![]() Consequently, AdoMet can exist in two diastereomeric forms with respect to its sulfonium ion, ( S, S)-AdoMet and ( R, S)-AdoMet, where the designations refer to the sulfur and the α carbon, respectively. In addition to the chiral carbon at the α amino position, the sulfur at the sulfonium center of AdoMet is also chiral. In fact, AdoMet competes with ATP as the most widely used enzyme substrate ( 31, 138). Since then, investigators have implicated AdoMet in thousands of different methylation reactions in biological systems. He elegantly demonstrated that methionine and ATP reacted to form a molecule, and after determination of its chemical structure, he named it AdoMet, capable of transferring a methyl group to nicotinamide or guanidinoacetic acid to form N-methylnicotinamide and creatine, respectively. Giulio Cantoni discovered AdoMet in 1953 ( 31). Structure of S-adenosyl- l-methionine (AdoMet), S-adenosyl- l-homocysteine (AdoHcy), and 5′-methylthioadenosine (MTA). AdoMet can also methylate other atoms, such as arsenic, an important step in the metabolism of this toxic metalloid ( 135). In AdoMet-dependent methylation reactions, the nucleophile may be a carbon atom, as in the C-methylation reaction of the C5-cytosine in DNA methylation a nitrogen atom, as in the N-methylation reaction of the amino group in glycine methylation an oxygen atom, as in the O-methylation reaction of the hydroxyl moiety in catecholamine methylation or a sulfur atom, as in the S-methylation reaction of the sulfur atom in thiopurines methylation. ![]() The sulfonium ion of AdoMet is particularly well suited for the transfer of its methyl group to a variety of nucleophilic atoms by a typical sn-2 substitution reaction with the concomitant release of S-adenosyl- l-homocysteine (AdoHcy) ( FIGURE 1) ( 87, 229, 263). Structurally, sulfonium salts form a pyramidal arrangement of the three substituents, and there is a lone electron pair also associated with the sulfur atom ( 17). AdoMet is a typical sulfonium salt, a compound in which the sulfur atom has three single covalent substituents and therefore has a positive charge analogous to an ammonium compound ( FIGURE 1). ![]() Nature's selection of AdoMet for this role is attributable to its unique chemical structure. Specific amino acid side chains in proteins, nucleotide bases in DNA and RNA, sugars, and many small molecules often carry a methyl group that is derived from AdoMet. This review will also briefly discuss the current status of AdoMet's therapeutic use in liver diseases and several extrahepatic disorders.Įarly in evolution AdoMet emerged as the foremost donor of methyl groups in methylation reactions. AdoMet is also available as a drug in many parts of the world and in the United States as a nutritional supplement. ![]() Much of current understanding has been gained through the use of genetic models that exhibit chronic hepatic AdoMet deficiency or excess. This review is focused mainly on the role of AdoMet in liver health, injury, and cancer. Although AdoMet is synthesized in all mammalian cells, liver can be considered as the body's AdoMet factory as this is where ~85% of all transmethylation reactions and 50% of methionine metabolism take place ( 67, 179). Widely known as the principal biological methyl donor, recent evidence illustrates its essential role in diverse cellular processes including growth and death. The discovery of S-adenosyl- l-methionine (AdoMet, also frequently abbreviated as SAM and SAMe) occurred nearly 60 years ago ( 31). In experimental models, it is effective as a chemopreventive agent in HCC and perhaps other forms of cancer as well. AdoMet is effective in cholestasis of pregnancy, and its role in other human liver diseases remains to be better defined. Thus a normal hepatic AdoMet level is necessary to maintain liver health and prevent injury and HCC. Children with GNMT mutation have elevated liver transaminases, and Gnmt knockout mice develop liver injury, fibrosis, and HCC. This can result from inactive mutation of the enzyme glycine N-methyltransferase (GNMT). However, injury and HCC also occur if hepatic AdoMet level is excessive chronically. ![]() In these mice, several signaling pathways are abnormal that can contribute to HCC formation. Mice lacking Mat1a have reduced hepatic AdoMet levels and develop oxidative stress, steatohepatitis, and hepatocellular carcinoma (HCC). Patients with chronic liver disease have reduced MAT activity and AdoMet levels. In mammals, two genes, MAT1A that is largely expressed by normal liver and MAT2A that is expressed by all extrahepatic tissues, encode MAT. Biosynthesis of AdoMet requires the enzyme methionine adenosyltransferase (MAT). S-adenosylmethionine (AdoMet, also known as SAM and SAMe) is the principal biological methyl donor synthesized in all mammalian cells but most abundantly in the liver. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |