Substrate specificity, plasma membrane localization, and lipid modification of the aldehyde dehydrogenase ALDH3B1

Abstract

The accumulation of reactive aldehydes is implicated in the development of several disorders. Aldehyde dehydrogenases (ALDHs) detoxify aldehydes by oxidizing them to the corresponding carboxylic acids. Among the 19 human ALDHs, ALDH3A2 is the only known ALDH that catalyzes the oxidation of long-chain fatty aldehydes including C16 aldehydes (hexadecanal and trans-2-hexadecenal) generated through sphingolipid metabolism. In the present study, we have identified that ALDH3B1 is also active in vitro toward C16 aldehydes and demonstrated that overexpression of ALDH3B1 restores the sphingolipid metabolism in the ALDH3A2-deficient cells. In addition, we have determined that ALDH3B1 is localized in the plasma membrane through its C-terminal dual lipidation (palmitoylation and prenylation) and shown that the prenylation is required particularly for the activity toward hexadecanal. Since knockdown of ALDH3B1 does not cause further impairment of the sphingolipid metabolism in the ALDH3A2-deficient cells, the likely physiological function of ALDH3B1 is to oxidize lipid-derived aldehydes generated in the plasma membrane and not to be involved in the sphingolipid metabolism in the endoplasmic reticulum.

A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase

“…5d). Interestingly, biochemical experiments revealed that the substrate specificity of ALDH3B1 resembles FALDH4647 and that it also participates in protection against lipid-derived oxidative stress4849. However, in contrast to FALDH, ALDH3B1 has no implication in sphingosine-1-phosphate metabolism46, which is in agreement with studies that show the sphingosine-1-phosphate producing Sphingosine-1-phosphate lyase localizes, analogue to FALDH, in the endoplasmic reticulum50.…”

“…5b) (ref. 46). Membrane insertion through lipid modification in this enzyme would result in a configuration similar to that of FALDH (Fig.…”

“…Interestingly, biochemical experiments revealed that the substrate specificity of ALDH3B1 resembles FALDH4647 and that it also participates in protection against lipid-derived oxidative stress4849. However, in contrast to FALDH, ALDH3B1 has no implication in sphingosine-1-phosphate metabolism46, which is in agreement with studies that show the sphingosine-1-phosphate producing Sphingosine-1-phosphate lyase localizes, analogue to FALDH, in the endoplasmic reticulum50. Our results indicate that, although membrane anchoring of FALDH and ALDH3B1 is achieved in two different ways, both enzymes could facilitate their specificity towards long-chain fatty aldehydes by the same molecular interaction of their hydrophobic patches with the lipid bilayer.…”

Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery

“…Human ALDH3, on the other hand, contains four ALDH3 subfamily members (ALDH3A1, ALDH3A2, ALDH3B1, and ALDH3B2, with no Aldh3b3 homolog). As their mouse homologs do, ALDH3A1, ALDH3A2, and ALDH3B1 exhibit high activity toward MC or LC fatty aldehydes (21)(22)(23). However, human ALDH3B2 lacks 94 N-terminal amino acids present in the corresponding mouse Aldh3b2 and has no enzyme activity, suggesting that human ALDH3B2 is a pseudogene (19).…”

Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum

“…Aldehyde-to-carboxylic acid conversion reactions are catalyzed by aldehyde dehydrogenases (ALDHs). Among ∼20 ALDHs in mammals (19 in human and 21 in mouse), ALDH3 subfamily members (ALDH3A1, A2, and B1 in human) are responsible for the oxidation of long-chain aldehydes (33,34). Among the ALDH3 subfamily members, only ALDH3A2 is localized to the ER (35), the same site as HACL2, whereas the minor splicing isoform of ALDH3A2 is localized to the peroxisomes (35).…”