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Dihydroceramide desaturase inhibition by a cyclopropanated dihydroceramide analog in cultured keratinocytes.

Brodesser S, Kolter T - J Lipids (2010)

Bottom Line: In the presence of 10-50 μM of compound (1), levels of biosynthetically formed dihydroceramide and-surprisingly-also of phytoceramide are elevated at the expense of ceramide.The cells respond to the lack of unsaturated sphingolipids by an elevation of mRNAs of enzymes required for sphingosine formation.At the same time, the analysis of proliferation and differentiation markers indicates that the sphingolipid double bond is required to keep the cells in a differentiated state.

View Article: PubMed Central - PubMed

Affiliation: CECAD Cologne Platform Lipidomics, Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstraße 19-21, 50935 Cologne, Germany.

ABSTRACT
Most mammalian sphingolipids contain a 4,5-(E)-double bond. We report on the chemical synthesis of a dihydroceramide derivative that prevents the introduction of the double bond into sphingolipids. Minimal alteration of the parent structure by formally replacing the hydrogen atoms in the 5- and in the 6-position of the sphinganine backbone by a methylene group leads to an inhibitor of dihydroceramide desaturase in cultured cells. In the presence of 10-50 μM of compound (1), levels of biosynthetically formed dihydroceramide and-surprisingly-also of phytoceramide are elevated at the expense of ceramide. The cells respond to the lack of unsaturated sphingolipids by an elevation of mRNAs of enzymes required for sphingosine formation. At the same time, the analysis of proliferation and differentiation markers indicates that the sphingolipid double bond is required to keep the cells in a differentiated state.

No MeSH data available.


Enzymatic reaction catalyzed by dihydroceramide desaturase DES1.
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sch1: Enzymatic reaction catalyzed by dihydroceramide desaturase DES1.

Mentions: Most mammalian sphingolipids contain an (E)-configured double bond between the carbon atoms C4 and C5 of the sphingoid moiety [1–3]. This structural element is introduced during the last step of ceramide biosynthesis by the enzyme dihydroceramide desaturase (DES1; Scheme 1), a protein bound to the membrane of the Endoplasmic Reticulum [4–7], encoded by the DEGS1 (degenerative spermatocyte homolog 1) gene, and myristoylated at its N-terminus [8]. While the mouse Des2 protein seems to have dihydroceramide Δ4-desaturase and 4-hydroxylase activity, the human homolog DES2 appears to be only a 4-hydroxylase [9]. The first and rate-determining step of the dihydroceramide desaturase-catalyzed reaction is the homolytic cleavage of the C-H-bond at C-4 of the sphinganine backbone by a non-heme oxo-diiron species [10]. The function of the double bond within the sphingolipids is not entirely known. Experiments, in which cell-permeable analogs of ceramide and dihydroceramide were exogenously added to cultured cells [11], indicated for the first time that the double bond is not only required for the signaling properties of ceramide, but also for those of sphingosine-1-phosphate (review: [12]). Dihydroceramide desaturase (Des1) knockout mice display decreased body weight, scaly skin, hematological abnormalities, and abnormal liver function, and die at 8 to 10 weeks after birth [13]. As an additional tool to study the function of the 4,5-double bond of sphingolipids, competitive inhibitors of the desaturase have been developed that share a cyclopropene moiety in positions 4 and 5 of the sphingoid backbone [14–18]. Dihydroceramide levels also increase in response to resveratrol treatment [19].


Dihydroceramide desaturase inhibition by a cyclopropanated dihydroceramide analog in cultured keratinocytes.

Brodesser S, Kolter T - J Lipids (2010)

Enzymatic reaction catalyzed by dihydroceramide desaturase DES1.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3066699&req=5

sch1: Enzymatic reaction catalyzed by dihydroceramide desaturase DES1.
Mentions: Most mammalian sphingolipids contain an (E)-configured double bond between the carbon atoms C4 and C5 of the sphingoid moiety [1–3]. This structural element is introduced during the last step of ceramide biosynthesis by the enzyme dihydroceramide desaturase (DES1; Scheme 1), a protein bound to the membrane of the Endoplasmic Reticulum [4–7], encoded by the DEGS1 (degenerative spermatocyte homolog 1) gene, and myristoylated at its N-terminus [8]. While the mouse Des2 protein seems to have dihydroceramide Δ4-desaturase and 4-hydroxylase activity, the human homolog DES2 appears to be only a 4-hydroxylase [9]. The first and rate-determining step of the dihydroceramide desaturase-catalyzed reaction is the homolytic cleavage of the C-H-bond at C-4 of the sphinganine backbone by a non-heme oxo-diiron species [10]. The function of the double bond within the sphingolipids is not entirely known. Experiments, in which cell-permeable analogs of ceramide and dihydroceramide were exogenously added to cultured cells [11], indicated for the first time that the double bond is not only required for the signaling properties of ceramide, but also for those of sphingosine-1-phosphate (review: [12]). Dihydroceramide desaturase (Des1) knockout mice display decreased body weight, scaly skin, hematological abnormalities, and abnormal liver function, and die at 8 to 10 weeks after birth [13]. As an additional tool to study the function of the 4,5-double bond of sphingolipids, competitive inhibitors of the desaturase have been developed that share a cyclopropene moiety in positions 4 and 5 of the sphingoid backbone [14–18]. Dihydroceramide levels also increase in response to resveratrol treatment [19].

Bottom Line: In the presence of 10-50 μM of compound (1), levels of biosynthetically formed dihydroceramide and-surprisingly-also of phytoceramide are elevated at the expense of ceramide.The cells respond to the lack of unsaturated sphingolipids by an elevation of mRNAs of enzymes required for sphingosine formation.At the same time, the analysis of proliferation and differentiation markers indicates that the sphingolipid double bond is required to keep the cells in a differentiated state.

View Article: PubMed Central - PubMed

Affiliation: CECAD Cologne Platform Lipidomics, Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstraße 19-21, 50935 Cologne, Germany.

ABSTRACT
Most mammalian sphingolipids contain a 4,5-(E)-double bond. We report on the chemical synthesis of a dihydroceramide derivative that prevents the introduction of the double bond into sphingolipids. Minimal alteration of the parent structure by formally replacing the hydrogen atoms in the 5- and in the 6-position of the sphinganine backbone by a methylene group leads to an inhibitor of dihydroceramide desaturase in cultured cells. In the presence of 10-50 μM of compound (1), levels of biosynthetically formed dihydroceramide and-surprisingly-also of phytoceramide are elevated at the expense of ceramide. The cells respond to the lack of unsaturated sphingolipids by an elevation of mRNAs of enzymes required for sphingosine formation. At the same time, the analysis of proliferation and differentiation markers indicates that the sphingolipid double bond is required to keep the cells in a differentiated state.

No MeSH data available.