Why is catalase important to cells

The length of the catalase gene is 34 kb, it contains 12 introns and 13 exons generating a mRNA of bp Quan et al. Conversely, some catalase mutations provoke changes in either catalase expression or activity and may be associated with some diseases.

Recent studies have focused on the associations of catalase polymorphisms with various types of cancer but many inconsistent results about the relationship between the catalase gene polymorphism and cancer risk were reported.

Recently, two meta-analyses pointed out a correlation exists between this polymorphism CT and prostate cancer Liu et al. Different catalase mutations in patients can cause decreased catalase activity leading to increased H 2 O 2 concentrations in the blood and tissues. Depending on the mutations, such patients may be subject to an increased risk of type 2 diabetes, vitiligo and increased blood pressure Goth et al.

When the mutations are located in exons as in Japanese and Hungarian acatalasemia, a truncated or mutated catalase is synthetized and functionally less active. This table was adapted from Goth et al. Decreased activity of catalase has also been observed in various genetic alterations, for example, loss of alleles i.

It is generally accepted that the cellular maintenance of redox homeostasis is controlled by a complex network of antioxidant enzymes i. Nevertheless, the molecular mechanisms regulating the expression of catalase — the oldest known and first discovered antioxidant enzyme — are independent of this pathway and not totally elucidated. Therefore, the fine-tuning regulation of this enzyme should be prior elucidated in order to find a new approach to modulate the antioxidant status in cancer cells.

Interestingly, despite the existence of diverse protection mechanisms against oxidant injuries, a consensus emerged in the scientific literature about an alteration of redox homeostasis within tumor cells. Indeed, they produce large amounts of ROS that are involved in the maintenance of genetic instability favoring cancer cell proliferation. Meanwhile, altered expression levels of catalase have been reported in cancer tissues as compared to their normal counterparts.

Thus, as compared to normal tissues of the same origin, some authors reported an increased catalase expression in tumors Sander et al. For instance, we have reported an important decrease of catalase activity in different cancer cell lines, as shown in Table 2 Verrax et al. Briefly, catalase levels can vary after short treatments to H 2 O 2 Rohrdanz and Kahl, ; Rohrdanz et al. Although mechanisms controlling catalase expression have been partially elucidated, the decreased catalase expression in cancer cells still remains an unanswered question.

Data were analyzed by unpaired t -test. The regulation of catalase expression in cancer cells is a complex process because different levels of regulation are thought to be involved. In a recent review, we discussed the different mechanisms playing a potential role in the regulation of its expression in both healthy and tumor cells Glorieux et al.

They include transcriptional regulation, represented by the activity of transcription factors that induce or repress the transcriptional activity of catalase promoters, post-transcriptional regulation mRNA stability and post-translational modification phosphorylation and ubiquitination of the protein.

In addition, epigenetic DNA methylation, modifications of histones changes or genetic alterations can also be involved playing a role in governing proper levels of catalase activity in these cells. Regarding transcription it should be noted that the catalase gene has all the characteristics of a housekeeping gene no TATA box, no INR sequence, high GC content in promoter and a core promoter which is highly conserved among species Quan et al.

In this core promoter, the presence of DNA binding sites for transcription factors like NF-Y and Sp1 has an essential role in the positive regulation of catalase expression Nenoi et al. Additional transcription factors have also been involved in this regulatory process.

Specifically, we investigated the transcriptional regulatory mechanism controlling catalase expression in human mammary cell lines. To this end, we have made a human breast MCF-7 cancer cell line resistant to oxidative stress, the so-called Resox cells. These cells show decreased ROS basal levels and an increased activity of some antioxidant enzymes, notably catalase Dejeans et al.

Thus, cancer adaptation to oxidative stress, regulated by transcriptional factors through chromatin remodeling appears as a new mechanism to target cancer cells. These cells show increased expression of catalase. HAT: Histobe acetyltransferase. Adapted from Glorieux et al. As previously mentioned, cancer cells are generally deficient in antioxidant enzymes, thus, any increase in ROS levels would be a menace to the precarious redox balance of cancer cells making them vulnerable to an additional oxidative stress.

Given that weakness, the loss of redox homeostasis represents an interesting target for research and development of new molecules with antitumor activity and numerous drugs are currently being clinically evaluated.

Therefore, several strategies have been developed looking for the disruption of tumor cell redox homeostasis and a subsequent cancer cell death Demizu et al. One of these strategies is the use of ROS-generating compounds such as arsenic trioxide ATO , currently employed against promyelocytic leukemia Valenzuela et al.

Indeed, the impairment of mitochondrial function due to increased levels of superoxide anion is supposed to be the main mechanism of both chemotherapeutic drugs Thayer, ; Pelicano et al. A decrease in antioxidant levels has also been proposed. The development of specific inhibitors of thioredoxin and thioredoxin reductases was also carried out. Inhibitors of thioredoxin, such as PX, were shown to have potent antitumor activities Welsh et al.

Conversely, the overexpression of Trx1 is correlated with resistance to anti-cancer drugs Baker et al. As quinones display redox cycling abilities thus generating ROS Kappus and Sies, , the association of menadione a naphthoquinone derivative and ascorbate Figure 3 , was employed to trigger tumor cell death Verrax et al.

We hypothesized that H 2 O 2 , issued from the redox cycling, is the oxidant species responsible for antitumor effects observed both in vitro and in vivo Verrax et al. The induced oxidative stress provokes cell necrosis by a wide variety of processes including ATP depletion Verrax et al. Based on the vulnerability of tumor cells to an oxidative stress, we have induced the alteration of their intracellular redox homeostasis as a new strategy in the research and development of new antitumor drugs Benites et al.

A similar approach has been recently developed by using the SnFe 2 O 4 nanocrystals, a heterogeneous Fenton catalyst, which once internalized into the cancer cells, convert H 2 O 2 into hydroxyl radicals inducing apoptotic cell death.

In normal cells, the oxidative injury induced by SnFe 2 O 4 is prevented by catalase Lee et al. The biological activity showed by menadione mainly relies upon its ability to accept one electron from ascorbate to form a semiquinone radical.

When the semiquinone is reduced back to its quinone form, superoxide anion is produced which by dismutation generates hydrogen peroxide. Despite that Resox cells display high antioxidant defenses Dejeans et al. Arsenic trioxide ATO decreases catalase expression in breast cancer cells and sensitizes them to pro-oxidant drugs.

Under stress conditions, the antioxidant enzyme catalase plays a major role by detoxifying H 2 O 2. As consequences, a change of its activity or expression will lead to pathological processes as Zellweger syndrome, acatalasemia or WAGR syndrome.

The subcellular localization of catalase is mainly peroxisomal but a shuttle between this organelle and cytoplasm exists and may be involved in the protection of key cellular elements i. Our group and others demonstrated that catalase expression is also altered in cancer cells, most likely to favor cell proliferation by inducing genetic instability and activation of oncogenes. The regulation of catalase expression appears to be mainly controlled at transcriptional levels although other mechanisms may also be involved.

Therefore, catalase can be a future therapeutic target in the context of cancer by using pro-oxidant approaches. The authors thank Professor Helmut Sies for the splendid discussion and his precious input. Akca, H. Enzyme Inhib. Search in Google Scholar. Akman, S. Antioxidant and xenobiotic-metabolizing enzyme gene expression in doxorubicin-resistant MCF-7 breast cancer cells. Cancer Res. Arenas, P. Echo-friendly synthesis and antiproliferative evaluation of oxygen substituted diaryl ketones.

Molecules 18 , — Baker, A. Expression of antioxidant enzymes in human prostatic adenocarcinoma. Prostate 32 , — The antitumor thioredoxin-1 inhibitor PX 1-methylpropyl 2-imidazolyl disulfide decreases thioredoxin-1 and VEGF levels in cancer patient plasma.

J Lab Clin Med. Barletta, C. Tumori 71 , — Bauer, G. Tumor cell-protective catalase as a novel target for rational therapeutic approaches based on specific intercellular ROS signaling. Anticancer Res. Increasing the endogenous NO level causes catalase inactivation and reactivation of intercellular apoptosis signaling specifically in tumor cells. Redox Biol. Mechanisms of selective antitumor action of cold atmospheric plasma-derived reactive oxygen and nitrogen species.

Plasma Process Polym. The antitumor effect of single-domain antibodies directed towards membrane-associated catalase and superoxide dismutase. Beck, R. Hsp90 cleavage by an oxidative stress leads to Bcr-Abl degradation and leukemia cell death.

An in vitro and in vivo mechanistic study. Invest New Drugs 29 , — Molecular chaperone Hsp90 as a target for oxidant-based anticancer therapies. Hsp90 is cleaved by reactive oxygen species at a highly conserved N-terminal amino acid motif. PLoS One 7 , e Benites, J.

Biological evaluation of donor-acceptor aminonaphthoquinones as antitumor agents. Extracellular localization of catalase is associated with the transformed state of malignant cells. Biol Chem. Brown, G. Reversible binding and inhibition of catalase by nitric oxide. Eur J Biochem. Brunelli, L. Modulation of catalase peroxidatic and catalatic activity by nitric oxide. Free Radic.

Buc Calderon, P. Potential therapeutic application of the association of vitamins C and K3 in cancer treatment. Chance, B. The enzyme-substrate compounds of catalase and peroxides. Nature , — The primary and secondary compounds of catalase and methyl or ethyl hydrogen peroxide; kinetics and activity. The mechanism of catalase action. Steady-state analysis.

Hydroperoxide metabolism in mammalian organs. Physiol Rev. Chung-man, H. Differential expression of manganese superoxide dismutase and catalase in lung cancer. Cullen, J. Expression of antioxidant enzymes in diseases of the human pancreas: another link between chronic pancreatitis and pancreatic cancer.

Pancreas 26 , 23— Deichman, G. Natural selection and early changes of phenotype of tumor cells in vivo: acquisition of new defense mechanisms. Biochemistry Mosc. Early phenotypic changes of in vitro transformed cells during in vivo progression: possible role of the host innate immunity.

Cancer Biol. Dejeans, N. Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells. Overexpression of GRP94 in breast cancer cells resistant to oxidative stress promotes high levels of cancer cell proliferation and migration: implications for tumor recurrence.

Demizu, Y. Alterations of cellular redox state during NNK-induced malignant transformation and resistance to radiation. Redox Signal. Dufier, J. Fenton, H. Oxidation of tartaric acid in presence of iron. Fita, I. USA 82 , — The active center of catalase. Fong, K. Correlation of loss of heterozygosity at 11p with tumour progression and survival in non-small cell lung cancer.

Genes Chromosomes Cancer 10 , — Forsberg, L. A common functional C-T substitution polymorphism in the promoter region of the human catalase gene influences transcription factor binding, reporter gene transcription and is correlated to blood catalase levels.

Gabdoulline, R. Concerted simulations reveal how peroxidase compound III formation results in cellular oscillations. Gebicka, L. Catalytic scavenging of peroxynitrite by catalase. Glorieux, C. Catalase overexpression in mammary cancer cells leads to a less aggressive phenotype and an altered response to chemotherapy. Regulation of catalase expression in healthy and cancer cells. Chromatin remodeling regulates catalase expression during cancer cells adaptation to chronic oxidative stress.

Life Sci. Goth, L. Catalase enzyme mutations and their association with diseases. Gregoire, M. Griffith, O. Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine S-n-butyl homocysteine sulfoximine.

Heinzelmann, S. Multiple protective functions of catalase against intercellular apoptosis-inducing ROS signalling of human tumor cells, Biol. Ho, Y. Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury. Hwang, T. Johansson, L. A spectrophotometric method for determination of catalase activity in small tissue samples, Anal. Jones, P. The mechanism of Compound I formation revisited. Kaimul, A. Thioredoxin and thioredoxin-binding protein-2 in cancer and metabolic syndrome.

Kalinina, E. Changes in expression of genes encoding antioxidant enzymes, heme oxygenase-1, Bcl-2, and Bcl-xl and in level of reactive oxygen species in tumor cells resistant to doxorubicin. Studies using type 1 and type 2 diabetic mice models with fold upregulated catalase expression showed amelioration in the functioning of the cardiomyocytes [ ].

Cardiomyopathy is related to improper functioning of heart muscles where the muscles become enlarged, thick, or stiff. It can lead to irregular heartbeats or heart failure. Many diabetic patients suffer from cardiomyopathy with structural and functional anomalies of the myocardium without exhibiting concomitant coronary artery disease or hypertension [ ]. As already discussed, catalase is interconnected to diabetes mellitus pathogenesis.

It has been observed that a fold increase of catalase activity could drastically reduce the usual features of diabetic cardiomyopathy in the mouse model [ ]. Due to catalase overexpression, the morphological impairment of mitochondria and the myofibrils of heart tissue were prevented. The impaired cardiac contractility was also inhibited with decrease in the production of reactive oxygen species mediated by high glucose concentrations [ ].

So this approach could be an effective therapeutic approach for the treatment of diabetic cardiomyopathy. An increase in focus on the role of catalase in the pathogenesis of oxidative stress-related diseases and its therapeutic approach is needed. Catalase plays a significant role in hydrogen peroxide metabolism as a key regulator [ 28 , 29 , — ]. Some studies have also shown the involvement of catalase in controlling the concentration of hydrogen peroxide which is also involved in the signaling process [ — ].

Acatalasemia is a rare genetic disorder which is not as destructive as other diseases discussed here, but it could be a mediator in the development of other chronic diseases due to prolonged oxidative stress on the tissues. We have also discussed the risk of type 2 diabetes mellitus among acatalasemic patients. But more research on the biochemical, molecular, and clinical aspects of the disease is necessary. There are many more questions about acatalasemia and its relation to other diseases which need to be answered.

Therefore, further studies are needed to focus on catalase gene mutations and its relationship to acatalasemia and other diseases with decreased catalase activity so that the link can be understood more completely. The therapeutic approaches using catalase needs more experimental validation so that clinical trials can be initiated.

Use of catalase as a medicine or therapy may be a new and broad field of study. Any novel finding about therapeutic uses of catalase will have a huge contribution in medical science. Positive findings can direct towards its possible use for treatment of different oxidative stress-related diseases.

Catalase is one of the crucial antioxidant enzymes which plays an important role by breaking down hydrogen peroxide and maintaining the cellular redox homeostasis.

While there are many factors involved in the pathogenesis of these diseases, several studies from different laboratories have demonstrated that catalase has a relationship with the pathogenesis of these diseases. Research in this area is being carried out by many scientists at different laboratories exploring different aspects of these diseases, but with an ever-increasing aging population, much remains to be achieved.

On the other hand, the potential of catalase as a therapeutic drug in the treatment of several oxidative stress-related diseases is not adequate and is still being explored. Additional research is needed to confirm if catalase may be used as a drug in the treatment of various age-related disorders. Supplementary Figure 1. In module 1, ACOX1 peroxisomal acyl coenzyme A oxidase , HSD17B4 peroxisomal multifunctional enzyme , and HAO1 hydroxyacid oxidase 1 are involved in the fatty acid oxidation pathway in the peroxisome while the protein DAO D amino acid oxidase is involved in the amino acid metabolism pathway in the peroxisome [ 4 — 6 ] Supplementary Figure 1.

Supplementary Materials. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors.

Read the winning articles. Journal overview. Special Issues. Academic Editor: Cinzia Signorini. Received 25 Mar Revised 18 Jun Accepted 14 Aug Published 11 Nov Abstract Reactive species produced in the cell during normal cellular metabolism can chemically react with cellular biomolecules such as nucleic acids, proteins, and lipids, thereby causing their oxidative modifications leading to alterations in their compositions and potential damage to their cellular activities.

Introduction Reactive species RS are highly active moieties, some of which are direct oxidants, and some have oxygen or oxygen-like electronegative elements produced within the cell during cellular metabolism or under pathological conditions.

Table 1. Examples of the various free radicals and other oxidants in the cell [ 2 ]. Figure 1. Relationship between catalase and other antioxidant enzymes.

Figure 2. Figure 3. Steps in catalase reaction: a first step; b second step. Table 2. Physicochemical characteristics of catalase from various sources. Figure 4. Figure 5. Figure 6. Association of catalase polymorphism with risk of some widespread diseases. Figure 7. Prevalence of diabetes amongst males and females in some countries in data source: World Health Organization-Diabetes Country Profile Types Position of mutation Types of mutation Results of mutation Effect on catalase References Type A Insertion of GA at position in exon 2 occurs which is responsible for the increase of the repeat number from 4 to 5 Frame shift mutation Creates a TGA codon at position Lacks a histidine residue, an essential amino acid necessary for hydrogen peroxide binding [ ] Type B Insertion of G at position 79 of exon 2 Frame shift mutation Generates a stop codon TGA at position 58 A nonfunctional protein is produced [ ] Type C A substitution mutation of G to A at position 5 in intron 7 Splicing mutation No change in peptide chain Level of catalase protein expression is decreased [ , ] Type D Mutation of G to A at position 5 of exon 9 Coding region mutation Replaces the arginine residue to histidine or cysteine Lowering of catalase activity [ ].

Table 3. References K. Halliwell and J. View at: Google Scholar M. Davis, S. Kaufman, and S. Szklarczyk, J. Morris, H. Cook et al. D1, pp. D—D, Kanehisa, Y. Sato, M. Furumichi, K. Morishima, and M. Kanehisa, M. Furumichi, M. Tanabe, Y. Sato, and K.

Kanehisa and S. Von Ossowski, G. Hausner, and P. Deisseroth and A. Ivancich, H. Jouve, B. Sartor, and J. Sumner and A. View at: Google Scholar D.

Herbert and J. Yabuki, S. Kariya, R. Ishisaka et al. Islam, Y. Kayanoki, H. Kaneto et al. Sandstrom and T. Kirkman and G. Putnam, A. Arvai, Y. Bourne, and J. Ko, M. Safo, F. Musayev et al. Musayev, S. Wu, D. Abraham, and T. Kirkman, M. Rolfo, A. Ferraris, and G. Al-Abrash, F. Al-Quobaili, and G. View at: Google Scholar L. Habib, M. Lee, and J. Gaetani, A. Ferraris, M. Roflo, R. Mangerini, S. Arena, and H. View at: Google Scholar S. Mueller, H. Riedel, and W. Tiedge, S.

Lortz, J. Drinkgern, and S. Lortz, R. Munday, and S. Park, E. Ha, Y. Uhm et al. Kodydkova, L. Vavroa, M. Kocik, and A. Chistiakov, K. Savost'anov, R. Turakulov et al. Quick, P. Shields, J. Nie et al. Ahn, M. Gammon, R. Santella et al. Forsberg, L.

Morgenstern, and U. Tarnai, M. Shemirani, M. Jiang, J. Akey, J. Shi et al. Watanabe, H. Metoki, T. Ohkubo et al. Fabre, A. Raynaud-Simon, J. Golmard et al. Liu, C. Li, J. Gao et al. Kim, J. Hong, B. Oh et al. Casp, J. She, and W. Gavalas, S. Akhtar, D. Gawkrodger, P. Watson, A. Weetman, and E. Rolo and C. Chiang, M.

Kirkman, L. Laffel, A. Laugesen, J. Juneja, I. Hirsch, R. Naik, B. Brooks-Worrell, C. Greenbaum, and J. Murata, M. Imada, S. Inoue, and S. Jorns, M. Lenzen, and R. Msolly and A. View at: Google Scholar K. Grankvist, S. Marklund, and I.

S4—S5, Ewald, C. Kaufmann, A. Raspe, H. Kloer, R. Bretzel, and P. Bhattamisra, T. Siang, C. Rong et al. Sasikala, R. Talukdar, P. Pavan kumar et al. Fujimoto and K. Li and J. Veal and A. Meszaros, L. Simeoni and D. Simeoni, I. Ligi, C. Buffat, and F. Toth, I. Berces, P. Torok, and W. Lekharu, R. Predhan, R. Sharma, and D. Lappas, A. Mittion, and M. Ivashchenko, P. Brees, Y. Ho, S. Terlecky, and M. Woo, S. Yim, D. Shin, D. Educational portal of. Molecule of the Month. Catalase Catalase protects us from dangerous reactive oxidizing molecules Catalase, with the heme in red and the central iron in green.

Living with oxygen is dangerous. We rely on oxygen to power our cells, but oxygen is a reactive molecule that can cause serious problems if not carefully controlled. One of the dangers of oxygen is that it is easily converted into other reactive compounds. Inside our cells, electrons are continually shuttled from site to site by carrier molecules, such as carriers derived from riboflavin and niacin.

If oxygen runs into one of these carrier molecules, the electron may be accidentally transferred to it. This converts oxygen into dangerous compounds such as superoxide radicals and hydrogen peroxide, which can attack the delicate sulfur atoms and metal ions in proteins.

To make things even worse, free iron ions in the cell occasionally convert hydrogen peroxide into hydroxyl radicals. These deadly molecules attack and mutate DNA. One theory, still controversial, is that this type of oxidative damage accumulates over the years of our life, causing us to age. Fortunately, cells make a variety of antioxidant enzymes to fight the dangerous side-effects of life with oxygen.

Two important players are superoxide dismutase, which converts superoxide radicals into hydrogen peroxide, and catalase, which converts hydrogen peroxide into water and oxygen gas. The importance of these enzymes is demonstrated by their prevalence, ranging from about 0. These many catalase molecules patrol the cell, counteracting the steady production of hydrogen peroxide and keeping it at a safe level.

Catalases are some of the most efficient enzymes found in cells. Each catalase molecule can decompose millions of hydrogen peroxide molecules every second.