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Antioxidants -- Antioxidants Biochemistry -- Free Radical ScavengersAntioxidant enzymes -
For instance, one study with a male murine model of myocardial infarction induced by coronary ligation, OH. Besides, ROS generated in mitochondria is related to vascular complications in diabetes, especially cardiomyopathy [ 54 , 56 ].
According to new data, in male Wistar rats with induced diabetes, a significant increase of ROS and decrease of CAT activity has been recorded in the heart muscle [ 57 ]. Regarding mitochondrial ROS participation in vascular disease pathogenesis, targeting mitochondria and their oxidative balance may be a promising approach for vascular complications medication.
A protective system for free radical excess removal is generated during the evaluation, whereas all antioxidants represent an antioxidant defensive system [ 58 ]. Antioxidants are divided into two groups: enzymes, the primary line of antioxidative defense SOD, CAT, GPx, GR, GSH and non-enzymes, the secondary line of antioxidative defense vitamins E and C, albumin, thiols, β-carotenes, etc.
SOD2 stands up against mitochondrial ROS and can minimalize vascular calcification among VSMC [ 65 , 66 ]. In male and female patients with idiopathic pulmonary arterial hypertension, the expressions of all three SOD isoforms were reduced compared to the healthy patients [ 67 ].
Nevertheless, gene rs locus polymorphism of SOD3 in male and female patients is a risk factor for ischemic stroke [ 68 ]. The association between SODs activities and vascular diseases is imperative for developing a new diagnostic biomarker and therapy strategy.
Regulation of CAT implicates OxS-associated pathways and diverse transcription factors, for instance, nuclear factor Y NF-Y , peroxisome proliferator-activated receptor δ PPAR δ , specificity protein 1 Sp1 , etc. CAT protective role versus ROS is established, and according to some authors, reduction of CAT activity enhances abdominal aortic dilatation appearance [ 73 ].
Similarly, in experimental male rats, CAT reactivation by curcumin in the heart and aorta displays protective properties against lipopolysaccharide [ 75 ]. In addition, results from Dai et al.
Another intracellular antioxidant enzyme, GPx1, transforms H 2 O 2 to H 2 O and lipid peroxides to alcohols and plays a significant role in ROS prevention [ 77 ].
According to new data, GPx1 protein expression was significantly reduced in male mice aortic tissue with induced diabetes [ 80 ]. GR also manifests a protective feature against OxS, and its overexpression in heart tissue of a Klotho-hypomorphic antiaging gene deficient male mice resulted in heart failure and apoptotic prevention [ 81 ].
GSH has a significant part in the antioxidant defense system and cell homeostasis and metabolism. Nevertheless, GSH deficiency has an essential part of aging and cardiovascular pathology [ 82 ]. Although data from studies with experimental animal models advocate the protective role of antioxidants versus vascular disorders [ 83 — 86 ], data from clinical trials are not conclusive [ 56 , 87 ].
For example, vitamin A has been rated as a beneficial supplement that may reduce OxS in diabetic individuals with ischemic heart disease [ 88 ]. Melatonin supplementation may reduce myocardial ischemic-reperfusion injury in male and female patients undergoing coronary artery bypass [ 89 ].
Further, vitamins E, A, and C decrease blood pressure in male patients with hypertension [ 90 ]. Consistent with these statements, a new meta-analysis that included 11 cross-sectional studies and 7 case-control studies with both gender individuals concluded that vitamin C positively influences blood pressure and endothelial function [ 91 ].
Still, long-term trials with an extensive number of participants are necessary for clarification of vitamin C benefit role in cardiac complications [ 92 , 93 ].
A large randomization study indicated that vitamin E supplementation at high doses might even elevate the risk for coronary artery disease development [ 94 ]. Indeed, treatment with vitamin E for an extended time did not affect vascular events in male and female individuals with diabetes or other cardiovascular comorbidities [ 95 ].
Micronutrient selenium, which is considered a potent antioxidant, failed to reduce chronic chagasic cardiomyopathy in 66 male and female patients, according to a randomized, placebo-controlled, double-blinded clinical trial [ 96 ].
Ye et al. It cannot be denied that reducing OxS via antioxidants is important; however, up to now, the results of clinical studies have been predominantly pessimistic [ 98 ]. We assume that there are several reasons for this attitude.
Most of the clinical trials regarding vascular comorbidities have been examined a single antioxidant, so antioxidant combinations and their molecular basis might be discussed in future investigations [ 3 ]. Secondly, OxS should be identified through enzymes activity rather than produced molecules [ 98 ].
The impact of OxS is detrimental to human health, and numerous studies confirmed that high ROS production contributes to the initiation and progression of CVD [ 5 , 99 , ].
Thus, the antioxidant defense has an essential role in the homeostatic functioning of the vascular endothelial system, whereby antioxidant enzymes represent the primary line of antioxidant protection [ 4 , 59 ].
Numerous studies have proven the association between reduced expression and activity of antioxidant enzymes and CVD development [ 68 , 73 , 80 ].
Hence, additional research on how ROS is utilized in the cardiovascular system and consequently impacts the regulation of antioxidant enzymes is needed to develop new diagnostic biomarkers and therapeutic strategies.
JR and KB wrote the manuscript and contributed conception. ERI and MO designed, wrote, and supervised the manuscript. All authors contributed to manuscript revision, read and approved the submitted version. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Home Exploration of Medicine Articles Abstract Keywords Introduction Search strategy Antioxidant enzymes OxS and vascular diseases Role of antioxidant enzymes in vascular diseases Antioxidants on vascular diseases Conclusion Abbreviations Declarations References. See in References.
Abstract Reactive oxygen species ROS and reactive nitrogen species RNS play a fundamental role in regulating endothelial function and vascular tone in the physiological conditions of a vascular system. Keywords Reactive oxygen species, reactive nitrogen species, oxidative stress, antioxidant enzymes, vascular diseases.
Introduction Cardiovascular disease CVD is the leading cause of mortality and morbidity worldwide, including a wide array of disorders—cardiac muscle diseases and diseases of the vascular system supplying the heart, brain, and other vital organs [ 1 ].
Antioxidant enzymes In physiological conditions, enzymatic and non-enzymatic antioxidant systems maintain an equilibrium between the production and neutralization of ROS and RNS [ 11 ].
Superoxide-dismutases Superoxide-dismutase is a group of metalloenzymes that have a major antioxidant role in human health. CAT CAT exists as a tetramer enzyme that consists of four polypeptide chains with four ferriprotoporphyrin prosthetic groups per molecule [ 11 ].
GPx and GSH reductase GPxs are enzymes that catalyze the reduction of H 2 O 2 to water or hydroperoxides to corresponding alcohols using reduced GSH [ 30 ].
OxS and vascular diseases ROS have physiological and pathological implications in cardiovascular tissues [ 33 ]. Display full size. Role of antioxidant enzymes in vascular diseases A protective system for free radical excess removal is generated during the evaluation, whereas all antioxidants represent an antioxidant defensive system [ 58 ].
Antioxidants on vascular diseases Although data from studies with experimental animal models advocate the protective role of antioxidants versus vascular disorders [ 83 — 86 ], data from clinical trials are not conclusive [ 56 , 87 ].
Conclusion The impact of OxS is detrimental to human health, and numerous studies confirmed that high ROS production contributes to the initiation and progression of CVD [ 5 , 99 , ]. Declarations Author contributions JR and KB wrote the manuscript and contributed conception. Conflicts of interest The authors declare that they have no conflicts of interest.
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Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. The three major families of antioxidants that target H 2 O 2 are monofunctional catalase CAT , peroxiredoxin PRX , and glutathione peroxidase GPX Fig.
Of these, CAT that uses iron as its electron acceptor, and PRX that uses sulfur-based cysteine 32 , both represent some of the most evolutionary ancient antioxidant enzymes targeting H 2 O 2 ; both predate the great oxidation event GOE 7.
The third family, GPX that uses glutathione GSH as a reductant, has a more recent evolutionary origin, after the GOE 7. Both the PRX and GPX enzyme families have been further classified into multiple subfamilies, but because these subfamily classifications have been based largely on mammalian gene complements, their relevance to the rest of the animal kingdom is not clear.
Summary of reaction mechanisms for A : CAT, B : PRX, and C : GPX. In the first step of the reaction mechanism of all PRXs and CysGPXs, and GPX7, H 2 O 2 reacts with the peroxidatic cysteine C P to form a sulfenic acid SOH intermediate. Whilst in SecGPXs, a catalytic selenocysteine first reacts to form a selenic acid SeOH.
If a second, resolving cysteine C R is present i. PRX6 instead forms a disulfide with another molecule, commonly GST, and is then recycled by glutathione GSH , generating oxidised glutathione GSSG.
In SecGPXs the SeOH is similarly reduced by two GSH generating GSSG, whilst GPX7 is described to be reactivated via the ER protein disulfide isomerase PDI. For PRXs under high concentrations of H 2 O 2 , SOH reacts with another molecule of H 2 O 2 to form a sulfenic acid SO 2 H , resulting in hyperoxidation.
Enzymes within the subfamily, AhpC-PRX1 only may then be slowly re-activated via the enzyme sulfiredoxin SRX via the inactivation loop. D : Generalised domain structure for CAT, PRX, and GPX enzyme families. Stars denote presence of active site, His and Asn respectively.
All PRX enzymes comprise the domain, Alkyl hydroperoxide reductase-Thiol specific antioxidant AphC-TSA. C P red and C R blue conserved active site are displayed, residues in bold denote absolutely conserved, and underlined residues denotes amino acids that deviated from that displayed within more than one metazoan sequence.
GPX enzymes comprise a single GSHPx domain. GPX enzymes may encode either C P or a catalytic Sec S within the active site.
In this study, we conduct a comparative genomic assessment of these three major antioxidant enzyme families—CAT, PRX, and GPX—in 19 species, with high-quality genomes that span 10 metazoan phyla, from sponges to chordates.
In doing so, we provide the first assessment of these enzymes in sponges phylum Porifera , including four marine and one freshwater species of three different classes. Sponges evolved at least million years ago 33 and are widely considered to be the oldest of the extant animal phyletic lineages 34 , As probable sister to all other animal phyla, traits shared by sponges and the rest of animal kingdom can logically be traced back to the last common animal ancestor Thus, sponges can provide unique insight into the evolutionary history of these ancient enzymatic antioxidant families that play a critical role throughout the animal kingdom.
Our metazoan-wide survey has provided the most comprehensive analysis to date of gene number and phylogenetic distribution of three key antioxidant gene families across the animal kingdom.
Genes encoding all three families were observed in 18 metazoan species; the exception is the ctenophore Mnemiopsis leidyi that has PRX and GPX, but not CAT Table 1. Our findings demonstrate that the antioxidants CAT and PRX both are evolutionary ancient and highly conserved enzyme families Figs.
By comparison, the GPX family is less conserved, with total gene numbers and functional types varying considerably among metazoan species Table 1. Below we discuss our expanded analysis, detailing substantial gene conservation across evolutionary diverse bilaterian and non-bilaterian phyletic lineages, and for the first time reporting a suite of H 2 O 2 -targeting enzymatic antioxidants in the basal metazoan phylum Porifera the sponges.
Maximum likelihood phylogenetic tree of monofunctional CAT enzyme family. A : Unrooted tree displaying three main CAT clades indicated by branch colour: clade 1 dark grey , clade 2 light grey , clade 3 black.
Within clade 3 coloured shapes indicate identified evolutionary groups; Nematoda orange , Demospongiae blue , Invertebrate yellow , inner dashed line indicates bilaterian-invertebrate species only, and Vertebrata green.
B : Rooted phylogenetic tree using metazoan CAT protein sequences and the choanoflagellate M. brevicollis CAT as an outgroup. M denotes mitochondrial localised CAT sequences. queenslandic a and T. wilhelma denotes full length CAT gene sequences for these two species.
Labels coloured blue denote sequences encoded by phylum Porifera. Black numbers on branches indicate bootstrap support. Circles denote collapse tree nodes. Coloured shapes in B correspond to those displayed in A.
Branch lengths represent evolutionary distances, indicated by tree scale. The monofunctional i. The metazoan CATs comprise a relatively small family; most metazoans that we assessed encode just one full length CAT sequence, and the evolutionary divergence among them is relatively small compared with the PRX and GPX enzyme families Table 1 and Fig.
HMM scans, based on hidden Markov probabilistic models, across coding sequences from 19 metazoan species revealed a total of 56 unique protein sequences encoding at least one CAT-associated domain.
Filtering these after sequence alignment and protein structure reduced this number to 44 Fig. On this basis, we identified CAT protein sequences in 18 of the 19 metazoans; the exception was the ctenophore M. leidyi, that likely represents evidence of gene loss, given the ancient origins of the CAT family.
Of these, Clade 3 enzymes that use NADPH as cofactor are the most widely distributed—all 44 of the animal CAT enzymes we identified belong to Clade 3 and are distinct from the 15 non-metazoan sequences Fig.
Notably, there are relatively short evolutionary distances among genes within clade 3 compared to genes within the non-metazoan clades 1 and 2. This reflects the relatively recent diversification of metazoan CATs within the much older evolutionary history of this enzyme family Fig.
Phylogenetic assessment of 44 animal CATs reveals three well-supported clades. These are Vertebrata Fig. Our findings are consistent with 14 , 38 , but our expanded analysis provides additional evolutionary insight at the base of the metazoan CAT tree.
We show that CATs in the basal metazoan phyla Cnidaria and Porifera are evolutionarily distinct from the rest of the metazoan CATs, including those of the phylum Placozoa that sit within an otherwise bilaterian invertebrate clade Fig.
The exception to this is S. Also consistent with Zámocký et al. Of these, the nematode clade displays the greatest evolutionary divergence, and sits as sister to all other metazoans Fig.
Notably, observed evolutionary distances within CAT clade 3 are comparatively shorter than within the non-metazoan clades 1 and 2 Fig. Considering this and the evolutionary divergence of Nematoda, we hypothesise that diversification of CAT within metazoans is relatively recent compared to the long evolutionarily history of this enzyme.
Consistent with previous descriptions, we found that metazoan CATs from 14 species are predicted to localise to the peroxisome 20 sequences Fig.
However, 17 species have CAT enzymes that localise to multiple subcellular compartments. Overall, we most commonly predicted CATs sequences that localise to the cytoplasm 24 sequences , but also the mitochondria 2 sequences , nucleus, cell membrane and extracellular space Fig.
Moreover, we identified four species, Xestospongia bergquistia , Nematostella vectensis , Ciona intestinalis , and Branchiostoma floridae that do not have any peroxisomal CAT but instead encode a cytoplasmic CAT Fig.
That said, 9 of the 24 cytoplasm-localised sequences do encode a peroxisomal targeting signal, whilst 10 sequences encode a nuclear targeting signal Supplementary file 3.
The phylogenetic distribution of cytoplasmic- or peroxisomal-localised CATs has no obvious pattern. However, the two mitochondrial-localised sequences, found in Xenopus tropicalis Vertebrata and Sycon ciliatum Calcarea , are each the most divergent within their respective clades indicated on Fig.
It has been hypothesised that having multiple CATs localised to various subcellular compartments may confer additional benefits against diseases such as cancer However, we cannot assume that all CAT enzymes localised to various subcellular regions are functionally active.
For instance, the sponges Amphimedon queenslandica and Tethya wilhelma class Demospongiae each encode only one full length CAT sequence localised within the cytoplasm, indicated by asterisks Fig. Presence of antioxidant enzymes within 8 different subcellular compartments of 19 metazoan species. Shapes denote enzyme family, namely CAT circle , PRX triangle , or GPX square.
Subcellular compartments indicated are predictions based on amino acid sequence analysis by DeepLoc Colours denote individual PRX and GPX enzyme subfamilies, based on phylogeny corresponding to Figs. Total number of CAT, PRX, and GPX gene sequences encoded by each species in Table 1.
A : Maximum likelihood phylogenetic tree of PRX enzyme family. Unrooted tree displaying PRX animal subfamilies; AhpC-PRX1 green , PRX5 blue , and PRX6 pink that correspond with the three broad classes, typical 2-Cys PRX, atypical 2-Cys PRX, and 1-Cys PRX, respectively.
Within AhpC-PRX1 orange shape denotes strongly supported monophyletic clade named PRX4. B : Depicts zoomed in region of AhpC-PRX1 clade. These isoforms were previously used to classify PRXs across all metazoan species until a revision of PRX system of classification 41 , CNID-PRX denotes recently established subfamily found only within species belonging to phylum Cnidaria Orange circle indicates collapsed nodes of PRX4 clade.
FW: fresh water, SW: sea water. The PRXs are a large yet highly conserved enzyme family amongst metazoans. Across all 19 metazoan species, we identified a total of unique protein sequences encoding at least one PRX-associated domain.
However, our taxonomic expansion highlights PRX diversity and supports use of the most recent system of PRX classification based on the peroxidatic cysteine C P active site sequence 41 , The PRXs comprise three animal subfamilies, of which AhpC-PRX1 is the largest.
For 12 of the 19 metazoan species, we find at least three AhpC-PRX1 genes each, compared to just one or two genes in subfamilies PRX5 and PRX6 Table 1. In a previous system of classification that used homology to mammalian PRX isoforms, subfamily AhpC-PRX was subdivided into isoforms PRX 41 , However, this system was later deemed insufficient to accurately describe PRXs across diverse animal species Instead, AhpC-PRX1 comprises multiple independent branches such as the recently described CNID-PRX that is a lineage specific divergence within phylum Cnidaria 43 Fig.
That said, sequences sharing similarity to mammalian isoform PRX4 orange do form a strongly supported subclade that is widespread across the animal kingdom, being absent only in C. Indeed, the only AhpC-PRX1 we find in the three marine species of demosponge are these PRX4-like sequences.
Additionally, the non-metazoan, M. breviocolis choanoflagellate encodes a single sequence that falls within the PRX4 subclade, indicating that PRX4 may predate the origin of metazoans.
Subsequently we propose that PRX4 may be the closest animal orthologue of the ancestral AhpC-PRX1. Here we use the most recently proposed PRX classification system, that identifies six subfamilies, of which three occur in animals, based on protein sequence similarities at the peroxidatic cysteine C P active site 41 , 42 Table S3.
Within metazoans, we find three variable residues within this motif among AhpC-PRX1 sequences, five variable residues among PRX5 sequences and only two variable residues among PRX6 sequences underlined residues in Fig.
However, we also find that non-metazoan sequences typically display more variability, particularly for subfamilies, PRX5 and PRX6.
We note that PRX classification based on active site profiles has been adopted in recent literature, such as 46 and 47 , although there still are exceptions, such as 48 , 49 , 50, Continuing challenges are the incorrect, vague or ambiguous annotations in online gene databases, in addition to annotations based on older nomenclature thus does not easily correspond with current literature 41 , Antioxidant or peroxiredoxin-specific online databases have been developed in attempts to address these challenges e.
Thus, it is often the less accurate annotations that are most commonly used. Few studies have described PRXs across diverse metazoan phyla, and even less so in an evolutionary context Consequently, we suggest that numerous apparently inaccurate online data base annotations may underestimate the true extent of metazoan PRX diversity, and we predict that a greater breadth of PRX research will reveal further lineage-specific PRXs.
The subfamily PRX5 is considered to be the closest animal orthologue to the ancestral, prokaryotic subfamily, PRXQ 52 ; in our study, it also appears to be the least conserved PRX subfamily.
PRX5 displays greater sequence diversity at the C R active site than subfamily AhpC-PRX1. Notably, in three sequences from two sponges phylum Porifera; X.
bergquistia and A. queenslandica , the catalytic cysteine of C R is replaced by a Valine V residue. Further, the bilaterians B. floridae and Capitella teleta both encode shortened PRX5 sequences in which the C R motif is absent altogether Supplementary file 1 , Fig.
Similarly, amongst PRX5 encoded by non-metazoans, we find that the catalytic C R is substituted in all sequences except for that of the choanoflagellate, M.
This is consistent with other studies that have noted that C R is not always present within atypical 2-Cys PRXs Additionally, PRX5 is absent from five species, making it the only subfamily with evidence of metazoan gene losses Table 1.
However, these five species do encode alternative sequences that are mitochondrially localised, as PRX5 typically is. Indeed, all metazoans except N.
vectensis encode at least one mitochondrially-localised PRX Fig. In mammals, mitochondrially-localised PRX3 is predicted to compensate PRX5 functioning Table 1 53 , and D. melanogaster mutants lacking PRX3 show few effects, supporting a functional redundancy of PRX5 and PRX3 In phylum Porifera, PRX5 is the only PRX subfamily for which we do not recover a monophyletic demosponge clade, but rather the freshwater FW demosponge Ephydatia muelleri branches independently from the three marine Mar demosponges Fig.
In contrast, PRX6 is present in all 19 metazoan species, and is the most consistently localised PRX subfamily; all species have PRX6 genes predicted to localise to the cytoplasm Fig.
Only Oscarella carmela and D. melanogaster that encode multiple PRX6 genes have one of these localised to nuclei as well as to the cytoplasm Fig.
PRX6 is unique amongst the PRXs in that it lacks a resolving cysteine C R and is multifunctional, additionally exhibiting both phospholipase, and PLA 2 activity Of the 28 metazoan PRX6 sequences, we found that 19 encode the full PLA 2 catalytic triad, H… S… D, and nine encode the full G X S X G with no substitutions Purple residues and purple box, respectively; Supplementary file 1 , Fig.
Its ubiquitous presence and metazoan-wide conservation suggests strong selection for specific PRX6 activity and function. For each of the 19 metazoan species, including phylum Porifera, we identified at least one AhpC-PRX1 sequence encoding the full motifs GGLG and YF that confer sensitivity to hyperoxidation SO 2 H under high concentrations of H 2 O 2 Fig.
Sensitivity to hyperoxidation has so far been observed only in animal AhpC-PRX1 i. To date, no other mechanisms for reactivation have been described. Thus, it is surprising to find 10 species that encode sensitive PRXs but not the SRX-like reductant; these are the six sponge species, the ctenophore M.
leidyi , and the bilaterians C. teleta , C. elegans , and X. tropicalis Supplementary file 1 , Table S4. SRX has not been widely studied, thus SRX sequence structure may exhibit greater diversity than has currently been described.
However, for X. bergquistia , O. carmela , and C. elegans , we could not find even the SRX domain ParBc PF Supplementary file 1 , Table S4. One possible explanation is that, despite encoding the GGLG and YF motifs, the susceptibility to hyperoxidation for each of these 10 species may in fact be sufficiently low that AhpC-PRX1 inactivation does not occur.
Indeed, it is known in mammals that not all AhpC-PRX1 genes are equally sensitive to hyperoxidation; isoforms PRX1, PRX2, and PRX3 are most susceptible 59 , 60 , 61 , whilst PRX4 and PRX5 are more resistant, with PRX4 being protected within the ER 53 , 62 , In marine demosponges, PRX4 is the only AhpC-PRX1 that we identified, and in two of these species it was predicted to localise extracellularly so would not be protected within the ER Fig.
Recently, Bolduc et al. Our assessment of PRX4 sequences revealed that at least one residue is substituted within these motifs across all species except for C. Most commonly, the missing residue is His from motif a , except for D.
S1 ; Table S5. Furthermore, E. muelleri and C. teleta that lack SRX encode substitutions for two residues Supplementary file 2 , Table S5 ; C. These substitutions suggest that the PRX4 genes of the species lacking SRX are at least somewhat susceptible to hyperoxidation, even if not to the same degree as PRX Alternatively, species may encode PRXs that are sensitive to hyperoxidation but that are not reactivated, given that reactivation may not always confer increased fitness.
In SRX-depleted D. melanogaster , McGinnis et al. This result was very surprising given the number of studies that have demonstrated reduced fitness from SRX under expression in cell cultures, plants, and mammals 65 , 66 , One possible explanation is that hyperoxidized PRXs in the SRX mutant could either signal as damage associated molecular patterns DAMPs themselves or alter post-translation modifications of other proteins that in turn signal as DAMPs, to induce beneficial response pathways DAMPs serve as alarm signals within the innate immune system, alerting cells to any damage or to the presence of non-native microbes, which in turn activates host immune responses Thus, perhaps species that encode sensitive PRX, but not SRX, use hyperoxidized PRXs for other diverse important signalling functions.
GPX, the most evolutionary recent antioxidant family to emerge, is considerably less conserved than CAT or PRX. Here we expand on previous assessments 69 , 37 by surveying an additional four species of Porifera, as well as the annelid C. teleta and urochordate C. intestinalis , not included by Trenz et al.
In these six species, we identified 19 unique protein sequences encoding the GSHPx domain. Filtering by domain structure characteristic of a GPX reduced this number to 15 Fig.
The only exceptions to this include cysteine-dependent GPXs in D. melanogaster GPX4, C. We find the total number and functional subfamilies of GPX genes encoded by each species is variable, with multiple cases of gene loss. Typically, we find fewer GPX genes in non-bilaterian species, and indeed GPX represents the smallest of the three antioxidant families within phylum Porifera Table 1.
Specifically, we find that GPX7 is most common within phylum Porifera, encoded by four species of classes Homoscleromorpha, Calcarea, and two marine species of Demospongiae, but absent from X.
bergquistia and the freshwater demosponge E. muelleri Fig. Maximum likelihood phylogenetic tree of GPX enzyme family. Labels in blue denote sequences encoded by phylum Porifera.
Labels with a star indicate cysteine GPXs, where cysteine is the catalytic residue. Subfamily GPX7 is exclusively cysteine dependant for all species. All metazoan GPX sequences fell into one of these four clades, whilst non-metazoan sequences were paraphyletic and phylogenetically distinct.
Only one sequence encoded by the choanoflagellate M. We found the subfamilies GPX4 and GPX7 are the most abundant across the metazoans. Subfamily GPX7, which is exclusively cysteine dependent, is the most commonly encoded GPX in metazoans Fig.
It also shows highly conserved subcellular localisation, being predicted to localise to the ER in 13 of the 14 metazoans that encode it Fig. GPX7 is an animal-specific subfamily that has a key role in facilitating ER protein folding 71 and has been described as the novel GPX GPX7 is similar to typical CysGPXs in more efficiently using thiols as its reductant rather than GSH, but different in lacking the second resolving cysteine within the canonical site Fig.
Instead, GPX7 uses the endoplasmic reticulum ER protein disulfide isomerase PDI as its reductant, thus helping to recycle it 73 , reviewed by Within the ER, newly synthesised proteins are oxidised by PDI, which in turn are again re-oxidised by ER oxidoreductase 1 ERO1α in a reaction that generates H 2 O 2 72 , reviewed by GPX7 can increase PDI-oxidising activity of ERO1α 70 , 76 , which promotes the refolding of misfolded proteins, and prevents ER oxidative stress response through H 2 O 2 scavenging This unique function may explain the strong conservation of GPX7 gene number and localisation across the Metazoa.
One explanation for this may be their functional redundancy shared with certain PRXs. Moreover, typical CysGPXs share a similar catalytic cycle to 2-Cys PRXs and are hypothesised to function in the same way 54 , 73 Fig.
Interestingly, GPXs show positive selection at residues located at or close to active sites, or at the dimer interface Notably, the catalytic residue within the active site, Sec U , is encoded by the nucleotide sequence UGA that also encodes the STOP codon 78 , It thus requires additional, energetically costly machinery to be encoded 80 , 81 , However, selenocysteine GPXs do exhibit significantly greater efficiency than Cys because of their higher nucleophilic activity, and capacity of Sec to efficiently catalyse both one-electron, as well as two-electron reactions 83 , 84 , Thus, we hypothesise that selection on GPX may favour seleno-dependent GPXs i.
However, without supporting Sec machinery, Sec may not be maintained in the protein, leading to a loss of function. Indeed, in selenocysteine-dependent subfamilies, GPX gene duplications and partial sequences are notably common, particularly within larger genomes of species such as H.
sapiens Supplementary file 3 77 , 86 , likely reflecting a more rapid rate of evolution. In our survey of 19 species spanning 10 animal phyla, we find that gene number and distribution are highly conserved in the antioxidant families CAT and PRX, but much less so in the GPX family.
We reveal for the first time that all three families—CAT, PRX, and GPX—are encoded by the six species of the basal metazoan phylum Porifera, considered sister to all other animal phyletic lineages.
From this we can infer the distribution of these three ancient antioxidant families in the last common animal ancestor LCAA. Monofunctional CAT comprises a comparatively small and conserved family in animals; its diversification since the LCAA is recent compared to the very long evolutionary history of this enzyme family.
We find both peroxisomal and cytoplasmic forms are common among metazoans; the exceptions are that we did not find any of the peroxisomal form in the marine demosponges or cnidarians surveyed in our study.
This suggests that the peroxisomal form may have arisen after the cnidarian-bilaterian split, with the addition of signal peptides. In contrast, the PRXs comprise a large enzyme family. Subfamilies AhpC-PRX1 and PRX6 are the most widely distributed and conserved, whilst PRX5 exhibits notable gene losses.
Interestingly, PRX5, the closest animal orthologue to ancestral PRXQ, appears to have been lost in several species that exhibit gene expansion of subfamily AhpC-PRX1.
We show that phylum Porifera encode all three animal PRX subfamilies. However, marine demosponges encode just a single AhpC-PRX1, belonging to PRX4, which is the only subclade conserved across the animal kingdom.
This indicates that PRX4, which is also found within non-metazoan choanoflagellate, may be the ancestral AhpC-PRX1. GPX is the most evolutionary recent origin of all the antioxidant enzyme families, is the least conserved among metazoans, and is the least abundant in phylum Porifera.
The subfamilies GPX4 and cysteine-dependent GPX7 are the most common in poriferans, with GPX7 present in all three classes, and GPX4 in Demospongiae only. We find strong conservation across the animal kingdom of ER-localised GPX7, which may reflect its unique role of preventing oxidative damage during protein folding within the ER.
That the enzyme families CAT and PRX have been so widely conserved since their ancient origins predating the evolution of aerobic life suggest a core role that is conserved across the animal kingdom.
Thus, our comparative genomic analyses illustrate that the fundamental functions of antioxidants have resulted in gene conservation throughout the animal kingdom, paving the way for functional analyses on these enzyme families in diverse animal phyla.
We searched for gene sequences encoding candidate members of the CAT, PRX, and GPX families in high quality genomes of 19 metazoan species representing 10 phyla Supplementary file 1 , Table S1. Specifically, predicted coding sequences were scanned against the Pfam A database using hmmscan in HMMER v3.
org for sequences encoding domains specific to each enzyme family, and their respective subfamilies Fig. Specifically, HMMER allows us to identify protein sequences encoding functional domains through implementing probabilistic Hidden Markov Models HMM to search for protein sequence homologs against a profile database such as Pfam.
The number and position of all identified domains was determined. For all identified candidate gene sequences, we predicted protein subcellular localisation regions using DeepLoc The methodology for enzyme identification was cross-validated by comparing the number and type of CAT, PRX, and GPX genes identified through our analysis with those that have previously been described.
No further criteria were applied. The C P motif is required for PRX catalytic activity on H 2 O 2 , so sequences that did not contain this motif were excluded from further analysis.
Additionally, we scanned for the presence of subfamily-specific motifs. For subfamily AhpC-PRX1, we searched for the motifs GGLG and YF that encode sensitivity to hyperoxidation, as well as a and b motifs that contribute to determining the degree of PRX sensitivity to hyperoxidation 56 , 57 , 58 , Accordingly, we also searched for the presence of enzymatic reductant sulfiredoxin SRX that can reactivate hyperoxidized PRXs Fig.
Candidate GPX amino acid sequences considered in our study include 61 sequences obtained previously by 37 from 13 metazoan species indicated in Table S1 Supplementary file 1. In addition to these, we assessed protein coding sequences of six species, that includes four sponges, that were not assessed by For these six species, we retained candidate GPX enzyme sequences encoding the domain GSHPx PF; Fig.
Sequences encoding Sec at the first residue of the catalytic tetrad were classified as selenium-dependent and those encoding Cys at the first residue of the catalytic tetrad were classified as cysteine dependant GPXs To provide evolutionary context to the metazoan phylogenetic relationships, we also incorporated non-metazoan sequences; these included the phylum Choanoflagellata that is closest extant animal relative, as well as other non-metazoan eukaryotics representing Amoebozoa, Red algae, and fungi.
To assess phylogenetic relationships, alignments were manually edited in AliView v1. Edited alignments were then imported to IQ-TREE 94 to construct maximum likelihood trees using ultrafast bootstrap 95 , based on bb and the most appropriate evolutionary model as identified by ModelFinder Resultant phylogenetic trees were first visualised in iTOL v.
Classification of PRX and GPX gene subfamilies were inferred from the relative placing of putative sequences within known subfamily clades of phylogenetic trees. All data generated or analysed during this study are included in this published article, its supplementary information files, and publicly available repositories.
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Antioxidant enzymes are compounds that inhibit oxidation Antioxidant enzymes occurring as Enzynesa chemical reaction Performance enhancing drinks can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Curcumin and Anxiety Antioxidant enzymes frequently added Antioxidant enzymes industrial products, such eznymes polymersfuelsand lubricantsto extend their usable lifetimes. In cellsantioxidants enztmes as AntioxidanfBody fat threshold Antioxivant bacillithioland enzyme systems like superoxide dismutasecan prevent damage from oxidative stress. Known dietary antioxidants are vitamins ACand Ebut the term antioxidant has also been applied to numerous other dietary compounds that only have antioxidant properties in vitrowith little evidence for antioxidant properties in vivo. As part of their adaptation from marine life, terrestrial plants began producing non-marine antioxidants such as ascorbic acid vitamin Cpolyphenols and tocopherols. The evolution of angiosperm plants between 50 and million years ago resulted in the development of many antioxidant pigments — particularly during the Jurassic period — as chemical defences against reactive oxygen species that are byproducts of photosynthesis. Body fat threshold ; Enzymes ; Antioxdiant Body fat threshold ; Oxidative stress ; Body fat threshold toxicity nezymes Antioxidant enzymes oxygen species. Antioxidant enzymes are Antioxidanh involved in the Antioxidant enzymes transformation of reactive Hyperglycemia and hormone imbalances species and their by-products into stable Antloxidant molecules Body fat threshold representing the most Antioxidanh defense mechanism against enzymed Antioxidant enzymes cell damage. Antioxiadnt biological Antioxidaht, Antioxidant enzymes is the process by which a molecule loses electrons spontaneously or by metabolic coupled reactions. In cell metabolism, molecule oxidation provides the driven force toward the production of energy-rich intermediates in the form of ATP. Molecule oxidation may be achieved by enzyme-catalyzed reactions or as a result of electron sequestration induced by specific molecules known as oxidants. Clear examples of oxidants are free radicals which are defined as molecules with unpaired electrons in their upper electron layer which explains their high affinity and tendency to Synonyms Antioxidants ; Enzymes ; Free radicals ; Oxidative stress ; Oxygen toxicity ; Reactive oxygen species.
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