Background: KAT I and GT-Kidney (K) are identical enzymes that ␤-eliminate and transaminate Se-methyl-L-selenocysteine (MSC). Results: KAT III and GT-Liver (L) are identical and metabolize L-selenomethionine (SM). Conclusion: MSC and SM are transaminated to seleno-keto acids, recognized HDAC inhibitors, by KAT/GT enzymes. Significance: Anticancer efficacy of MSC and SM depends in part on tissue expression of KAT/GT enzymes.

Chemoprevention trials show that MSC and SM reduce the risk of prostate, lung, and colon cancers. Mechanisms underlying the protective effects of selenoamino acids remain unclear. Our studies show that GTK and GTL in the presence of α‐keto acid co‐substrates (α‐keto‐γ‐methiolbutyrate, phenylpyruvate, glyoxylate) transaminate MSC and SM to selenoketo acids, β‐methylselenopyruvate (MSP) and α‐keto‐γ‐methylselenobutyrate (KMSB), respectively. Both MSP and KMSB (10–20 μM) inhibit histone deacetylases and differentially regulate protein targets critical for in vitro growth of human cancer cells. GTK is identical to kynurenine aminotransferase I (KAT I) and our recent study reveals that GTL is identical to KAT III. Using recombinant hGTK/KAT I and mGTL/KAT III, we show that GTK/KAT I rapidly transaminates MSC whereas SM is less effective. Conversely, GTK/KAT III rapidly transaminates SM whereas MSC is less effective. MSP and KMSB formation are measured using HPLC with coulometric detection. Selenoketo acids generated vary from 2‐ to 6‐fold depending on α‐keto acid co‐substrates. Even in the presence of supra‐physiological glutamine levels (>;6 mM, molar ratio >;10:1), selenoamino acids are effectively transaminated to MSP and KMSB. Our studies show that MSC and SM are transaminated to direct‐acting selenoketo acid metabolites whose formation depend on tissue expression of GTK and/or GTL, respectively and vary with α‐keto acid co‐substrates. Thus, the extent of MSC and SM transamination within cells can influence the outcome of chemoprevention.