in accumulation of PA and hydroxyacetone according to scheme (12): Free-radical transformations of PG demonstrated that PA yield was significantly lower in the presence of oxygen due to the oxidation of αhydroxyl-containing carbon-centered radicals of the starting compound [24,57,59]. PA yields were also found to decrease in the presence of Ca2+, which interacted with negatively charged phosphate groups of the original lipid [42]. PG containing unsaturated fatty acid residues and free hydroxyl groups underwent both peroxidation and fragmentation, when its aqueous dispersions were treated with ionizing radiation, as it was shown in Refs. [24,57,59]. γ-Radiolysis of multilamellar liposomes led to the formation of peroxidation products, as well as PA and hydroxyacetone – fragmentation products of the initial lipid, according to Fig. 2. Comparable radiation-chemical yields of conjugated-diene products and PA indicated approximately equal probability of oxidation and fragmentation processes in this case. In our further experiments, free-radical transformations of lipids were initiated in various ways (γ-irradiation, redox systems), and analysis of the final products was carried out using MALDI-TOF-MS [23–26,58,59]. The starting compounds were PG, PI, PC and PE. It has been shown that reaction of •OH with polar components of GPL containing an OH-group at β-position to the phosphoester bond resulted in free-radical destruction due to the formation and fragmentation of C-2 radicals via rupture of β-CeO and OeH bonds. Therefore, PI containing polyol residues in its hydrophilic part, underwent the free-radical destruction to form PA [24,58] and desoxyketoinosityl radicals (scheme (13)). PI is an important substrate for obtaining phosphatidylinositol-3-
3. Free-radical fragmentation of products formed in phospholipase C-catalyzed reactions Phosphatidylinositol diphosphate is the main substrate for phospholipase C (PLC), which catalyzes its hydrolysis to inositol triphosphate (IP3) and diacylglyceride (DAG) [15,17] (scheme (9)). The substances formed in the reaction (9) play an important role as second messengers [45–47]. IP3 activates calcium channels in the endoplasmic reticulum, causing elevation of cytosolic free Ca2+ [48]. Together with Ca2+, DAG activates protein kinase C [49]. Hydrolysis of DAG results in monoacylglycerol and unsaturated fatty acid (usually arachidonic), which is a precursor of eicosanoids. The products being formed in PLC-catalyzed processes contain hydroxyl groups in their structures, and therefore can enter into the ROS-induced fragmentation reactions. Decomposition of DAG in such case can occur according to a reaction similar to (8). Furthermore, compounds such as IP3 were shown to undergo ROSinduced dephosphorylation as depicted in scheme (10). Homolytic dephosphorylation of polyols according to the reaction (10) proceeds effectively, since the rate constant value for decomposition of C-2 radicals of glycerol-1-phosphate is extremely high (∼107 s−1) [50,51]. Using glycerol-1-phosphate as example, it was demonstrated that yield of inorganic phosphate was equal to the amount of •OH that reacted with the substrate [21]. Hence, elevated level of ROS in living systems can trigger free-radical transformation of IP3, leading to its dephosphorylation and modifying its signaling properties.
Scheme 7. Free-radical fragmentation of α-diol esters. 4
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Scheme 8. Free-radical fragmentation of lyso-lipids forming in PLA1-catalyzed reactions.
Scheme 9. PLC-catalyzed hydrolysis of phosphatidylinositol diphosphate.
Scheme 10. Free-radical dephosphorylation of glycerol-1-phosphate.
Scheme 11. PLD-catalyzed formation of PA.
phosphate (PI3P), which functions as a signaling molecule in the biological systems [60]. Hence, the free-radical fragmentation of PI according to (13) should decrease the level of PI3P involved in biochemical reactions. Free-radical transformations of PC and PE did not result in PA formation [21–23], demonstrating inability of polar components of these lipids to undergo fragmentation in response to ROS. Free-radical fragmentation was found to be characteristic of CL, which belongs to polyphospholipids [24,26,58,59,61] and is the main component of mitochondrial membranes [62]. CL is a unique lipid having four fatty acid residues and two phosphate groups. Radiolysis of CL resulted in its fragmentation involving rupture of phosphoester bond and led to the formation of PA and a radical
intermediate reduced to phosphatidylhydroxyacetone (PGA), as identified by MALDI-TOF-MS [26,59,61] (scheme (14)). Reactions of CL performed in both model membranes and mouse liver mitochondria with Cu2+(Fe2+)/H2O2- or Cu2+(Fe2+)/H2O2/ascorbate-containing systems led to the formation of the same fragmentation products [26,59,61,63]. It has been confirmed [24] that the freeradical decomposition of CL occurred with higher probability than those of PI or PG (Table 1) due to the presence of two phosphate groups at β-position to hydroxyl-containing carbon-centered radicals of the starting phospholipid. Thus, the fragmentation of α-hydroxyl-containing carbon-centered radicals via cleavage of two β-bonds in the polar part of lipid is characteristic of hydroxyl-containing GLP. Destruction of such lipids results
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Scheme 12. Free-radical fragmentation of PG.
Fig. 2. Free-radical processes of phosphatidylglycerol peroxidation and fragmentation.
in PA formation. Considering that PA can be formed via biochemical reactions catalyzed by PLD, the PGA originating exclusively from the reaction (14), might serve as a marker of PA formation due to freeradical decomposition of CL. Establishing a new pathway for decomposition of GLP and formation of PA appears to be relevant for understanding the role of these compounds in cellular metabolism.
5. Inhibitors of free-radical and biochemical processes occurring in polar part of glycerophospholipids One of the common methods to inhibit free-radical transformations of various organic substances is application of antioxidants (AOs), capable of reducing oxygen-centered radicals to more stable products [1,64]. The general scheme (15) for inhibition processes looks like this: There is a large number of natural and synthetic AOs inhibiting the 6
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Scheme 13. Free-radical fragmentation of PI.
Scheme 14. Free-radical fragmentation of CL.
Quinones readily oxidize hydroxyl-containing carbon-centered radicals, thereby blocking their fragmentation. So, quinones of various structures were found to suppress formation of PA during free-radical transformations of GLP [65]. Further studies showed that apart from quinone-type substances some other naturally occurring compounds (having in their structures a carbonyl group conjugated with one or more C]C bonds) are also capable of inhibiting the free-radical-induced fragmentation. The following reactions (Scheme 17) occur in this case:
Table 1 Radiation-chemical yields of phosphatidic acid formed as a product of γ-irradiation of deaerated aqueous dispersions of liposomes from phospholipids (0.02 mol/l). Initial compounds
Radiation-chemical yields of phosphatidic acid (G) × 107, mol/J
References
PG PI CL PC
1,31 ± 0,06 1,95 ± 0,13 2,20 ± 0,17 no detected
[24] [24] [24] [21]
oxidation according to the scheme shown above [1,64]. Our studies [65–73] have demonstrated that quinones can efficiently inhibit the free-radical fragmentation processes. In this case, the following reactions (Scheme 16) take place:
Scheme 15. Inhibition of lipid peroxidation.
Scheme 16. Inhibition of free-radical-induced fragmentation of organic compounds by quinones. 7
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Scheme 17. Inhibition of free-radical fragmentation of organic compounds by substances having a conjugated carbonyl group.
Fig. 3. Structures of phospholipase A2 inhibitors.
The structural units mentioned above are present in a large number of natural compounds, such as flavonoids, curcuminoids, phenylpropanoids, group B vitamins, ascorbic acid, etc. The radical-inhibiting properties of these compounds are described in details [69,74–83]. Taking into account importance and prevalence of the reactions catalyzed by PLA2, various concepts have been developed to perform the search for regulating agents of PLA2 activity [15,18]. Here, we focus only on substances that can simultaneously target both biochemical reactions involving PLA2 and free-radical fragmentation processes of lyso-lipids. As mentioned above, Ca2+ activates PLA2 and affects the free-radical decomposition of lyso-lipids. This suggests that the chelating agents, such as EDTA, can regulate the lipid fragmentation. In some conditions, the rate of PLA2-catalyzed hydrolysis of phospholipids that have undergone peroxidation increased significantly [84]. Therefore, AOs, such as quercetin, rutin, rosmarinic acid (Fig. 3) normally decrease the PLA2 activity [85–89] because since they delay the lipid oxidation processes. At the same time, oxidants might provoke an increase of PLA2 activity via an oxidation of the original substrate (see Schemes 16 and 17). The interest towards PLD inhibitors is determined mainly by their potential pharmacological activities as an antitumor drug. It has been found that some PLD inhibitors have carbonyl groups, nitrogen-containing heterocycles and halogens in their structures [15,90,91]. It was shown [65,72] that these substances can inhibit free-radical fragmentation processes of hydroxyl-containing lipids, including CL. Searching substances capable of inhibiting both PLD-dependent reactions and
free-radical fragmentation processes resulting in formation of PA can be very helpful in identifying the compounds with a potential for the development of anti-tumor drugs. 6. Conclusion The data discussed here provide evidence for the involvement of polar components of glycerophospholipids in both biochemical and non-enzymatic ROS-induced fragmentations. The presence of hydroxyl groups in the structures of glycerophospholipids is necessary for their free-radical destruction resulting in the synthesis of biologically active products. The biochemical hydrolytic cleavage of glycerophospholipids yields products that serve as starting substrates for the subsequent freeradical-mediated fragmentation. It appears to be of importance to assess the biological consequences of such processes. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.freeradbiomed.2019.02.033. References [1] B. Halliwell, J.M.C. Gutteridge, Free Radicals in Biology and Medicine, fifth ed., Oxford Univ. Press, New York, 2015. [2] H. Lodish, A. Berk, S.L. Zipursky, P. Matsudaira, D. Baltimore, J. Darnell, Molecular Cell Biology, fourth ed., W.H. Freeman, New York, 2000.
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Review Article
Free-radical and biochemical reactions involving polar part of glycerophospholipids Oleg Shadyroa,b,∗, Svetlana Samovicha,b, Irina Edimechevab a b
Department of Chemistry of the Belarusian State University, Nezavisimosti av., 4, 220030, Minsk, Belarus Research Institute for Physical and Chemical Problems of the Belarusian State University, Leningradskaya st., 14, 220050, Minsk, Belarus
ARTICLE INFO
ABSTRACT
Keywords: Glycerophospholipids Free-radical fragmentation Phospholipases Inhibitors
The review summarizes and critically discusses data on biochemical and free-radical transformations of glycerophospholipids. The results presented therein demonstrate that hydroxyl-containing glycerophospholipids, such as cardiolipin, lyso-lipids and others, can undergo fragmentation upon interaction with radical agents forming the biologically active products. Hydrolysis of glycerophospholipids catalyzed by different phospholipases was shown to yield compounds, which can be involved in the free-radical fragmentation leading to significant changes in structures of original lipids.
1. Introduction Glycerophospholipids (GPL) have a multitude of functions in living systems [1–3]. As major components of biological membranes, GPL have a strong influence on membrane stability and permeability [4]. Furthermore, they play an important role in signal induction, ion transport and substances trafficking [5]. Such variety of biological functions support constant scientific interest towards investigating the properties of lipids and their functions on molecular, cellular and organismal level, shared by researchers from virtually all life sciences, including medicine. Each category of researchers has its own approach to studying lipid properties in both model systems and in organisms functioning under various conditions. In many cases, the data obtained using such methods are mutually complementary and provide a significant insights into lipid-mediated processes. GPL are amphiphilic substances, with a polar component consisting of a glycerol and a phosphate moiety [1–3]. The lipophilic part contains residues of unsaturated carboxylic acids, which are perfect substrates for free-radical oxidation due to the presence of double C]C bonds. Lipid peroxidation (LPO) reactions can be initiated by both internal and external factors [1,6,7]. As a rule, the role of initiator is played by reactive oxygen species (ROS). The primary oxidation products include various hydroperoxides being formed according to scheme 1. If ROS mediating the process (1) are formed in the course of biochemical reactions catalyzed by various oxidases, such lipid oxidation is considered to be of a biochemical type. Chemical (non-enzymatic) oxidation of lipids is initiated by external (e.g., UV-, γ-irradiation) or
∗
internal (e.g., Fenton-like reactions) initiators. However, both mechanisms share the same reaction steps, although the probabilities of their realization might be different. Besides the process (1) hydroperoxides are also formed in reactions catalyzed by lipoxygenases. The substrates for these reactions are generally unsaturated carboxylic acids, for instance, arachidonic acid [8]. The hydroperoxide group may be formed at various positions, as it is indicated in scheme (2). It has been shown that lipoxygenases can also catalyze oxidation of GPL [9]. Along with hydroperoxides, the oxidation processes of GPL are accompanied by accumulation of endo-peroxides (cyclic peroxides), which upon decomposition, form products of oxidative destruction, such as low-molecular species, the malonic dialdehyde and some others [1,10,11]. The oxidation of unsaturated acids with more than two double bounds catalyzed by cyclooxygenase results in formation of cyclic peroxides, which can generate a variety of oxidized products containing five-member ring (e.g. eicosanoids). Both biochemical and non-enzymatic reactions of lipids oxidation require oxygen. The oxygen level varies in different organs, cells and their organelles [12] that affects the oxidation processes. Intriguingly, molecular oxygen is one of the most important variables in modern cell culture systems. Fluctuations in its concentration affect culture growth, differentiation, signaling, and free-radical production [13]. Regarding the polar component of lipids, the biochemistry of its hydrolytic cleavage has been explored by numerous studies [14–20], with the principal role assigned to phospholipase-catalyzed reactions leading to cleavage of various ester bonds according to Fig. 1:
Corresponding author. Department of Chemistry of the Belarusian State University, Nezavisimosti av., 4, 220030, Minsk, Belarus. E-mail address: [email protected] (O. Shadyro).
https://doi.org/10.1016/j.freeradbiomed.2019.02.033 Received 27 December 2018; Received in revised form 20 February 2019; Accepted 28 February 2019 0891-5849/ © 2019 Elsevier Inc. All rights reserved.
Please cite this article as: Oleg Shadyro, Svetlana Samovich and Irina Edimecheva, Free Radical Biology and Medicine, https://doi.org/10.1016/j.freeradbiomed.2019.02.033
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Scheme 1. Free-radical lipid peroxidation.
Scheme 2. Lipoxygenase-catalyzed lipid peroxidation.
Fig. 1. Biochemical hydrolysis of phospholipids.
Such phospholipase-mediated reactions result in a number of products containing hydroxyl group(s) crucial for further free-radical driven fragmentation (see further in the text). Interaction of ROS with polar components of phospholipids was the subject of our studies for the past 25 years. We have found that the polar part of completely esterified lipids, such as phosphatidylcholine (PC), phosphatidylehanolamine (PE) or phosphatidylserine (PS), are relatively stable towards the action of radical agents [21–23], while hydroxyl-containing GPL (phosphatidylglycerol (PG), phosphatidylinositol (PI), lyso-lipids and cardiolipin (CL)) undergo •OH-induced decomposition accompanied by formation of various molecular products without oxygen involvement [21–26]. This review is summarizing the interrelations between biochemical and free-radical reactions of GPL polar components.
including several cytosolic and secreted PLA2 isoforms. Here, we will not discuss specific features of different PLA2 types, although they are certainly very interesting and important for the consequences of the reactions they catalyze. Reviews on PLA2 enzymes can be found elsewhere [14,15,18,27–29]. We will rather address the principal issue of this paper, which is PLA2-dependent formation of lyso-lipids, as shown in scheme (3): The major substrate for PLA2 is PC, which is cleaved in the reaction (3) to give unsaturated acids and lyso-phosphatidylcholine (lyso-PC). If arachidonic acid is released during these processes, it is subsequently involved in an important cycle of reactions leading to formation of eicosanoids [15,30]. Another product of the PLA2 hydrolysis is lyso-PC, the lipid with a variety of biological activity [31–33]. Lyso-phospholipids have negative effects on the stability of biomembranes. At low concentrations, they induce membrane fusion and regulate activity of certain membrane proteins. At high concentrations, they can act as detergents, damaging membrane proteins and lipids organization. The properties of lyso-lipids are described in details elsewhere [34,35]. Our studies [21,22] have shown that the interaction of ROS with
2. Free-radical fragmentation of products formed in phospholipase A2 and phospholipase A1 catalyzed reactions Phospholipase A2 (PLA2) represents a large family of enzymes 2
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Scheme 3. PLA2-dependent formation of lyso-lipids.
Scheme 4. Free-radical fragmentation of lyso-lipids forming in PLA2-catalyzed reactions.
lyso-lipids can cause their fragmentation leading to the accumulation of phosphocholine and 2-oxopropyl palmitate according to scheme (4). The yield of phosphocholine was shown to be higher than that of 2oxopropyl palmitate, apparently because the latter is initially formed as a radical product (reaction 4) which could be consumed in various reactions [21,22]. To prove the mechanism of the reaction (4), special precursors of lyso-lipids C-2 radicals were synthesized, enabling selective generation of the named intermediates and studying their properties [36]. Using this approach, it was found that the C-2-radicals of lyso-PC were unstable and underwent fragmentation. The reaction involving precursors of the glyceride C-2 radicals occurred as shown in scheme (5): A detailed study of lyso-PC C-2 radical properties was presented in paper [36]. The fragmentation of lyso-PC C-2 radicals was shown to proceed via a cyclic transition state with a high rate constant of ∼107 s−1. Thus, PLA2 is a significant enzyme for biochemistry of phospholipids. It catalyzes the formation of lyso-phospholipids, which are substrates in the ROS-induced free-radical fragmentation reaction. The physiological significance of these two processes is yet to be elucidated.
The data presented above demonstrate that lyso-lipids are capable of undergoing fragmentation according to a free-radical mechanism, with 2-oxopropyl palmitate being one of the main products (5). It's hard to think of other way to form these compounds. Such reaction could occur with other lyso-lipids containing various fatty acid residues, leading to formation of 2-oxopropyl fatty acids derivates. Taking into account the fact that the PLA2-catalyzed reaction mainly results in the accumulation of lyso-lipids, whereas our data demonstrated the freeradical formation of 2-oxopropyl palmitate from lyso-PC, the interrelation between the activity of PLA2 and the content of 2-oxopropyl fatty acids derivates in a biological system can be proposed. Hence, 2oxopropyl fatty acids derivates could potentially serve as biomarkers for the activity of PLA2. The role of Ca2+ cations in biochemical reactions catalyzed by PLA2 is of special interest. Calcium ions are critical factors activating PLA2 [29,37]. On the other hand, cytocolic Ca2+ is the most important second messenger regulating virtually all cell functions in eukaryotes [38–40]. Increase in cytosolic concentration of free Ca2+ lead to ROS production via activation of NADPH oxidase, a major ROS generating enzyme in different animal and plant systems [41]. In our studies, we
Scheme 5. Free-radical fragmentation of lyso-PC precursor. 3
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Scheme 6. PLA1-dependent formation of lyso-lipids.
have shown that calcium ions can inhibit the fragmentation of hydroxyl-containing lipids due to the interaction with negatively charged phosphate groups, inhibiting formation of the cyclic transition state necessary for decomposition of C-2 radicals [42]. The phospholipase A1 (PLA1) catalyzed reactions of phospholipids also give hydroxyl-containing products according to scheme (6): PLA1 is an active component of snake venom having hemolytic effects and plays an important role in lipid exchange in living organisms [15,20,43]. While studying free-radical transformations of α-diol esters, the possibility of realization of the following reaction has been demonstrated [44] (scheme (7)). Elimination of acids according to (7) occurred very effectively, since the rate constant for decomposition of HOC%HCH2OCOR was measured to be ∼105 s−1 [44]. This indirectly points to the possibility for the PLA1-catalyzed reaction products to undergo the fragmentation according to a free-radical mechanism, as shown in scheme (8): In reaction (8) the abstraction of fatty acid occurs from the second position in glycerol backbone of PC, which is usually occupied by unsaturated fatty acids [1,3]. Therefore, the reaction (8) could be an additional source of unsaturated fatty acids formed from GPL.
4. Phospholipase D and free-radical transformations of glycerophospholipids Phospholipase D (PLD) catalyzes hydrolysis of PC to phosphatidic acid (PA) [15,16,19,52]. PLD can use other lipids as substrates, including cardiolipin (CL) [52]. The reaction of such type proceeds according to scheme (11): Other PLD activities have been described, including catalysis of trans-phosphorylation reactions, in which short chain primary alcohols are transferred on GPL polar groups to generate phosphatidylalcohols. For example, the addition of ethanol to cell cultures led to the formation of phosphatidylethanol [53]. Still PA remains the main metabolite of biochemical reactions catalyzed by PLD. PA is a critical metabolite for heart membrane phospholipid biosynthesis [54]. PA also serves as a critical lipid second messenger both in animals and plants regulating several proteins implicated in the control of cell cycle progression and cell growth [55,56]. We have discovered a free-radical pathway for PA formation [21,22,24,57–59]. It has been found that interaction of ROS with PG results in accumulation of PA and hydroxyacetone according to scheme (12): Free-radical transformations of PG demonstrated that PA yield was significantly lower in the presence of oxygen due to the oxidation of αhydroxyl-containing carbon-centered radicals of the starting compound [24,57,59]. PA yields were also found to decrease in the presence of Ca2+, which interacted with negatively charged phosphate groups of the original lipid [42]. PG containing unsaturated fatty acid residues and free hydroxyl groups underwent both peroxidation and fragmentation, when its aqueous dispersions were treated with ionizing radiation, as it was shown in Refs. [24,57,59]. γ-Radiolysis of multilamellar liposomes led to the formation of peroxidation products, as well as PA and hydroxyacetone – fragmentation products of the initial lipid, according to Fig. 2. Comparable radiation-chemical yields of conjugated-diene products and PA indicated approximately equal probability of oxidation and fragmentation processes in this case. In our further experiments, free-radical transformations of lipids were initiated in various ways (γ-irradiation, redox systems), and analysis of the final products was carried out using MALDI-TOF-MS [23–26,58,59]. The starting compounds were PG, PI, PC and PE. It has been shown that reaction of •OH with polar components of GPL containing an OH-group at β-position to the phosphoester bond resulted in free-radical destruction due to the formation and fragmentation of C-2 radicals via rupture of β-CeO and OeH bonds. Therefore, PI containing polyol residues in its hydrophilic part, underwent the free-radical destruction to form PA [24,58] and desoxyketoinosityl radicals (scheme (13)). PI is an important substrate for obtaining phosphatidylinositol-3-
3. Free-radical fragmentation of products formed in phospholipase C-catalyzed reactions Phosphatidylinositol diphosphate is the main substrate for phospholipase C (PLC), which catalyzes its hydrolysis to inositol triphosphate (IP3) and diacylglyceride (DAG) [15,17] (scheme (9)). The substances formed in the reaction (9) play an important role as second messengers [45–47]. IP3 activates calcium channels in the endoplasmic reticulum, causing elevation of cytosolic free Ca2+ [48]. Together with Ca2+, DAG activates protein kinase C [49]. Hydrolysis of DAG results in monoacylglycerol and unsaturated fatty acid (usually arachidonic), which is a precursor of eicosanoids. The products being formed in PLC-catalyzed processes contain hydroxyl groups in their structures, and therefore can enter into the ROS-induced fragmentation reactions. Decomposition of DAG in such case can occur according to a reaction similar to (8). Furthermore, compounds such as IP3 were shown to undergo ROSinduced dephosphorylation as depicted in scheme (10). Homolytic dephosphorylation of polyols according to the reaction (10) proceeds effectively, since the rate constant value for decomposition of C-2 radicals of glycerol-1-phosphate is extremely high (∼107 s−1) [50,51]. Using glycerol-1-phosphate as example, it was demonstrated that yield of inorganic phosphate was equal to the amount of •OH that reacted with the substrate [21]. Hence, elevated level of ROS in living systems can trigger free-radical transformation of IP3, leading to its dephosphorylation and modifying its signaling properties.
Scheme 7. Free-radical fragmentation of α-diol esters. 4
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Scheme 8. Free-radical fragmentation of lyso-lipids forming in PLA1-catalyzed reactions.
Scheme 9. PLC-catalyzed hydrolysis of phosphatidylinositol diphosphate.
Scheme 10. Free-radical dephosphorylation of glycerol-1-phosphate.
Scheme 11. PLD-catalyzed formation of PA.
phosphate (PI3P), which functions as a signaling molecule in the biological systems [60]. Hence, the free-radical fragmentation of PI according to (13) should decrease the level of PI3P involved in biochemical reactions. Free-radical transformations of PC and PE did not result in PA formation [21–23], demonstrating inability of polar components of these lipids to undergo fragmentation in response to ROS. Free-radical fragmentation was found to be characteristic of CL, which belongs to polyphospholipids [24,26,58,59,61] and is the main component of mitochondrial membranes [62]. CL is a unique lipid having four fatty acid residues and two phosphate groups. Radiolysis of CL resulted in its fragmentation involving rupture of phosphoester bond and led to the formation of PA and a radical
intermediate reduced to phosphatidylhydroxyacetone (PGA), as identified by MALDI-TOF-MS [26,59,61] (scheme (14)). Reactions of CL performed in both model membranes and mouse liver mitochondria with Cu2+(Fe2+)/H2O2- or Cu2+(Fe2+)/H2O2/ascorbate-containing systems led to the formation of the same fragmentation products [26,59,61,63]. It has been confirmed [24] that the freeradical decomposition of CL occurred with higher probability than those of PI or PG (Table 1) due to the presence of two phosphate groups at β-position to hydroxyl-containing carbon-centered radicals of the starting phospholipid. Thus, the fragmentation of α-hydroxyl-containing carbon-centered radicals via cleavage of two β-bonds in the polar part of lipid is characteristic of hydroxyl-containing GLP. Destruction of such lipids results
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Scheme 12. Free-radical fragmentation of PG.
Fig. 2. Free-radical processes of phosphatidylglycerol peroxidation and fragmentation.
in PA formation. Considering that PA can be formed via biochemical reactions catalyzed by PLD, the PGA originating exclusively from the reaction (14), might serve as a marker of PA formation due to freeradical decomposition of CL. Establishing a new pathway for decomposition of GLP and formation of PA appears to be relevant for understanding the role of these compounds in cellular metabolism.
5. Inhibitors of free-radical and biochemical processes occurring in polar part of glycerophospholipids One of the common methods to inhibit free-radical transformations of various organic substances is application of antioxidants (AOs), capable of reducing oxygen-centered radicals to more stable products [1,64]. The general scheme (15) for inhibition processes looks like this: There is a large number of natural and synthetic AOs inhibiting the 6
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Scheme 13. Free-radical fragmentation of PI.
Scheme 14. Free-radical fragmentation of CL.
Quinones readily oxidize hydroxyl-containing carbon-centered radicals, thereby blocking their fragmentation. So, quinones of various structures were found to suppress formation of PA during free-radical transformations of GLP [65]. Further studies showed that apart from quinone-type substances some other naturally occurring compounds (having in their structures a carbonyl group conjugated with one or more C]C bonds) are also capable of inhibiting the free-radical-induced fragmentation. The following reactions (Scheme 17) occur in this case:
Table 1 Radiation-chemical yields of phosphatidic acid formed as a product of γ-irradiation of deaerated aqueous dispersions of liposomes from phospholipids (0.02 mol/l). Initial compounds
Radiation-chemical yields of phosphatidic acid (G) × 107, mol/J
References
PG PI CL PC
1,31 ± 0,06 1,95 ± 0,13 2,20 ± 0,17 no detected
[24] [24] [24] [21]
oxidation according to the scheme shown above [1,64]. Our studies [65–73] have demonstrated that quinones can efficiently inhibit the free-radical fragmentation processes. In this case, the following reactions (Scheme 16) take place:
Scheme 15. Inhibition of lipid peroxidation.
Scheme 16. Inhibition of free-radical-induced fragmentation of organic compounds by quinones. 7
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Scheme 17. Inhibition of free-radical fragmentation of organic compounds by substances having a conjugated carbonyl group.
Fig. 3. Structures of phospholipase A2 inhibitors.
The structural units mentioned above are present in a large number of natural compounds, such as flavonoids, curcuminoids, phenylpropanoids, group B vitamins, ascorbic acid, etc. The radical-inhibiting properties of these compounds are described in details [69,74–83]. Taking into account importance and prevalence of the reactions catalyzed by PLA2, various concepts have been developed to perform the search for regulating agents of PLA2 activity [15,18]. Here, we focus only on substances that can simultaneously target both biochemical reactions involving PLA2 and free-radical fragmentation processes of lyso-lipids. As mentioned above, Ca2+ activates PLA2 and affects the free-radical decomposition of lyso-lipids. This suggests that the chelating agents, such as EDTA, can regulate the lipid fragmentation. In some conditions, the rate of PLA2-catalyzed hydrolysis of phospholipids that have undergone peroxidation increased significantly [84]. Therefore, AOs, such as quercetin, rutin, rosmarinic acid (Fig. 3) normally decrease the PLA2 activity [85–89] because since they delay the lipid oxidation processes. At the same time, oxidants might provoke an increase of PLA2 activity via an oxidation of the original substrate (see Schemes 16 and 17). The interest towards PLD inhibitors is determined mainly by their potential pharmacological activities as an antitumor drug. It has been found that some PLD inhibitors have carbonyl groups, nitrogen-containing heterocycles and halogens in their structures [15,90,91]. It was shown [65,72] that these substances can inhibit free-radical fragmentation processes of hydroxyl-containing lipids, including CL. Searching substances capable of inhibiting both PLD-dependent reactions and
free-radical fragmentation processes resulting in formation of PA can be very helpful in identifying the compounds with a potential for the development of anti-tumor drugs. 6. Conclusion The data discussed here provide evidence for the involvement of polar components of glycerophospholipids in both biochemical and non-enzymatic ROS-induced fragmentations. The presence of hydroxyl groups in the structures of glycerophospholipids is necessary for their free-radical destruction resulting in the synthesis of biologically active products. The biochemical hydrolytic cleavage of glycerophospholipids yields products that serve as starting substrates for the subsequent freeradical-mediated fragmentation. It appears to be of importance to assess the biological consequences of such processes. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.freeradbiomed.2019.02.033. References [1] B. Halliwell, J.M.C. Gutteridge, Free Radicals in Biology and Medicine, fifth ed., Oxford Univ. Press, New York, 2015. [2] H. Lodish, A. Berk, S.L. Zipursky, P. Matsudaira, D. Baltimore, J. Darnell, Molecular Cell Biology, fourth ed., W.H. Freeman, New York, 2000.
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