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Title: Methionine transmethylation and transsulfuration in the piglet gastrointestinal tract

Author
item RIEDIJK, MAAIKE - SOPHIA CHILD HOSP. NL
item STOLL, BARBARA - BAYLOR COLLEGE MED
item CHACKO, SHAJI - BAYLOR COLLEGE MED
item SCHIERBEEK, HENK - SOPHIA CHILD HOSP. NL
item SUNEHAG, AGNETA - BAYLOR COLLEGE MED
item VAN GOUDOEVER, JOHANNES - SOPHIA CHILD HOSP. NL
item Burrin, Douglas - Doug

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/27/2006
Publication Date: 2/27/2007
Citation: Riedijk, M.A., Stoll, B., Chacko, S., Schierbeek, H., Sunehag, A.L., Van Goudoever, J.B., Burrin, D.G. 2007. Methionine transmethylation and transsulfuration in the piglet gastrointestinal tract. Proceedings of the National Academy of Sciences. 104(9):3408-3413.

Interpretive Summary: Growing infants, especially those born prematurely, have a critical need for adequate protein in the diet. Methionine is a component amino acid of most proteins and cannot be made by the infant body and thus it is required in the diet. In addition to being a component of body protein, methionine is a key precursor for production of other important amino acids and proteins that function as antioxidants in the body and fight off cellular stress. The aim of this study was to establish the metabolic fate of methionine in the infant gut and quantify the amount used for gut growth. We used our well-established piglet animal model to simulate the gut physiology of human infants. We gave the piglets specialized chemical forms of methionine labeled with isotopes that enabled us to track its metabolism through the gut and whole body. We found that a substantial portion of the dietary methionine is converted to homocysteine, a potentially toxic amino acid to cells in the body. We also found that the remaining methionine is converted to either cysteine or used for growth. Our findings are novel and show that the gut is an important site of homocysteine production and may contribute to diseases marked by homocysteinemia, such as inflammatory bowel disease, colon cancer, and stroke.

Technical Abstract: Methionine is an indispensable sulfur amino acid that functions as a key precursor for the synthesis of homocysteine and cysteine. Studies in adult humans suggest that splanchnic tissues convert dietary methionine to homocysteine and cysteine by means of transmethylation and transsulfuration, respectively. Studies in piglets show that significant metabolism of dietary indispensable amino acids occurs in the gastrointestinal tissues (GIT), yet the metabolic fate of methionine in GIT is unknown. We show here that 20% of the dietary methionine intake is metabolized by the GIT in piglets implanted with portal and arterial catheters and fed milk formula. Based on analyses from intraduodenal and intravenous infusions of [1-13C]methionine and [2H3]methionine, we found that the whole-body methionine transmethylation and remethylation rates were significantly higher during duodenal than intravenous tracer infusion. First-pass splanchnic metabolism accounted for 18% and 43% of the whole-body transmethylation and remethylation, respectively. Significant transmethylation and transsulfuration was demonstrated in the GIT, representing approximately 27% and approximately 23% of whole-body fluxes, respectively. The methionine utilized by the GIT was metabolized into homocysteine (31%), CO2 (40%), or tissue protein (29%). Cystathionine beta-synthase mRNA and activity was present in multiple GITs, including intestinal epithelial cells, but was significantly lower than liver. We conclude that the GIT consumes 20% of the dietary methionine and is a significant site of net homocysteine production. Moreover, the GITs represent a significant site of whole-body transmethylation and transsulfuration and these two pathways account for a majority of methionine used by the GITs.