Evaluation of spice and herb as phyto-derived selective modulators of human retinaldehyde dehydrogenases using a simple in vitro method

Abstract

Selective modulation of retinaldehyde dehydrogenases (RALDHs) – the main aldehyde dehydrogenase (ALDH) enzymes converting retinal into retinoic acid (RA), is very important not only in the RA signaling pathway but also for the potential regulatory effects on RALDH isozyme-specific processes and RALDH-related cancers. However, very few selective modulators for RALDHs have been identified, partly due to variable overexpression protocols of RALDHs and insensitive activity assay that needs to be addressed. In this paper, deletion of the N-terminal disordered regions is found to enable simple preparation of all RALDHs and their closest paralog ALDH2 using a single protocol. Fluorescence-based activity assay was employed for enzymatic activity investigation and screening for RALDH-specific modulators from extracts of various spices and herbs that are well known for containing many phyto-derived anti-cancer constituents. Under the established conditions, spice and herb extracts exhibited differential regulatory effects on RALDHs/ALDH2 with several extracts showing potential selective inhibition of the activity of RALDHs. In addition, the presence of magnesium ions was shown to significantly increase the activity for the natural substrate retinal of RALDH3 but not the others, while His-tag cleavage considerably increased the activity of ALDH2 for the non-specific substrate retinal. Altogether we propose a readily reproducible workflow to find selective modulators for RALDHs and suggest potential sources of selective modulators from spices and herbs.

Emerging Biopharmaceuticals from Pimpinella Genus

“…RALDHs were assigned to convert retinaldehyde to retinoic acid (RA), acting as the dominant mechanism in RA signaling pathways and relevant cancers. The current study indicated that ethanol extracts of P. anisum selectively and intensively inhibited RALDH3 expression, while it did not modulate RALDH1 and RALDH2, highlighting the selectivity of that in the regulation of RALDHs and the RA-governed metabolic process [ 145 ]. On the other hand, studies on P. anisum ingredients found that abundant bergapten ( 256 ), iso-pimpinellin ( 274 ), and methoxsalen ( 275 ) were inhibitors of CYP-1A2, which are involved in drug metabolism and carcinogenic bioactivity [ 70 ].…”

Aldehyde Dehydrogenase Enzyme Functions in Acute Leukemia Stem Cells

“…Notably, the terpenoid citral (3,7-dimethyl-2,6-octadien-1-al), a component of essential oils obtained from several plants, which is used as a food additive and fragrance, inhibits human lens ALDH1A1 at low IC50 values of the micromolar range [59]. Spice and herb extracts have shown a wealth in modulatory activities of ALDH family members ALDH1A1, ALDH1A2, ALDH1A3 and ALDH2; even though it may be possible that extracts contain selective modulators, certain extracts manifested general effects, with sage and thyme extracts indicating the potential for complete suppression of the enzymatic activity of all four proteins tested [153].…”

A commentary on the paper: ‘Evaluation of spice and herb as phytoderived selective modulators of human retinaldehyde dehydrogenases using a simple in vitro method’

“…Bui et al in their interesting paper [ 1 ] focus their attention mainly on retinaldehyde dehydrogenases (RALDHs), which are enzymes converting retinal into retinoic acid (RA). The authors emphasized the need for the search for the compounds having an influence on the activity of these enzymes because of their potential use in cancer therapy.…”