Methionine Oxidation (i.e. oxidation of sulfur in vivo)
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| Fig. 1 Methionine (1) |
Methionine (Fig.1), an essential amino acid, plays many important roles in vivo, ranging from protein synthesis and transfer of methyl groups to even being involved in the pathogenesis of coronary artery disease (2). In genetics, we learn of the initial start codon and how it "codes" for fMet (a formylmethionine) to initiate protein synthesis...although it is further modified and removed from most proteins via the work of additional enzymes, such as deformylases and aminopeptidases.
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| Fig. 2 Methionine metabolism (3) |
Methionine metabolism is much more complex than what we are initially taught in genetics and general biochemistry courses. As indicated in Fig 2, methionine plays important roles in a plethora of processes. In the course of "normal" methionine metabolism involved in the transfer of methyl groups to a variety of acceptors, homocysteine is formed.
High homocysteine (Fig. 3) levels (hyperhomocysteinemia), according to a study published in JAMA (4), is a modest predictor of ischemic heart disease and stroke. The work done by Dr. Rowena Matthews at the University of Michigan (lab webpage can be found in reference 5) has shown the enzyme mechanisms for some of the enzymes involved in methionine metabolism; moreover, she has been honored for her work by being named a Fellow in the National Academy of Sciences and more recently named a Member of the Institute of Medicine (5).
Another methionine "mishap" (so to speak) is its oxidation. As discussed in Organic Chem 2, unlike the C-O bond, the carbon in the C-S bond is not oxidized, but rather the sulfur can become oxidized. This oxidation of Met can yield methionine sulfoxide (as the major oxidation product) or even methionine sulfone.
In vivo, a group of enzymes called Methionine sulfoxide reductases (Msr) reduce the oxidized forms back to the biologically important oxidation state. These enzymes are important for a multitude of metabolic processes, including antioxidant defense and protein regulation. A decrease in the activity of Msr enzymes may even play a role in Alzheimer's disease (8).
Scientists in Belgium have recently reported that they have created a method to actually measure the degree of protein-bound oxidized methionine compounds within a mouse sepsis model. They have dubbed this method as COFRADIC (Combined Fractional Diagonal Chromatography). Interestingly, they have discovered 35 different in vivo methionine oxidation events in this disease-state model (9). Within the introduction of their paper (found at the link below), they list the number of possible enzyme modification (and potentially affected disease states) that can result from these oxidized methionine compounds.
Ghesquiere et al. (2011) Redox Proteomics of Protein-bound Methionine Oxidation
This is fascinating! Think of the possibilities of being able to test a wide array of disease models (in vivo nonetheless!) that one could test on a proteomic level. Imagine what this means....
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| Fig. 3 (6) |
Another methionine "mishap" (so to speak) is its oxidation. As discussed in Organic Chem 2, unlike the C-O bond, the carbon in the C-S bond is not oxidized, but rather the sulfur can become oxidized. This oxidation of Met can yield methionine sulfoxide (as the major oxidation product) or even methionine sulfone.
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| Fig. 4 Oxidation of Methionine (7) |
Scientists in Belgium have recently reported that they have created a method to actually measure the degree of protein-bound oxidized methionine compounds within a mouse sepsis model. They have dubbed this method as COFRADIC (Combined Fractional Diagonal Chromatography). Interestingly, they have discovered 35 different in vivo methionine oxidation events in this disease-state model (9). Within the introduction of their paper (found at the link below), they list the number of possible enzyme modification (and potentially affected disease states) that can result from these oxidized methionine compounds.
Ghesquiere et al. (2011) Redox Proteomics of Protein-bound Methionine Oxidation
This is fascinating! Think of the possibilities of being able to test a wide array of disease models (in vivo nonetheless!) that one could test on a proteomic level. Imagine what this means....
References
- http://premiumpetfood.wikidot.com/methionine
- J Clin Invest. 1976 April; 57(4): 1079–1082.
- Proc Natl Acad Sci U S A. 2004 March 23; 101(12): 4234–4239.
- JAMA. 2002;288(16):2015-2022.
- http://www.biochem.med.umich.edu/?q=rmatthews
- http://www.wiley.com/college/boyer/0470003790/cutting_edge/homocysteine/homocysteine.htm
- http://www.ionsource.com/Card/MetOx/metox.htm
- Biochim Biophys Acta. 2005 Jan 17;1703(2):213-9.
- Mol Cell Proteomics. 2011 May; 10(5): M110.006866.
Please note that the URL link to the Proteomics paper is a little slow in loading....sorry!
ReplyDeleteWow, this article carries incredible implications for the future of preventative medicine and diagnostic testing for neurological diseases! In this article, the researchers are investigating the effects of sulfur oxidation within the body. As one of the body’s major elements, sulfur plays a crucial role in many different functions. Its role in the first amino acid in translation (as methionine), for instance, cannot be overemphasized. When sulfur-containing compounds are oxidized and never corrected, however, dire consequences can result. Protein damage, the researchers discuss in their article, is one of the main signs of uncorrected oxidation. Damaged proteins tend to misfold and form aggregates in brain tissue, which can cause neurodegenerative diseases like Parkinson’s, ALS, and PSP. When sulfur is oxidized in an otherwise healthy person, a gene coding for methionine sulfoxide reductases (msr’s) is switched on and msr’s are expressed. Msr’s travel throughout the body and correct the oxidized forms of sulfur-containing compounds back to their original conformations. Interestingly, mice without an operative gene for msr displayed signs of neurological irregularities like ataxia (walking on one’s tip-toes) and some early signs of Parkinson’s. Mice that did not express msr typically lived only about half the normal life span as normal wild-type mice. Also, the mice experienced changes in cells function, which led to a lowered antioxidant defense.
ReplyDeleteNow that these mechanisms have been uncovered, researchers can begin to work towards a potential cure for neurodegenerative diseases. By using a special method of chromatography (combined fractional diagonal chromatography), researchers can isolate oxidized forms of sulfur. This method carries important applications for preemptive in vivo detection of proto-pathological conditions within the body (and especially the nervous system). Is a cure for ALS, PSP, and Alzheimer’s in sight? Most likely within the next 20 to 30 years, researchers will be able to effectively use gene therapy to target the msr-expressing gene (and any other series-related genes), so as to reverse or prevent neurological disease. Neurodegenerative diseases carry a great deal of mystery, but as more pieces of the pathological puzzle are fitted together, a cure will most likely emerge within the next 30 years.