Human MnSOD and Cancer Research

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History

Since their discovery in 1968, all forms of Superoxide dismutases have proven to be very important antioxidants that play a huge role in cellular health, however, the mechanism in which they convert ROS to hydrogen peroxide and oxygen is still unknown ^[2]. The most significant SOD is the human body is the human manganese superoxide dismutase, which deals with the majority of the created ROS in the mitochondria’s matrix ^[2].

Structure

Human Superoxide Dismutase (MnSOD) is a 22kD homotetrameric protein that is characterized by each subunit containing an N-terminus helical hairpin and alpha/beta domain that contribute to the catalytic site, the enzyme has four manganese active sites ^[3]. MnSOD alpha and beta C-terminus domains contain a “...three stranded antiparallel beta-sheet and five alpha-helices” ^[3]. The N-terminus helical hairpins are composed of “...two long antiparallel alpha-helices separated by a tight turn to form a helical hairpin” (Borgstahl et al). The active sites themselves are positioned between the helical and beta-sheet areas, while also joining the two domains ^[3]. A couple of amino acid residues from both domains and a water molecule are responsible for the ligation of Manganese ^[3]. The four active sites associate in pairs on either side of the enzyme. PMID: 8464931

Function

Human Manganese Superoxide Dismutase functions to rid the cell of reactive oxygen species. Reactive oxygen species (ROS) are free radical oxygen species/molecules that are derived from molecular oxygen (Turrens). ROS will oxidize various biomolecules within the cell, whether that be fatty acids or DNA. ROS are naturally created as a byproduct of oxidative phosphorylation. In complex IV of the electron transport chain, electrons are transferred through to reduce oxygen gas to water. However, when electrons are brought into contact with oxygen via other parts of the chain, then we have the potential for oxygen gas to become an oxygen radical anion species (Turrens). There are a variety of defenses that take care of these species. One of these is MnSOD. In the mitochondrial matrix, MnSOD is present, which allows it to bind and convert ROS in its active sites to produce hydrogen peroxide and oxygen gas. MnSOD has a Kcat of 40,000 1/s and a Kcat/Km of 10^9, making it one of the fastest/most efficient enzymes ^[2]. The levels of MnSOD increase as certain factors like high levels of oxygen and radiation that are present through the activation of the transcription factor NF kappa B (Turrens). Human Manganese Superoxide dismutase is a current protein of interest due to its role in the protection of the mitochondrial DNA from ROS that will react and cause destruction of the nucleic acids ^[3].

Diseases/Research

Human Manganese Superoxide Dismutase has been recently studied due to its role in malignancy in cancer. It was shown that when MnSOD is overexpressed so that there is a large amount of MnSOD present in the cancerous cells, there was a decrease in the multiplicity of those cells (UVB). Moreover, it was also shown in a “...mouse skin keratinocyte model…” that overexpression of MnSOD can also protect mitochondrial proteins from UVB radiation (UVB). When MnSOD was deactivated by UVB radiation, which is caused by the disruption of active site Tyr34 residues via nitration by the formation of Peroxynitrite (Dhar et al). Peroxynitrite is created by the combination of Nitric oxide and Superoxide. The effect of this nitration can have various effects on function depending upon which residues are nitrated (Dhar et al). By altering the tyrosine residues peroxynitrite decreases the activity of MnSOD. The deactivation of MnSOD showed that the cell increased its ability to undergo autophagy via signaling pathways that depend on the relative level of ROS in the cell, this allows the cell to stop the buildup of defective mitochondria (Dhar et al). If the level of ROS and defective mitochondria is lethal then the cell will undergo apoptosis (Dhar et al). If MnSOD is deactivated then we will have an increase of ROS in the cell, this will cause oxidative stress. It has been shown that this oxidative stress promotes tumor formation and cell division ^[4]. The Human Manganese SOD gene was located to be on chromosome six, this area of DNA was found to be missing in cases of malignant melanoma ^[4]. This shows that MnSOD plays a big role by degrading ROS as well as a role in tumor growth/malignancy. This characteristic of MnSOD is why MnSOD is being targeted in recent research.

SODs, in general, have also been used in response to the side effects of radiation therapy. While undergoing radiation therapy or chemotherapy the patient’s cells become quite toxic due to an increase in the amount of ROS, this occurs in both tumor cells and normal tissue. Although its greater in cancer cells there is still considerably toxicity in regular human tissue (“Utilizing Superoxide Dismutase”). One of the drugs that are being used is GC4419 which is a class of Mn (II) SOD, it is very specific for the removal of superoxide and no other ROS (“Utilizing Superoxide Dismutase”). The reason this medication is thought to be protective of normal tissue is that in the differences in oxidative metabolism between the two types of cells (“Utilizing Superoxide Dismutase”). This toxicity has been found to be decreased by Superoxide dismutase which leads to improved patient recovery by aiding in the removal of ROS after treatment. Nevertheless, SODs have been shown in this type of therapy to aid in the treatment of other side effects like Mucositis which are a result of the chemoradiation therapy (“Utilizing Superoxide Dismutase”). The shows the use of MnSOD in therapeutic strategies can lead to positive results for the patient. Using MnSOD to treat certain patients has shown to be quite effective with very promising results, however, the enzyme itself has a very short half-life of around six minutes (Azadmanesh). One of the ways they can increase the half-life is by using liposomal delivery which increases the half-life to four hours, although it’s a large increase, the downfall is that the MnSOD drugs must be administered regularly and often ^[2].

Another project that was done regarding MnSOD and colon cancer. The research looked at Sirtuin 3, which is the predominant mitochondrial deacetylase that balances ROS concentration by the regulation of Mitochondrial proteins like MnSOD (Hernández‐López, Reyniel, et al). The aim of the research was to figure out what effect silencing SIRT3 had on the response of antioxidants, and whether this response improved the ability of the drug “Oxaliplatin” to treat colon cancer (Hernández‐López, Reyniel, et al). The results for the knockdown of SIRT3 showed an increased number of ROS species due to the acetylation of MnSOD, which effectively deactivated MnSOD (Hernández‐López, Reyniel, et al). This led to more apoptosis of cells due to more ROS and the presence of Oxaliplatin, which reduced the cellular viability (Hernández‐López, Reyniel, et al). Moreover, in another paper, researchers found that a small molecule is involved into the activation of SIRT3, this molecule called C12 binds to SIRT3 and from there SIRT 3 would deacetylate the lys68 residue on MnSOD (Lu, J, et al.). This activation would then allow the MnSOD to function to rid the cell of ROS (Lu, J, et al.). This is an important piece of information because it allows us to see how MnSOD is activated and deactivated in regard to the activation and knockdown of SIRT3. From this, they were able to determine a way to modify the structure of MnSOD to use it correctly for colon cancer therapies.

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