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Chemopreventive mechanisms of alpha-keto acid metabolites of naturally occurring organoselenium compounds Pinto JT; Lee JI; Sinha R; MacEwan ME; Cooper AJAmino Acids 2011[Jun]; 41 (1): 29-41Previous studies on the chemopreventive mechanisms of dietary selenium have focused on its incorporation into antioxidative selenoproteins, such as glutathione peroxidase and thioredoxin reductase. Several studies, however, have revealed that dietary selenium in the form of L-selenomethionine and the 21st amino acid, selenocysteine, also have intrinsic anti-cancer properties. Biochemical mechanisms previously investigated to contribute to their anticancer effects involve beta- and gamma-lyase reactions. Some pyridoxal 5'-phosphate (PLP)-containing enzymes can catalyze a beta-lyase reaction with Se-methyl-L-selenocysteine (MSC) generating pyruvate and ammonia. Other PLP-enzymes can catalyze a gamma-lyase reaction with L-selenomethionine (SM) generating alpha-ketobutyrate and ammonia. In both cases, a purported third product is methylselenol (CH(3)SeH). Although not directly quantifiable, as a result of its extreme hydrophobicity and high vapor pressure, CH(3)SeH has been indirectly observed to act through the alteration of protein-sulfhydryl moieties on redox-responsive signal and transcription factors, thereby maintaining a non-proliferative intracellular environment. We have considered the possibility that alpha-keto acid analogues of MSC (i.e., methylselenopyruvate; MSP) and SM (i.e., alpha-keto-gamma-methylselenobutyrate; KMSB), generated via a transamination and/or L-amino acid oxidase reaction may also be chemoprotective. Indeed, these compounds were shown to increase the level of histone-H3 acetylation in human prostate and colon cancer cells. MSP and KMSB structurally resemble butyrate, an inhibitor of several histone deacetylases. Thus, the seleno alpha-keto acid metabolites of MSC and SM, along with CH(3)SeH derived from beta- and gamma-lyase reactions, may be potential direct-acting metabolites of organoselenium that lead to de-repression of silenced tumor suppressor proteins and/or regulation of genes and signaling molecules.|Animals[MESH]|Antineoplastic Agents/chemistry/*metabolism/pharmacology[MESH]|Humans[MESH]|Keto Acids/chemistry/*metabolism[MESH]|Organoselenium Compounds/chemistry/*metabolism/pharmacology[MESH] |
