[³H]-13-<i>cis</i>-Retinoic Acid Covalently Binds to Thioredoxin Reductase in Human Keratinocytes

Abstract

13-cis-Retinoic acid is a stereospecific suicide inhibitor of thioredoxin reductase. [³H]-labeled 13-cis-retinoic acid has been used to covalently label thioredoxin reductase in human keratinocytes. The acid-soluble cytosol fraction of human keratinocytes contained three radioactive proteins labeled by the addition of high-specific-activity [³H]-13-cis-retinoic acid to cell cultures. One of these proteins was identified as cytosolic keratinocyte thioredoxin reductase by fast-protein liquid chromatography and SDS-gel radioautography. The inhibition of thioredoxin reductase by 13-cis-retinoic acid may explain the known cytostatic and teratogenic properties attributed to this retinoid.

Retinoic acid receptors: From molecular mechanisms to cancer therapy

“…A further mechanism for all-trans-RA binding to protein was proposed to explain the stereospecific inhibition of thioredoxin reductase by 13-cis-RA. In particular, it has been speculated that there may be a thioether bond formed between a Cys moiety and either the C-13 or C-14 of all-trans-RA (Schallreuter et al, 1991). Of note, the incorporation of all-trans-RA and retinoyl-CoA into proteins is enzymatic (Genchi and Olson, 2001).…”

Retinoylation of proteins in mammalian cells

“…Another mechanism for RA binding to protein was proposed by Schallreuter et al [21] to explain the stereospecific inhibition o f thioredoxin reductase by 13-cis-RA. These workers proposed that there may be a thioether bond formed between a cysteine moiety and either the C-13 or C-14 of RA.…”

“…One metabolic pathway for retinoylation is the formation of a retinoyl-CoA intermediate and the subsequent transfer and covalent binding of the retinoyl moiety to protein [ 191 ( Figure 1). RA is incorporated into protein of the human myeloid leukaemia cell line HL60 and of many other cell types [14][15][16][17]20,21]. The proteins labelled by RA are cell-type-dependent.…”