Chemopreventive mechanisms of α-keto acid metabolites of naturally occurring organoselenium compounds

Abstract

Previous 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 Lselenomethionine and the 21st amino acid, selenocysteine, also have intrinsic anti-cancer properties. Biochemical mechanisms previously investigated to contribute to their anticancer effects involve β-and γ-lyase reactions. Some pyridoxal 5′-phosphate (PLP)-containing enzymes can catalyze a β-lyase reaction with Se-methyl-L-selenocysteine (MSC) generating pyruvate and ammonia. Other PLP-enzymes can catalyze a γ-lyase reaction with L-selenomethionine (SM) generating α-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 proteinsulfhydryl moieties on redox-responsive signal and transcription factors, thereby maintaining a non-proliferative intracellular environment. We have considered the possibility that α-keto acid analogues of MSC (i.e., methylselenopyruvate; MSP) and SM (i.e., α-keto-γ-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 α-keto acid metabolites of MSC and SM, along with CH 3 SeH derived from β-and γ-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.

Methylseleninic acid downregulates hypoxia‐inducible factor‐1α in invasive prostate cancer

“…[22][23][24][25][26][27][28] The majority of the inhibitory effects of selenium compounds involve apoptosis as a critical event, and several effective organic selenium compounds including seleno-keto acids have been reviewed on the basis of their apoptotic potential in several cancer models including prostate cancer. 29,30 A promising anticancer agent methylseleninic acid (MSeA) has been shown to be effective in inhibiting prostate cancer growth in vitro and in TRAMP model. 31,32 However, the potential of MSeA as a therapeutic agent has not been tested in humans, and the underlying mechanism(s) of selenium compounds including MSeA have not been studied in hypoxic conditions.…”

Kynurenine Aminotransferase III and Glutamine Transaminase L Are Identical Enzymes that have Cysteine S-Conjugate β-Lyase Activity and Can Transaminate l-Selenomethionine

“…KMSB) and MSC (i.e. MSP) are HDAC inhibitors (K i ϭ 10 -20 M) in human prostate and colon cancer cells in culture (30,62,63). However, MSC, but not SM, elicited HDAC inhibition in these cells.…”

“…In both cases, the eliminated fragment is predicted to be methylselenol (CH 3 SeH). Thus, the capacities of mammalian tissues to catalyze transamination and elimination reactions with selenoamino acids are well established (30). Although methylselenol has never been isolated or measured in situ within tissue, it can be generated simultaneously with seleno-␣-keto acid metabolites, which are measurable by electrochemical detection, as part of competing transaminase/lyase reactions that can occur at the active site of the KAT enzymes.…”

“…The seleno-␣-keto acids generated via transamination of MSC and SM are ␤-methylselenopyruvate (MSP) and ␣-keto-␥-methylselenobutyrate (KMSB), respectively. Standard solutions of these seleno-␣-keto acids were generated in situ from the corresponding L-amino acids with Crotalus adamanteus L-amino acid oxidase (30).…”

New Selenoderivatives as Antitumoral Agents

“…Other authors affirm that the effect is due to methylselenol, a metabolite active in a study carried out in the transgenic adenocarcinoma mouse prostate model by oral administration of MeSeCys (J. . This hypothesis has been reinforced and completed in 2011 with the inclusion of new metabolites, the α-keto acids analogues of MeSeCys (Pinto et al, 2011). Related to selenomethionine (SeMet) (Figure 3) one of the mechanism that is gaining interest is the HDAC inhibition by metabolites of SeMet accompanied of redox signaling proteins modulation (J.I.…”