Abstract
Stearoyl-CoA desaturase-1 (SCD1 or delta-9 desaturase, D9D) is a key metabolic protein that modulates cellular inflammation and stress, but overactivity of SCD1 is associated with diseases, including cancer and metabolic syndrome. This transmembrane endoplasmic reticulum protein converts saturated fatty acids into monounsaturated fatty acids, primarily stearoyl-CoA into oleoyl-CoA, which are critical products for energy metabolism and membrane composition. The present computational molecular dynamics study characterizes the molecular dynamics of SCD1 with substrate, product, and as an apoprotein. The modeling of SCD1:fatty acid interactions suggests that: (1) SCD1:CoA moiety interactions open the substrate-binding tunnel, (2) SCD1 stabilizes a substrate conformation favorable for desaturation, and (3) SCD1:product interactions result in an opening of the tunnel, possibly allowing product exit into the surrounding membrane. Together, these results describe a highly dynamic series of SCD1 conformations resulting from the enzyme:cofactor:substrate interplay that inform drug-discovery efforts.
Highlights
Stearoyl-CoA desaturase-1 (SCD1), an endoplasmic reticulum membrane enzyme, is a central regulator of energy metabolism [1]
While SCD1 activity is critical to health, because it is important to the modulation of cellular inflammation and stress [5], SCD1 activity can be associated with disease under certain conditions
During the molecular dynamics simulations, that same distance was found to vary between 6.5 Å and 10.5 Å, with the most frequently sampled distances between 7.5 Å
Summary
Stearoyl-CoA desaturase-1 (SCD1), an endoplasmic reticulum membrane enzyme, is a central regulator of energy metabolism [1]. SCD1 desaturates stearoyl-CoA and palmitoylCoA into the monounsaturated fatty acids (MUFA) oleoyl-CoA and palmitoleoyl-CoA through the insertion of a double bond in the ∆-9 position of the substrate [2] (Figure 1a–c), as indicated by SCD1’s alternative name, delta-9 desaturase (D9D). This oxidative reaction requires electron transport cytochrome b5 and molecular oxygen [2]. The well-controlled activity of SCD1 is critically important to health as the products are used in the formation of phospholipids, triglycerides, and cholesteryl esters, and contribute to membrane fluidity, adiposity, and signal transduction [3].
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