Figure 2.
DHRSX or SRD5A3 deficiency leads to metabolic changes prompting a revision of the model of dolichol biosynthesis
(A) Commonly accepted9 model of dolichol biosynthesis, where SRD5A3 directly forms dolichol from polyprenol. Additional related polyisoprenoids detected in our study are shown on the right.
(B) Polyisoprenoid species in wild-type, DHRSX KO, and SRD5A3 KO HAP1 cells and respective complementations. Data represent area under the curve (AUC) normalized to total ion count (TIC) (means ± SEM; n = 4; ∗∗∗∗p < 0.0001). Here and in subsequent figures, one species is shown (“−19” means 19 isoprenoid units), but additional chain lengths and chromatograms are shown in Figures S2A and S2B, and Table S2.
(C) Polyisoprenoid species in EBV-immortalized lymphoblasts from controls, parents and patients. Data are presented as in (B) (means ± SEM; n = 4; §, p < 0.05 compared to every control). See also Table S2.
(D) Working hypothesis of the revised pathway of dolichol biosynthesis. Reaction 1: NAD+-dependent conversion of polyprenol to polyprenal by DHRSX; Reaction 2: NADPH-dependent reduction of polyprenal to dolichal by SRD5A3; Reaction 3: reduction of dolichal to dolichol via an as-yet unknown enzyme.
See also Figure S2.