Applying Computational Systems Biology Techniques to Explore Disease-Related Methionine Cycle

Abstract

Methionine is an essential amino acid, meaning that it must be provided in the diet. Its derivatives play a significant role in the health of humans. It has been proven that malfunctions in the methionine cycle lead to many severe diseases. In this paper, we have constructed a complete model of the methionine cycle based on computational systems biology techniques. Our results show that alterations of the methionine cycle can lead to many severe diseases. An excess of methionine intake causes an increase in cystathionine, resulting in diseases such as Down Syndrome, hepatic cancer, and hepatic disease. Methionine deficiency can dramatically decrease the concentration of AdoMet and cystathionine. Decreased AdoMet leads to cirrhosis and hepatocellular carcinoma, while a decrease in cystathionine can result in cardiovascular disease. In the case of MATI/III deficiency, methionine accumulates quickly, blocks the synthesis of all subsequent intermediates, and eventually results in hypermethioninemia and cirrhosis. Deficiency of SM or AH dramatically decreases homocysteine and cystathionine, leading to vascular disease. When folate is removed, homocysteine accumulates to an elevated level that in turn causes colorectal cancer, neural tube defects, and an increased risk of vascular occlusion. Finally, deficiency of betaine and MS result in the increase of cystathionine and homocysteine, which can lead to megaloblastic anemia and neurological abnormalities. Our study has demonstrated the utility of using a program based model to predict various effects on the methionine cycle.