Sandbox HEC
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Human erythrocyte catalase is used to protect hemoglobin by removing hydrogen peroxide generated from erythrocytes. Human catalase is a heme-containing enzyme whose primary function is to break down hydrogen peroxide into two molecules of water and one molecule of oxygen. Human catalase plays a major part in the defense against oxidative damage and inactivation of hemoglobin by removing the hydrogen peroxide formed by human erythrocytes <ref name="putnam">PMID:10656833</ref> . Hydrogen peroxide is a byproduct of normal cellular respiration, but is toxic at high concentrations. If catalase does not break down hydrogen peroxide, it gets converted into a reactive oxygen species and can damage DNA, proteins, and cell membranes <ref name="goth">PMID:15771551</ref>. Human catalase enzyme has been noted as an important factor in prevention of apoptosis and stimulation of tumors. During a normal catalytic cycle hydrogen peroxide is the source of both oxidative and reductive potential. NADPH has been known to also bind to human catalase, however, it does not serve as an oxidizing or reducing agent, but protects the catalase from being inactivated by hydrogen peroxide <ref name="putnam" />. | Human erythrocyte catalase is used to protect hemoglobin by removing hydrogen peroxide generated from erythrocytes. Human catalase is a heme-containing enzyme whose primary function is to break down hydrogen peroxide into two molecules of water and one molecule of oxygen. Human catalase plays a major part in the defense against oxidative damage and inactivation of hemoglobin by removing the hydrogen peroxide formed by human erythrocytes <ref name="putnam">PMID:10656833</ref> . Hydrogen peroxide is a byproduct of normal cellular respiration, but is toxic at high concentrations. If catalase does not break down hydrogen peroxide, it gets converted into a reactive oxygen species and can damage DNA, proteins, and cell membranes <ref name="goth">PMID:15771551</ref>. Human catalase enzyme has been noted as an important factor in prevention of apoptosis and stimulation of tumors. During a normal catalytic cycle hydrogen peroxide is the source of both oxidative and reductive potential. NADPH has been known to also bind to human catalase, however, it does not serve as an oxidizing or reducing agent, but protects the catalase from being inactivated by hydrogen peroxide <ref name="putnam" />. | ||
| - | [[Image:Hec.jpg.png | thumb |left|400px|'''Structure of Human Erythrocyte Catalase''' This figure shows an individual subunit of human catalase (a), an arm-exchanged dimer with a catalase fold where both heme active sites are exposed on one surface (b), and a catalase tetramer with the addition of a second arm exchanged dimer where the heme active site is buried within the enzyme. In this figure the beta-barrel domain is colored yellow, the alpha helices are blue, NADPH is dark green, and the active site heme is red. <ref name="putnam" />]] | + | [[Image:Hec.jpg.png | thumb |left|400px|'''Structure of Human Erythrocyte Catalase''' This figure shows an individual subunit of human catalase (a), an arm-exchanged dimer with a catalase fold where both heme active sites are exposed on one surface (b), and a catalase tetramer with the addition of a second arm exchanged dimer where the heme active site is buried within the enzyme. In this figure, the beta-barrel domain is colored yellow, the alpha helices are blue, NADPH is dark green, and the active site heme is red. <ref name="putnam" />]] |
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| - | Human erythrocyte catalase is a negatively charged heme-containing monofunctional tetrameric enzyme that is prevalent among aerobic organisms <ref name= "Kodydková" >PMID:25152049</ref><ref name=Alfonso-Prietro>PMID:22516655</ref><ref name=Dash>PMID:22521743</ref><ref name=Diaz>PMID:22209752 </ref><ref name=Nishikawa>PMID:19385054 </ref>. The catalase fold contains an eight-sheeted anti-parallel beta-barrel domain linked to a six alpha-helical domain via a lengthy protein sequence. Residues within β1-β4 contribute to the heme variant, while residues within β5-β8 establish the NADPH binding site <ref name="Diaz" />. The positioning of the heme is determined by the proximal aromatic pyrrole compounds; in human erythrocyte catalase, catalytic His75 is <scene name='72/728053/Position_of_his75/ | + | Human erythrocyte catalase is a negatively charged heme-containing monofunctional tetrameric enzyme that is prevalent among aerobic organisms <ref name= "Kodydková" >PMID:25152049</ref><ref name=Alfonso-Prietro>PMID:22516655</ref><ref name=Dash>PMID:22521743</ref><ref name=Diaz>PMID:22209752 </ref><ref name=Nishikawa>PMID:19385054 </ref>. The catalase fold contains an eight-sheeted anti-parallel beta-barrel domain linked to a six alpha-helical domain via a lengthy protein sequence. Residues within β1-β4 contribute to the heme variant, while residues within β5-β8 establish the NADPH binding site <ref name="Diaz" />. The positioning of the heme is determined by the proximal aromatic pyrrole compounds; in human erythrocyte catalase, catalytic His75 is <scene name='72/728053/Position_of_his75/3'>positioned</scene> above pyrrole ring III, further producing a His-III orientation and heme-b variant. The <scene name='72/728053/Active_site_1/2'>NADPH Binding site </scene> is located at the β,α-domain junction <ref name="Alfonso-Prietro" /><ref name="Diaz" />. When the NADPH molecule is bound, a right-handed clockwise helical formation is produced. In human erythrocyte catalase, only two of the four subunits allow for NADPH binding <ref name="Kodydková" /><ref name="Diaz" />. The active site contains a negatively charged tyrosine and a positively charged histidine situated, respectively, proximal and distal to the heme group. The histidine is responsible for the formation of Compound I during the first step of the catalase mechanism <ref name="Alfonso-Prietro" />. |
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[[Image:HEC mechanism.jpg.png|thumb|400px|'''Human Erythrocyte Catalase Mechanism''' This figure illustrates the two step mechanism of catalase. ]] | [[Image:HEC mechanism.jpg.png|thumb|400px|'''Human Erythrocyte Catalase Mechanism''' This figure illustrates the two step mechanism of catalase. ]] | ||
| - | == Mechanism == | ||
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Stable forms of hydrogen peroxide are beneficial in biological reactions including hypoxia signal transduction, cell proliferation and differentiation regulation, as well as immune response mediation; however, it is toxic at high levels as free hydroxyl ions cannot be catalyzed by the body <ref name= Lennicke >PMID:26369938</ref>. Hydrogen peroxide acts to both the oxidizing and reducing agent of the iron. Catalase ultimately functions to break down hydrogen peroxide<ref name="Dash" />. This is accomplished in a two-step mechanism where the heme is first oxidized by a molecule of hydrogen peroxide to produce Compound I, a high energy oxyferryl cation radical intermediate, as well as a water molecule. Compound I is then immediately reduced by a second hydrogen peroxide molecule to produce a second molecule of water <ref name="Alfonso-Prietro" /><ref name="Diaz" />. The overall reaction results in two single-electron transfers from the iron atom of the heme group and the porphyrin from the oxoferryl radical, as well as a proton transfer from histidine. The mechanism is enthalpically driven by the distal histidine proton transfer as it is more exothermic than the electron transfers <ref name="Alfonso-Prietro" /><ref name="Diaz" /> . | Stable forms of hydrogen peroxide are beneficial in biological reactions including hypoxia signal transduction, cell proliferation and differentiation regulation, as well as immune response mediation; however, it is toxic at high levels as free hydroxyl ions cannot be catalyzed by the body <ref name= Lennicke >PMID:26369938</ref>. Hydrogen peroxide acts to both the oxidizing and reducing agent of the iron. Catalase ultimately functions to break down hydrogen peroxide<ref name="Dash" />. This is accomplished in a two-step mechanism where the heme is first oxidized by a molecule of hydrogen peroxide to produce Compound I, a high energy oxyferryl cation radical intermediate, as well as a water molecule. Compound I is then immediately reduced by a second hydrogen peroxide molecule to produce a second molecule of water <ref name="Alfonso-Prietro" /><ref name="Diaz" />. The overall reaction results in two single-electron transfers from the iron atom of the heme group and the porphyrin from the oxoferryl radical, as well as a proton transfer from histidine. The mechanism is enthalpically driven by the distal histidine proton transfer as it is more exothermic than the electron transfers <ref name="Alfonso-Prietro" /><ref name="Diaz" /> . | ||
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Acatalasemia is also associated with type 2 diabetes mellitus, the most common form of diabetes. The build-up of hydrogen peroxide from the decrease in human erythrocyte catalase activity can damage beta cells in the pancreas. The pancreas releases insulin, which helps the body regulate your blood sugar levels. However, the damaged beta cells cannot utilize the insulin as well as normal beta cells, which leads to type 2 diabetes mellitus. These defective beta cells are thought to be why people with acatalasemia have an increased risk for type 2 diabetes mellitus. A larger percentage of people with diabetes have acatalasemia than those without. Those with acatalasemia also tend to develop diabetes at an earlier age <ref name="Góth" />. | Acatalasemia is also associated with type 2 diabetes mellitus, the most common form of diabetes. The build-up of hydrogen peroxide from the decrease in human erythrocyte catalase activity can damage beta cells in the pancreas. The pancreas releases insulin, which helps the body regulate your blood sugar levels. However, the damaged beta cells cannot utilize the insulin as well as normal beta cells, which leads to type 2 diabetes mellitus. These defective beta cells are thought to be why people with acatalasemia have an increased risk for type 2 diabetes mellitus. A larger percentage of people with diabetes have acatalasemia than those without. Those with acatalasemia also tend to develop diabetes at an earlier age <ref name="Góth" />. | ||
| - | Common variations in the human erythrocyte gene and variations in the regions of DNA that help to regulate the gene’s activity may also lead to an increased risk of a person developing specific common, complex diseases such as hypertension, osteoporosis, heart attack and stroke due to the elevated levels of cholesterol and other fats in the blood <ref name="Góth" />. However, not all people experience health problems when they have a loss of catalase activity and others do not have an identified mutation in the human erythrocyte catalase gene when they have a loss in catalase activity. The cause of both of these situations is unclear. | + | Common variations in the human erythrocyte gene and variations in the regions of DNA that help to regulate the gene’s activity may also lead to an increased risk of a person developing specific common, complex diseases such as hypertension, osteoporosis, heart attack and stroke due to the elevated levels of cholesterol and other fats in the blood <ref name="Góth" />. However, not all people experience health problems when they have a loss of catalase activity and others do not have an identified mutation in the human erythrocyte catalase gene when they have a loss in catalase activity. The cause of both of these situations is unclear. It has been hypothesized by Dr. Laszlo Goth and Dr. John Eaton that the activity is also influenced by other genetic factors as well as environmental conditions<ref name="Góth" />. |
== References == | == References == | ||
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