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

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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 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 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 (CH3SeH). Although not directly quantifiable, as a result of its extreme hydrophobicity and high vapor pressure, CH3SeH 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 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 CH3SeH 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.

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Abbreviations

DMDSe:

Dimethyldiselenide

KMSB:

α-Keto-γ-methylselenobutyrate

GTK:

Glutamine transaminase K

GTL:

Glutamine transaminase L

HDAC:

Histone deacetylase

LAAO:

l-Amino acid oxidase

MSC:

Se-Methyl-l-selenocysteine

MSA:

Methylseleninic acid

MSP:

β-Methylselenopyruvate

NaB:

Sodium butyrate

PBS:

Phosphate buffered saline

PLP:

Pyridoxal 5′-phosphate

PMP:

Pyridoxamine 5′-phosphate

SM:

l-Selenomethionine

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Acknowledgments

This work was supported in part by NIH grants CA111842 (to JTP & RS) and ES8421 (to AJLC).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA

    John T. Pinto, Jeong-In Lee, Melanie E. MacEwan & Arthur J. L. Cooper

  2. Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA

    Raghu Sinha

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  1. John T. Pinto
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  2. Jeong-In Lee
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Correspondence to John T. Pinto.

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This article is published as part of the Special Issue on sulfur- and seleno-containing amino acids.

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Pinto, J.T., Lee, JI., Sinha, R. et al. Chemopreventive mechanisms of α-keto acid metabolites of naturally occurring organoselenium compounds. Amino Acids 41, 29–41 (2011). https://doi.org/10.1007/s00726-010-0578-3

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