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J Lipid Res. Halliwell B. Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies? Download references. The author wish to thank Dr. Yakup Gumusalan for pre-reviewing this manuscript.

The sponsors had no involvement neither in the study design, collection, analysis, and interpretation of data, nor in the writing of the manuscript and in the decision to submit the manuscript for publication.

Department of Medical Biochemistry, Faculty of Medicine, Sutcu Imam University, Avsar Campus, Kahramanmaras, , Turkey.

You can also search for this author in PubMed Google Scholar. Correspondence to Ergul Belge Kurutas. EBK was involved in the literature survey, analysis and evaluation of the data and preparation of the manuscript.

She read and approved the final manuscript. Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. Kurutas, E. Nutr J 15 , 71 Download citation. Received : 17 February Accepted : 29 June Published : 25 July Anyone you share the following link with will be able to read this content:.

Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Download ePub. Full size image. Protein tyrosine phosphatases All tyrosine phosphatases have a conserved amino acid domain that contains a reactive and redox-regulated cysteine, which catalyzes the hydrolysis of protein phosphotyrosine residues by the formation of a cysteinyl-phosphate intermediate, that later is hydrolyzed by an activated water molecule.

Antioxidants An antioxidant substance in the cell is present at low concentrations and significantly reduces or prevents oxidation of the oxidizable substrate. Antioxidant defenses in the organism. Chemical structure of the tocopherols. Oxidized and reduced forms of lipoic acid.

Chemical structure of melatonin. Chemical structure of selected carotenoids. Chemical structure of some flavonoids. Antioxidant supplementation The last 60 years have been characterized by the understanding of the impact of nutrition and dietary patterns on health. References Kurutas EB, Ciragil P, Gul M, Kilinc M.

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Antioxidants are classified into three categories [ 56 — 58 ] as follows:. Primary antioxidants: It is involved in the prevention of oxidant formation. They act by suppressing the formation of free radicals examples: glutathione peroxidase, catalase, selenoprotein, transferrin, ferritin, lactoferrin, carotenoids, etc.

Secondary antioxidants: These exhibit scavengers of ROS. They act by suppressing chain initiation and breaking chain propagation reactions radical scavenging antioxidants. Tertiary antioxidants: They act by repairing the oxidized molecules some proteolytic enzymes, enzymes of DNA, etc.

through sources like dietary or consecutive antioxidants. The human body employs three general categories of antioxidants to safeguard against free radicals. They are endogenous antioxidants, dietary antioxidants, and metal-binding proteins [ 16 ]. These are categorized into primary antioxidants and secondary antioxidants.

SOD, catalase, and glutathione peroxidase are the primary antioxidant enzymes that inactivate the ROS into intermediates [ 13 ].

Secondary antioxidant enzymes glutathione reductase, glucosephosphate dehydrogenase, glutathione-s-transferase, and ubiquinone detoxify ROS and supply the NADPH and glutathione for primary antioxidant enzymes for proper functioning. Metals such as copper, iron, manganese, zinc, and selenium up-regulate the antioxidant enzyme activities [ 14 , 15 ].

Many polyphenolic compounds such as flavonoids, isoflavones, flavones, anthocyanins, coumarins, lignans, catechins, isocatechins, epicatechins, and phenolic acids have gained importance as antioxidant drugs [ 16 ].

Dietary antioxidants act through scavenging free radicals to break the chain reaction responsible for lipid peroxidation.

Vitamins C and E, carotenoids, and flavonoids are the dietary antioxidants. These vitamins are also known as chain-breaking antioxidants [ 16 ]. The metal-binding proteins albumin, ferritin, and myoglobin inactivate the transition metal ions that catalyze the production of free radicals [ 17 , 18 ].

Antioxidant enzymes — catalase, SOD, glutathione peroxidase, glutathione reductase, and thioredoxin — act against the ROS.

The non-enzymatic antioxidants are the scavengers of ROS and RNS [ 59 ]. These compounds have low activation energy to donate the hydrogen atom and, therefore, cannot initiate the secondary free radicals.

The free radical electrons are stable and, thus, slow down the oxidation. Prevention of excessive ROS and repair of cellular damage are essential for the life of cells, and cells, in turn, contain many antioxidant systems to prevent the oxidative injury [ 60 , 61 ].

Primary or chain-breaking antioxidants: break chain reaction and the resulting radical are less reactive. A schematic diagram of the antioxidant defense mechanism Adapted from [ 5 ]. Antioxidant defensive agents Adapted from [ 66 ]. Major ROS scavenging antioxidant enzymes Adapted from [ 67 ].

Antioxidants are present with protective efficiency. If there is an electron-donating group, especially a hydroxyl group loaded on o- or p -positions of the phenolic compounds, it makes the compound polar, and, therefore, antioxidant activities and metal chelating ability are increased.

These groups make the phenols more easily donate hydrogen atoms to activate free radicals to interrupt the chain reaction of autoxidation. Antioxidants of natural origin such as polyphenols tannins, flavonoids, and chalcones act by donating an electron to the intermediate radicals formed in oxidative stress or tissue damage, which helps in the inhibition of lipid peroxidation.

A computational study also supports that the compounds having more electron donating potentials are better inhibitors of hydroperoxides that suggest many of the antioxidant agents [ 62 — 67 ]. Several human pathologies such as neurodegenerative diseases, cancer, stroke, and many other ailments are believed to be caused by ROS.

Antioxidants are assumed to prevent the harmful effects of ROS and therefore treat oxidative stress-related diseases Figure 5. Oxidative stress-induced diseases in humans Adapted from [ 65 ]. Antioxidant approach to disease management holds potential as most of the diseases are mediated through ROS; also with the rapid advancement of civilization, industrialization, and overpopulation, there has been a significant rise in oxidative stressors.

Epidemiological researches strongly suggested that foods containing antioxidants and scavengers have a potential protective effect against disorders caused by ROS [ 66 ]. Many chronic diseases can be prevented, and disease progression can be slowed by increasing the body natural antioxidant defenses or by supplementing with dietary antioxidants.

Natural antioxidants such as flavonoids, tannins, and polyphenols act by donating electrons to intermediate radicals and help in inhibition of lipid peroxidation. Antioxidants are essential to prevent the formation and oppose the actions of reactive oxygen and nitrogen species, which are generated in vivo and cause damage to DNA, lipids, proteins, and other biomolecules.

The antioxidant system contains exogenous antioxidants dietary sources and endogenous antioxidants. Many polyphenolic compounds such as flavonoids, isoflavones, flavones, anthocyanins, coumarins, lignans, catechins, isocatechins, epicatechins, and phenolic acids have gained importance as antioxidant drugs.

Protein and amino acids play an important role in the synthesis of antioxidant enzymes. Small peptides like GSH and carnosine and nitrogenous metabolites like creatine and uric acid directly scavenge the reactive metabolites [ 67 ].

iNOS expression and synthesis in various cells are controlled by taurine and taurine chloramines. Deficiency of dietary protein can have a harmful effect on the antioxidant system of the cell.

Arginine and tetrahydrobiopterin deficiency directly affect the superoxide enzyme production. Decreased protein intake affects the availability of zinc, which is a cofactor of SOD. Similarly, a high-protein diet exhibits oxidative stress. Homocysteine increases inducible and constitutive NOS synthesis and stimulates ROS generation in polymorphonuclear leukocytes and monocytic cells [ 68 — 70 ].

There is a generation of ROS due to the intake of polyunsaturated fatty acids which are neutralized by vitamins C and E and carotenoids. There is an increase in the risk of cardiovascular diseases due to high intake of polyunsaturated fatty acids.

On the other hand, a high-saturated-fat diet increases the risk of iNOS activity in the liver and colon. Fish oil decreases the cardiovascular risk by reducing triacylglycerol production in plasma as it contains ω-3 PUFA that is the inhibitor of ROS, iNOS expression, and NOS synthesis [ 71 ].

Vitamins exhibit anti-atherogenic and anti-inflammatory properties. Vitamin A inhibits iNOS in vascular muscle cells, endothelial cells, cardiac myocytes, and mesangial cells.

Vitamins D3, K2, and niacin inhibit iNOS activity in the neuronal cells macrophage, microglia, and astrocytes Lipid peroxidation of the membrane is prevented by vitamin E as it inhibits the ROS generation. Irradiation decreases the concentration of vitamin C and folate, thus leading to ROS generation.

It has been reported that vitamin B12 and folic acid reduce radical-induced radiation damage and improve leukocyte counts. DNA damage and hepatocellular carcinoma are prevented by vitamin C and choline.

Vitamins B12, B6, and folate are essential for the synthesis of cystathionine synthase and cystathionase B6 and methionine synthase B These vitamins prevent cardiovascular diseases in humans and rodents.

NADP, NADH, FAD, nicotinamide, and riboflavin protect the cells from ROS generation. NADPH and FAD are essential for glutathione reductase. NADPH is required for catalase activity [ 70 — 75 ].

Copper, zinc, and manganese, the important trace elements in our body, serve as cofactors of SOD enzyme. Deficiency of either copper or zinc increases the cytochrome P activity in microsomes of the liver and lungs, and thus increases the generation of ROS and iNOS expression [ 76 ].

Selenium possesses potential antioxidant activity as it is a cofactor of glutathione transferase enzyme and other selenoproteins. Many medicinal plants contain phytochemicals like phenolic and polyphenolic compounds such as flavonoids, isoflavones, flavones, anthocyanins, coumarins, lignans, catechin, isocatechin, gallic acid, and esculatin that possess antioxidant activities [ 77 ].

These phytochemicals are present in many plants and herbs like grapes, berry crops, tea, herbs, nutmeg, and tea. Many medicinal plants contain phenolics like gallic acids and other active constituents. Terminalia chebula, T. bellerica, T. muelleri , Phyllanthus emblica, Hemidesmus indicus, Cichorium Intybus, Withania somnifera, Ocimum sanctum, Mangifera indica, and Punica granatum are known to have potential antioxidant activities [ 78 ].

Recent human studies exploring the efficiency of antioxidants in prevention and treatment of various diseases are reviewed Table 4.

Many of these studies, either due to the small patient sample size, with uncontrolled admissions and treatment criteria, or due to relevant bias of the clinical studies failed to give precise information on effectiveness and practical advantage in taking antioxidants.

Antioxidants therapies have been in progress these days. Edaravone for ischemic stroke , N-acetylcysteine for acetaminophen toxicity , alfa-lipoic acid for diabetic neuropathy , and some flavonoids for chronic venous insufficiency as well as baicalein and catechins for osteoarthritis have clinical importance.

The evidence from human epidemiological studies about the beneficial effects of dietary antioxidants and preclinical in vitro and animal data are compelling. Attention needs to be drawn on focusing more on disease-specific, target-directed, highly bioavailable antioxidants [ ].

In the recent years, due to the increase in the consumption of food and medicinal products, we are exposed to the adverse effects of various compounds noticed in the above products. For example, in our animal experimental studies, we have determined induction of oxidative stress induced by the compound cinnamaldehyde, a food flavor and also an anticancer drug [ — ].

As a therapeutic measure, addition of vegetables and fruits, the great sources of vitamins or antioxidants, in our routine diet might protect our health from toxic effects of food chemicals or drugs to a certain extent [ ].

In this advanced materialistic life, monitoring the levels of free radicals and oxidative stress is important in case of clinical practice. FORD Free Oxygen Radicals Defense is an easy, cheap, and reliable diagnostic device to monitor oxidative stress [ 19 , ].

It discriminates the high risk of oxidative damage on sick or healthy individuals, monitoring with precise laboratory parameters in the clinical situation at the baseline and in the follow-up of a medical prescription.

FORD Free Oxygen Radicals Defense is a colorimetric test based on the influence of antioxidants present in plasma to reduce the activity of free radicals.

The principle of the assay is that at an acidic pH 5. Antioxidant molecules AOH present in the sample which are able to transfer a hydrogen atom to the FORD chromogen radical cation, reduce it, quenching the color and producing a discoloration of the solution which is proportional to their concentration in the sample.

This instrument will be helpful in understanding the problem of the individual bioavailability of each antioxidant molecule which can be monitored during the administration, with a pre-post measure of the oxidative balance.

In order to achieve the evidence of the oxidative background related to the outcome of specific symptoms and diseases, epidemiological studies can be encouraged, and the role of nutrition and targeted antioxidant therapy can be better defined.

Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Edited by Sivakumar Joghi Thatha Gowder. Open access peer-reviewed chapter Members of Antioxidant Machinery and Their Functions Written By Shalini Kapoor Mehta and Sivakumar Joghi Thatha Gowder.

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Impact of this chapter. Abstract In this modern world, due to the rapid advancement of civilization, industrialization, and overpopulation, scientific knowledge on antioxidants is important since most of the diseases are mediated through reactive oxygen species ROS.

Keywords Antioxidants Free Radicals Oxidative Stress Drugs Therapy. Classification of antioxidants Guttering and Halliwell classified the antioxidants into three categories: primary, secondary, and tertiary antioxidants [ 11 ]. Non-enzymatic antioxidants These antioxidants are quite a few, namely vitamins A, C, E, and K , enzyme cofactors Q10 , minerals Zn, Se, etc.

Hydrophilic antioxidants Antioxidants that react with oxidants in the cell cytoplasm and the blood plasma are termed as hydrophilic antioxidants ascorbic acid, glutathione, and uric acid.

Hydrophobic antioxidants These compounds are known to protect cell membranes from lipid peroxidation ubiquinol, carotenes, and α-tocopherol. Endogenous antioxidants Endogenous antioxidants can be categorized into primary antioxidants and secondary antioxidants.

Exogenous antioxidants Many foods and various dietary components exhibit antioxidant activities. Enzymatic antioxidants Enzymatic antioxidants are categorized into primary and secondary enzymatic defenses.

Catalase Catalase was the first antioxidant enzyme to be characterized and catalyzes the two-stage conversion of hydrogen peroxide to water and oxygen. Non-enzymatic endogenous antioxidants There are a number of non-enzymatic antioxidants: vitamins A, C, E, and K , enzyme cofactors Q10 , minerals Zn and Se , organosulfur compounds allium and allium sulfur , nitrogen compounds uric acid , peptides glutathione , and polyphenols flavonoids and phenolic acid.

Vitamin A Vitamin A is produced as a result of the breakdown of β-carotene and is a carotenoid produced in the liver. Coenzyme Q10 Coenzyme Q10 has been reported to act by preventing the formation of lipid peroxyl radicals.

Uric acid The end product of purine nucleotide metabolism in humans is uric acid. Glutathione Glutathione is an endogenous tripeptide that protects the cells against free radicals by donating either a hydrogen atom or an electron.

Vitamin C Ascorbic acid and tocopherols are generic names for vitamin C and vitamin E. Vitamin E Vitamin E is the only major lipid-soluble, chain-breaking antioxidant found in plasma, red cells, and tissues, thus protecting the integrity of lipid structures, mainly membranes.

Vitamin K This vitamin has two natural isoforms: vitamins K1 and K2. Flavonoids Flavonoids are a group of compounds composed of diphenyl propane C6C3C6 skeleton.

Phenolic acids Phenolic acids are composed of hydroxycinnamic and hydroxybenzoic acids. Carotenoids Carotenoids are a group of natural pigments and are synthesized by plants and microorganisms.

Minerals Minerals are found in trace quantities in animals and are a small part of dietary antioxidants, but play significant roles in their metabolism. Peroxiredoxins These may be of three basic types: typical 2-cysteine peroxiredoxins; atypical 2-cysteine peroxiredoxins; and 1-cysteine peroxiredoxins.

Synthetic antioxidants Synthetic antioxidants have been developed to have a standard antioxidant activity measurement system and to compare with natural antioxidants that are incorporated into food.

Pro-oxidants Pro-oxidants are defined as chemicals that induce oxidative stress, usually through the formation of reactive species or by inhibiting antioxidant systems. Table 1. Endogenous antioxidants These are categorized into primary antioxidants and secondary antioxidants.

Exogenous antioxidants Many polyphenolic compounds such as flavonoids, isoflavones, flavones, anthocyanins, coumarins, lignans, catechins, isocatechins, epicatechins, and phenolic acids have gained importance as antioxidant drugs [ 16 ]. ROS scavengers ROS protective enzymes Sequestration of transition metal ions which form ROS Glutathione Superoxide dismutase Transferrin Uric acid Catalase Ferritin Ascorbic acid Glutathione peroxidase Metallothionein Albumin Glutathione reductase Ceruloplasmin.

Table 2. Table 3. Exogenous antioxidants as drugs Many polyphenolic compounds such as flavonoids, isoflavones, flavones, anthocyanins, coumarins, lignans, catechins, isocatechins, epicatechins, and phenolic acids have gained importance as antioxidant drugs. Role of dietary nutrients in defensive mechanism Protein and amino acids play an important role in the synthesis of antioxidant enzymes.

Lipids There is a generation of ROS due to the intake of polyunsaturated fatty acids which are neutralized by vitamins C and E and carotenoids. Vitamins Vitamins exhibit anti-atherogenic and anti-inflammatory properties.

Micronutrients and minerals Copper, zinc, and manganese, the important trace elements in our body, serve as cofactors of SOD enzyme.

Phytochemicals Many medicinal plants contain phytochemicals like phenolic and polyphenolic compounds such as flavonoids, isoflavones, flavones, anthocyanins, coumarins, lignans, catechin, isocatechin, gallic acid, and esculatin that possess antioxidant activities [ 77 ].

Disease studied Antioxidant used Reference Reference no. Evans et al. Weber et al. Cancer Lipid-soluble antioxidant vitamins, Kirsh et al. Patel et al. Pleiner et al [ 95 ] Chronic Obstructive Pulmonary Disease COPD Polyphenol-rich pomegranate juice PJ Cerda et al.

Table 4. The efficiency of antioxidants in prevention and treatment of various diseases. Oxidative stress test In this advanced materialistic life, monitoring the levels of free radicals and oxidative stress is important in case of clinical practice.

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Eur Rev Med Pharmacol Sci ; — Rahman K. Studies on free radicals, antioxidants and co-factors. Clin Inverv Aging ; — Gamble PE, Burke J. Effect of water stress on the chloroplast antioxidant system.

Plant Physiol ; — Ratnam DV, Ankola DD, Bhardwaj V, Sahana DK, Kumar MN. Role of antioxidants in prophylaxis and therapy: A pharmaceutical perspective. J Control Release ; — Liou W, Chang LY, Geuze HJ, Strous GJ, Crapo JD, Slot JW. Distribution of Cu Zn superoxide dismutase in rat liver. Free Rad Biol Med ; — Marklund S.

Human copper-containing superoxide dismutase of high molecular weight. Proc Natl Acad Sci U S A. Karlsson K, Sandstrom J, Edlund A, Edlund T, Marklund SL. Pharmacokinetics of extracellular superoxide dismutase in the vascular system.

McIntyre M, Bohr DF, Dominiczak AF. Endothelial function hypertension—the role of superoxide anion. Hypertension ; — Kirkman HN, Galiano S, Gaetani GF. The function of catalase-bound NADPH. J Biol Chem ; — Takahashi K, Cohen HJ. Selenium-dependent glutathione peroxidase protein and activity: immunological investigations on cellular and plasma enzymes.

Blood ; — Nakane T, Asayama K, Kodera K, Hayashibe H, Uchida N, Nakazawa S. Effect of selenium deficiency on cellular and extracellular glutathione peroxidases: immunochemical detection and mRNA analysis in rat kidney and serum.

Holben DH, Smith AM. The diverse role of selenium within selenoproteins: a review. J Am Diet Assoc ; — 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 ,

Antioxidant enzymes and their functions access. Submitted: Antioxidant enzymes and their functions November Published: 03 October com customercare anr. During normal metabolic functions, highly reactive compounds called free radicals are generated functiions the Nutrition for recovery from heavy lifting sessions however, function may also be introduced from the environment. These molecules are inherently unstable as they possess lone pair of electrons and hence become highly reactive. They react with cellular molecules such as proteins, lipids and carbohydrates, and denature them. As a result of this, vital cellular structures and functions are lost and ultimately resulting in various pathological conditions. Nutrition Journal volume Healthy eating for athletesArticle Antioxidant enzymes and their functions 71 Cite this Supportive recovery communities. Functiions details. They Antioxivant act from directly scavenging free radicals ans increasing antioxidative defences. Antioxidant deficiencies can develop as a result of decreased antioxidant intake, synthesis of endogenous enzymes or increased antioxidant utilization. Antioxidant supplementation has become an increasingly popular practice to maintain optimal body function. However, antoxidants exhibit pro-oxidant activity depending on the specific set of conditions.