Abstract
Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of the aldehyde dehydrogenase superfamily that oxidizes aldehydes to their corresponding acids, reactions that are coupled to the reduction of NAD+ to NADH. We report here that ALDH1A1 can also use glutathione (GSH) and dihydrolipoic acid (DHLA) as electron donors to reduce NAD+ to NADH. The GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 is not affected by the aldehyde dehydrogenase inhibitor or by mutation of the residues in its aldehyde-binding pocket. It is thus a distinct biochemical reaction from the classic aldehyde-dehydrogenase activity catalyzed by ALDH1A1. We also found that the ectopic expression of ALDH1A1 decreased the intracellular NAD+/NADH ratio, while knockout of ALDH1A1 increased the NAD+/NADH ratio. Simultaneous knockout of ALDH1A1 and its isozyme ALDH3A1 in lung cancer cell line NCI-H460 inhibited tumor growth in a xenograft model. Moreover, the ALDH1A1 mutants that retained their GSH/DHLA-dependent NAD+ reduction activity but lost their aldehyde-dehydrogenase activity were able to decrease the NAD+/NADH ratio and to rescue the impaired growth of ALDH1A1/3A1 double knockout tumor cells. Collectively, these results suggest that this newly characterized GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 can decrease cellular NAD+/NADH ratio and promote tumor growth.
Highlights
The aldehyde dehydrogenase superfamily in humans is comprised of 19 isozymes that are responsible for the oxidation of endogenous and exogenous aldehydes
We discovered that these enzymes can use glutathione (GSH) and dihydrolipoic acid (DHLA) as the electron donor to reduce NAD+ to NADH
Cell extracts (S-100, supernatants of cell lysates that had been centrifuged at 100,000 g) from the EKVX lung cancer cell line were fractionated on a Q HP anion exchange column
Summary
The aldehyde dehydrogenase superfamily in humans is comprised of 19 isozymes that are responsible for the oxidation of endogenous and exogenous aldehydes. Other substrates of ALDH1A1 include acetaldehyde, 3,4-dihy droxyphenylacetaldehyde, and so on [4,5,6] Another aldehyde dehydrogenase, ALDH3A1, functions in the detoxification of lipid peroxidation-derived reactive aldehydes like 4-hydroxynonenal [7]. ALDH1A1 and ALDH3A1 can metabolize the active form of oxazaphosphorine drugs (e.g., cyclophosphamide, mafosfamide, and ifosfamide) and are, at least partially, responsible for the chemo-resistance associated with these drugs [11, 12]. It is still not clear how aldehyde dehydrogenases contribute to the increased tumorigenesis and the poor prognosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
