A novel isoenzyme of aldehyde dehydrogenase specifically involved in the biosynthesis of 9-cis and all-trans retinoic acid

Abstract

The pleiotropic effects of retinoids are mediated by two families of nuclear receptors: RAR (retinoic acid receptors) and RXR (retinoid X receptors). 9-cis-Retinoic acid is a specific ligand for RXR receptors, whereas either 9-cis- or all-trans-retinoic acid activates the RAR receptor family. The existence of RXRs suggests a new role for isomerization in the biology of retinoic acid. We report here the identification of an aldehyde dehydrogenase in the rat kidney that catalysed the oxidation of 9-cis- and all-trans-retinal to corresponding retinoic acids with high efficiency, 9-cis-retinal being 2-fold more active than all-trans-retinal. Based on several criteria, such as amino acid sequence, pH optimum, and inhibition by chloral hydrate, this enzyme was found to be a novel isoenzyme of aldehyde dehydrogenase. 9-cis-Retinol, the precursor for the biosynthesis of 9-cis-retinal was identified in the rat kidney. The occurrence of endogenous 9-cis-retinol and the existence of specific dehydrogenase which participates in the catalysis of 9-cis-retinal suggest that all-trans-retinoi(d) isomerization to 9-cis-retinoi(d) occurs at the retinol level, analogous to all-trans-retinol isomerization to 11-cis-retinol in the visual cycle.

Xenopus Cytosolic Thyroid Hormone-binding Protein (xCTBP) Is Aldehyde Dehydrogenase Catalyzing the Formation of Retinoic Acid

“…The kinetics for NAD ϩ were characterized by K m of 38 Ϯ 3 and 9.2 Ϯ 1.8 M, and V max of 0.44 Ϯ 0.10 and 0.18 Ϯ 0.03 mol/min/mg, for xALDH1-I and -II, respectively, at the concentration of NAD ϩ ranging from 6 to 120 M. Compared with the kinetics of the purified xCTBP, the K m of Xenopus recombinant proteins exhibited values 3-8 times higher, although their V max value was very similar. The order of substrate specificity of the Xenopus enzymes was in agreement with that of mammalian ALDH1 enzymes (38,46,47) but quite distinct from other classes of mammalian ALDHs (48 -51). Positive cooperativity showing allosteric kinetics could only be detected when the ALDH activities of the xALDH1-I and -II proteins were examined with various concentration of retinal (Hill coefficients, n ϭ 1.8 Ϯ 0.4 and 2.7 Ϯ 0.6, respectively) (Fig.…”

Detection of Endogenous Retinoids in the Molluscan CNS and Characterization of the Trophic and Tropic Actions of 9-cisRetinoic Acid on Isolated Neurons

“…In addition, neither Nowickyj et al (2008), or Biesalski et al (1992 detected any significant trans to cis-isomerization, while Brodeur et al (2007) also failed to demonstrate endogenous RA isomerase activity in cultured HeLa cells. Indeed, the existence of cis-retinol isomers and the enzymes capable of oxidizing them to their characteristic RAs (Labrecque et al, 1995, Driessen et al, 1998, Romert et al, 1998, Paik et al, 2005, strongly suggests that 9-cis-RA (and other cis-RA isomers) may be synthesized independently from atRA.…”

Effect of retinoic acid on midkine gene expression in rat anterior pituitary cells

“…2). Rat RALDH1 catalyzes oxidation of all-trans-retinal (Km = 9.8 μM) to ATRA [14]. ATRA controls gene transcription via the nuclear receptor RAR [15]; however, retinal does not substantially bind RAR [16].…”