There are three major types of autoantibodies found in type 1 diabetes such as GDP65, IA2, and insulin autoantibodies, but antibodies against insulin can be identified mostly in young patients and may be lacking in adults [ 52 , 53 ].
These antibodies bind mainly to the conformational epitopes on the B chain of insulin. The genetic feature shows a relationship between type 1 diabetes and some alleles of the HLA complex. There is a strong connection between the progression of type 1 diabetes and the presence of HLA class II alleles. Oxidative stress has been demonstrated to be an important factor responsible for the advancement of type 2 diabetes.
According to a study from Prof. Another form of diabetes known as pancreatogenic diabetes has been classified as type 3c diabetes mellitus T3cDM.
T3cDM is the result of pancreatitis both acute and chronic , cystic fibrosis in the tissue of pancreas, inflammation, and damage of pancreatic tissue [ 58 , 59 ]. The damage of exocrine pancreatic peptide PP and pancreatic enzymes occurs at the early phase of pancreatic diabetes. The resultant elevated level of glucagon can lead to hyperglycemia in diabetes mellitus [ 60 ].
There are many aspects associated with the pathophysiology of pancreatic diabetes. Immunopathogenesis is one of the important aspects which contribute to the development of pancreatic diabetes. Hydrogen peroxide plays a central role in this pathway as a signaling molecule [ 64 ]. At lower concentration, hydrogen peroxide plays as a signaling molecule while it becomes toxic at higher concentration [ 65 ] and catalase plays an important role in maintaining homeostasis of the cells by degrading hydrogen peroxide.
The activity of catalase in the serum was observed to be high in acute pancreatitis [ 66 ] and persists at its elevated level for as long as 10 to 14 days [ 66 ].
Therefore, the high catalase activity may contribute to the pathogenesis of T3cDM in an indirect way by maintaining the hydrogen peroxide concentration which would induce the synthesis of proinflammatory cytokines resulting in pancreatic diabetes.
Gestational diabetes mellitus GDM is another common form of diabetes among pregnant women. The pathogenesis of GDM is very similar to type 2 diabetes mellitus. There are several factors including ethnicity, maternal age, hypertension, obesity, and polycystic ovary syndrome PCOS which are associated with the possibility of developing GDM [ 67 , 68 ]. Pregnant women with GDM have higher risk of developing type 2 diabetes mellitus after pregnancy [ 68 ].
The offspring of gestational diabetic mothers are prone to development of different diseases like hypertension, different metabolic syndrome, and chronic kidney disease [ 69 , 70 ]. These birth defects might be due to higher concentration of reactive oxygen species and lowering of the antioxidant defense which in turn make the cell more susceptible to oxidative insults [ 70 , 71 ].
GDM usually develops in the second and third trimesters of the pregnancy period. Reports on the link of catalase with GDM are very conflicting. It has been reported that oxidative stress is high in the second and third trimesters of pregnancy and the catalase activity was also low during this period [ 72 , 73 ]. The blood catalase activity has been reported to be low in pregnant women with GDM compared to nonpregnant and pregnant nondiabetic healthy control women [ 72 ].
However, the blood catalase activity was observed to increase in the third trimester than in the second trimester in pregnant individuals with GDM [ 72 ].
In another study, low blood catalase activity has been observed in pregnant women with GDM [ 40 ]. The mRNA expression of the CAT gene in the placenta of gestational diabetic pregnant women was found to be higher in comparison to that in normal pregnant women [ 74 ]. So it may be concluded from the above that catalase might have a relation with GDM pathophysiology during pregnancy, but further research to establish the facts is needed. Hydrogen peroxide has been implicated to act as a cellular messenger in the signaling pathway for insulin secretion by inactivating tyrosine phosphatase [ 65 , 75 — 78 ].
It has been postulated that catalase in the liver may confer cellular protection by degrading the hydrogen peroxide to water and oxygen [ 28 — 31 ]. Lack of catalase can contribute to the development of diabetes mellitus [ 76 , 79 ] with a positive correlation being observed between diabetes mellitus in acatalasemic patients.
It is estimated that approximately It was proposed that catalase deficiency may be responsible for the development of diabetes mellitus in an indirect way [ 24 ]. These cells are not only deprived of catalase but also have a higher concentration of mitochondria [ 80 ] which is one of the major sources of superoxide and hydrogen peroxide in the cell through the electron transport pathway. There are many vascular complications in diabetes mellitus including microvascular complications diabetic retinopathy, nephropathy, neuropathy, etc.
Oxidation plays an important role in different complications which occur in both type 1 and type II diabetes. Due to the low expression levels or activity of catalase, the concentration of hydrogen peroxide may increase in the cells creating oxidative stress conditions causing the progression of different types of complications.
In the case of diabetes retinopathy, the retina is damaged by retina neovascularization where new vessel origination from existing veins extends to the retinal inner cells [ 82 ] leading to blindness [ 83 ]. Vascular endothelial growth factor VEGF is a prime inducer of angiogenesis, a procedure of new vessel development. It causes the generation of hydrogen peroxide instead of other reactive species [ 84 ]. Hydrogen peroxide may have a role as a signaling molecule in the VEGF signaling molecule.
In a study on a diabetic rat model, high concentration of hydrogen peroxide was observed in the retinal cells, creating oxidative stress conditions within the cell [ 85 ]. Since retinal cells have high content of polyunsaturated fatty acid content [ 86 ], they can be oxidized by the hydroxyl radicals generated from hydrogen peroxide by the Fenton reaction. High levels of lipid peroxides and oxidative DNA damage have been observed in diabetic retinopathy [ 87 — 90 ].
In a recent study, researchers have been able to distinguish five distinct clusters of diabetes by combining parameters such as insulin resistance, insulin secretion, and blood sugar level measurements with age of onset of illness [ 91 ].
Group 1 essentially corresponds to type 1 diabetes while type 2 diabetes is further subdivided into four subgroups labelled as group 2 to group 5.
Individuals with impaired insulin secretion and moderate insulin resistance are labelled under group 2 the severe insulin-deficient diabetes group while in group 3, the severe insulin-resistant diabetes patients with obesity and severe insulin resistance are included. Group 4 is composed of the mild obesity-related diabetes patients who are obese and fall ill at a relatively young age while the largest group of patients is in group 5 with mild age-related diabetes in mostly elderly patients. A relationship between this new classification of diabetes with catalase expression levels or its activity has still not been probed for a link, if any, and needs further research.
Many factors including smoking and diabetes are associated with a higher risk of dementia. Its clinical manifestations include bradykinesia, rigidity, resting tremor, and postural instability.
It starts with rhythmic tremor of limbs especially during periods of rest or sleep. At the developing stage of the disease, patients face difficulties in controlling movement and muscle rigidity. Due to this muscular rigidity, slowness of movement and slowness of initiation of movement occur. The disease is characterized by the exhaustion of dopamine due to damage of dopamine-producing neurons in the substantia nigra pars compacta SNpc [ — ].
The small neurotransmitter molecules like dopamine are synthesized in the cytoplasm and are transferred to small vesicles as it becomes oxidized at the physiological pH. Vitiligo is one of the chronic pigmentary disorders where skin melanocyte cells—the pigment responsible for the color of the skin—are damaged or are unable to produce melanin. Various studies have shown that the catalase levels in the epidermis of vitiligo patients are lower as compared to those of the healthy control subjects [ , ] with a resultant increase in the concentration of hydrogen peroxide.
In the cell, hydroxyl radicals can be produced spontaneously from hydrogen peroxide through photochemical reduction, i. These hydroxyl radicals are able to oxidize lipids in the cell membrane.
This may be the cause behind damage of keratinocytes and melanocytes in the epidermal layer of the skin in such patients [ — ]. Moreover, the inhibitory effect of hydrogen peroxide or allelic modification of the CAT gene results in low catalase activity. However, it has been observed that there is an erratic relationship between catalase polymorphism and vitiligo. But the results were not observed to be consistent.
Though the results are inconsistent from population studies, an interconnection between the pathogenesis and catalase may still be possible as scattered demonstrations are reported in the literature.
Therefore, further studies to understand the link is necessary. Acatalasemia AC is a hereditary disorder which is linked with the anomaly of catalase enzyme affecting its activity. In , Takahara, a Japanese otolaryngologist, first reported this disorder [ , ].
He found that four out of seven races in Japan had the same genetic flaw [ ]. His ex vivo experiments consisted of filling the mouth ulcer of a diseased patient with hydrogen peroxide. Since no bubble formation was observed, he concluded that a catalase or its enzymatic activity is absent in the saliva of the patients. In honor of his primary findings, this disease was christened as the Takahara disease. Acatalasemia and hypocatalasemia signify homozygotes and heterozygotes, respectively.
The heterozygote of acatalasemia shows half of the catalase activity than normal and this phenotype is known as hypocatalasemia [ ]. Depending on the geographical location from where it has been first studied, there are different types of acatalasemia described as Japanese, Swiss, Hungarian, German, and Peruvian types. Approximately acatalasemic patients have been reported to date from all over the world.
Two kinds of mutations in the catalase gene have been reported to be involved in the Japanese acatalasemia. A splicing mutation has been held responsible for Japanese acatalasemia I where a substitution of a guanine residue with adenine residue at position 5 of intron 4 disturbed the splicing pattern of the RNA product producing a defective protein [ ]. In Japanese acatalasemia II, a frame shift mutation occurs due to the deletion of thymine in position of exon 4 which modifies the amino acid sequence and produces a new TGA stop codon at the 3 terminal.
Translation of this mutated strand produces a polypeptide of amino acid residues. This is a truncated protein that is unstable and nonfunctional [ ]. Aebi et al. The study on the fibroblast from Swiss acatalasemia patients suggests that structural mutations in the CAT gene are responsible for inactivation of catalase [ ].
Goth, a Hungarian biochemist, first described Hungarian acatalasemia in after studying the disease in two Hungarian sisters. He found that the catalase activities in the blood of these two acatalasemic sisters were 4. Studies at his laboratory led Goth to suggest that mutations of the CAT gene and resultant structural changes in the catalase protein are responsible for Hungarian acatalasemia.
This laboratory also reported that there was a risk of diabetes mellitus amongst the Hungarian acatalasemic family members though further biochemical and genetic analysis needs to be performed to validate the hypothesis that acatalasemic patients have more chance of developing diabetes mellitus [ 79 ]. There are generally four types of Hungarian acatalasemia which varies according to the different site of gene mutation in the DNA.
The same is represented in Table 3. Catalase is one of the most important antioxidant enzymes. As it decomposes hydrogen peroxide to innocuous products such as water and oxygen, catalase is used against numerous oxidative stress-related diseases as a therapeutic agent. The difficulty in application remains in delivering the catalase enzyme to the appropriate site in adequate amounts.
Poly lactic co-glycolic acid nanoparticles have been used for delivering catalase to human neuronal cells, and the protection by these catalase-loaded nanoparticles against oxidative stress was evaluated [ ]. The nanoparticle-loaded catalase showed significant positive effect on neuronal cells preexposed to hydrogen peroxide reducing the hydrogen peroxide-mediated protein oxidation, DNA damage, mitochondrial membrane transition pore opening, and loss of membrane integrity.
Thus, the study suggests that nanoparticle-loaded catalase may be used as a therapeutic agent in oxidative stress-related neurological diseases [ ]. EUK is a salen-manganese complex which has both high catalase and superoxide dismutase activity. It was concluded from these studies on the rat stroke model that EUK may play a protective role in management of this disease. To study the effect of these fusion proteins under oxidative stress conditions, mammalian cell lines HeLa, PC12 were transduced with purified fusion Tat-CAT and 9Arg-CAT protein and these cells were exposed to hydrogen peroxide.
It was found that the viability of the transduced cells increased significantly. It was also observed that when the Tat-CAT and 9Arg-CAT fusion proteins were sprayed over animal skin, it could penetrate the epidermis and dermis layers of the skin. This study suggests that these fusion proteins can be potentially used as protein therapeutic agents in catalase-related disorders [ ].
Amyotrophic lateral sclerosis ALS is one of the most common types of progressive and fatal neurological disorders which results in loss of motor neurons mostly in the spinal cord and also to some extent in the motor cortex and brain stem. Rather, the mutated SOD1 has toxic properties with no lowering of the enzymatic activity. This mutated SOD1 protein reacts with some anomalous substrates such as hydrogen peroxide using it as a substrate and produces the most reactive hydroxyl radical which can severely damage important biomolecules [ ].
Mutated SOD1 also has the potential to use peroxynitrite as an atypical substrate leading to the formation of 3-nitrotyrosine which results in the conversion of a functional protein into a nonfunctional one [ ]. Catalase can reduce the hydrogen peroxide concentration by detoxifying it.
Therapeutic approaches using putrescine-modified catalase in the treatment of FALS have also been attempted [ ]. It was found that putrescine-catalase—a polyamine-modified catalase—delayed the progression of weakness in the FALS transgenic mouse model [ ]. Thus, the delay in development of clinical weakness in FALS transgenic mice makes the putrescine-modified catalase a good candidate as a therapeutic agent in diseases linked with catalase anomaly.
In this connection, it must be mentioned that the putrescine-modified catalase has been reported to exhibit an augmented blood-brain barrier permeability property while maintaining its activity comparable to that of native catalase with intact delivery to the central nervous system after parenteral administration [ ].
Therefore, further studies with this molecule seem to be warranted. Investigations using synthetic SOD-catalase mimetic, increase in the lifespan of SOD2 nullizygous mice along with recovery from spongiform encephalopathy, and alleviation of mitochondrial defects were observed [ ]. 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 [ ].
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Your documents are now available to view. Confirm Cancel. Accessible Published by De Gruyter April 6, Christophe Glorieux and Pedro Buc Calderon. From the journal Biological Chemistry. Cite this. Abstract This review is centered on the antioxidant enzyme catalase and will present different aspects of this particular protein. Keywords: antioxidant enzyme ; cancer ; catalase ; catalase regulation ; hydrogen peroxide ; pro-oxidant therapy. Figure 1: Time line of catalase main discoveries and findings.
Table 1: Catalase gene polymorphisms in patients suffering from hypocatalasemia or acatalasemia. Table 2: Catalase enzyme activity in cells from diver origins. Type of cells Normal origin Cancer origin References Mouse hepatocytes Figure 2: Hypothetical mechanism of catalase regulation in breast cancer cell lines.
Figure 3: The quinone redox cycling hypothesis. Figure 4: Arsenic trioxide ATO decreases catalase expression in breast cancer cells and sensitizes them to pro-oxidant drugs. Acknowledgments The authors thank Professor Helmut Sies for the splendid discussion and his precious input.
Received: Accepted: Published Online: Published in Print: Article Catalase, a remarkable enzyme: targeting the oldest antioxidant enzyme to find a new cancer treatment approach Christophe Glorieux, Pedro Buc Calderon Catalase, a remarkable enzyme: targeting the oldest antioxidant enzyme to find a new cancer treatment approach. Biological Chemistry , 10 , Biological Chemistry, Vol.
Glorieux, Christophe and Calderon, Pedro Buc. Glorieux C, Calderon P. Biological Chemistry. Copy to clipboard. Log in Register. The results obtained are presented in Figure 3 a, b, c. All mitochondrial fractions contained a single band specifically stained for catalase.
At the same time the visualization of the peroxidase activity was not successful, probably due to very low activity of the protein Figure 4. The low peroxidase activity, measured spectrophotometrically, could be due to some kind of peroxidase activity of the catalase, as it has been shown for Candida boidinii Ueda et al. The results obtained for the mitochondrial catalase in the three strains clearly indicated that a catalase enzyme located in the mitochondria of Saccharomyces cerevisiae exists.
The Rm value of the enzyme pattern is 0. From the data presented in Figure 3 , it is evident that for all strains studied, the electrophoretic pattern of the mitochondrial catalase is different from the known profile for these enzymes in Saccharomyces cerevisiae Traczyk et al.
Obviously the concentrations of this protein in the total cell-free extract, where catalase A and T has been found, is very low and its visualization becomes possible after isolation of pure mitochondrial fraction.
Its availability in three different strains of Saccharomyces cerevisiae indicated that it is their common feature. Evidence for correlation of mitochondrial catalase with Mn superoxide dismutase activity.
These investigations were performed with the three Saccharomyces cerevisiae strains , and using the mitochondrial fraction obtained from different hours of cultivation. The dynamics of above mentioned enzyme activities are presented in Figure 5 a, b, c. These data clearly showed that the specific activities of catalase and Mn superoxide dismutase enzymes correlated with the growth and their maximum has been measured at 48 h of cultivation.
These results suggested that the role of mitochondrial catalase is coupled mainly with the function of manganese superoxide dismutase for detoxification of mitochondria from reactive oxygen species, generated during respiratory processes within these organelles. The presence of low peroxidase activity indicated that it also takes part in this reaction of the cells as an additional mechanism.
Evidently enzymes catalase and superoxide dismutase play the basic detoxifying function in the mitochondria. High activity of antioxidant enzymes found during cultivation on YPD medium in spite of the presence of glucose as a carbon source indicated that a respiratory metabolism also takes place, because of the formation of ethanol Walker, It is well known that Saccharomyces cerevisiae utilize glucose in aerobic conditions mainly fermentatively Kappeli, , but the diauxic growth and high values of Ys showed that utilization of additional growth substrates likely occurred.
Determination of charge and molecular weight of Saccharomyces cerevisiae mitochondrial catalase. The native PAGE method developed by Hedrick and Smith, provides site estimation for proteins analyzed on gels of successive high acrylamide concentration. As it has been mentioned above, the molecular weight of catalase T is between - kD, and for catalase A - considerably lower - kD.
The electrophoretic pattern shows abnormal mobility of both cytosolic catalase enzymes. Applying the method of Hedrick and Smith, , investigation of their behavior in native PAGE with different concentrations of acrylamide was performed Figure 6.
The results obtained Figure 6 and Figure 7 suggest that both enzymes are charge isomers which explains why catalase A, although with lower molecular weight possess lower Rm value than catalase T. Evaluating the plot of Rm, the mitochondrial enzyme could be also considered as charge isomer. For estimation the molecular weight of the mitochondrial enzyme, comparison of its relative mobility with the ones of known proteins was done Figure 8. Plotting the HRm against molecular weight values of the markers allowed drawing an equation, describing the electrophoretic profile Figure 9.
On this basis we could calculate the MW of the mt enzyme, which is approximately Da. These data open the question about the origin of this new catalase protein, located in the mitochondria and its relationship to catalases A and T.
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