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Literature summary for 1.14.19.17 extracted from

  • Aurelio, L.; Scullino, C.V.; Pitman, M.R.; Sexton, A.; Oliver, V.; Davies, L.; Rebello, R.J.; Furic, L.; Creek, D.J.; Pitson, S.M.; Flynn, B.L.
    From sphingosine kinase to dihydroceramide desaturase a structure-activity relationship (SAR) study of the enzyme inhibitory and anticancer activity of 4-((4-(4-chlorophenyl)thiazol-2-yl)amino)phenol (SKI-II) (2016), J. Med. Chem., 59, 965-984 .
    View publication on PubMed
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Inhibitors

Inhibitors Comment Organism Structure
(Z)-4-((5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)amino)-N-hydroxybenzimidamide completely inhibits Des1 activity at 0.01 mM but shows little activity at 0.001 mM Homo sapiens
4-((4-(4-chlorophenyl)thiazol-2-yl)amino)phenol i.e. SKI-II, noncompetitive inhibitor of enzyme Des1, structure-activity relationship analysis, inhibition mechanism, overview Homo sapiens
4-((5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)amino)phenol
-
 Homo sapiens
5-(4-chlorophenyl)-N-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-amine
-
 Homo sapiens
fenretinide a direct inhibitor of Des1 that initially shows competitive inhibition but becomes an irreversible inhibitor over longer incubation times. The 4-aminophenol may play an important role in mediating its irreversible inhibition of Des1, where Des1 oxidation of this group generates a reactive iminoquinone intermediate that reacts with nucleophilic sites on the protein, leading to time-dependent irreversible inhibition of Des1, inhibition mechanism, overview Homo sapiens
additional information no inhibition by (2S,3S)-2-((4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)benzyl)-carbamoyl)-3-hydroxypyrrolidin-1-ium, 4-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)phenol, (Z)-4-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-N?-hydroxybenzimidamide, amino(4-((5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)amino)-phenyl)methaniminium, (E)-4-((5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)amino)-benzaldehyde oxime, and 5-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)-1,3,4-oxadiazol-2-amine Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
a dihydroceramide + 2 ferrocytochrome b5 + O2 + 2 H+ Homo sapiens
-
 a (4E)-sphing-4-enine ceramide + 2 ferricytochrome b5 + 2 H2O
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens
-
-
-

Source Tissue

Source Tissue Comment Organism Textmining
JURKAT cell
-
 Homo sapiens
-
PC-3 cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
a dihydroceramide + 2 ferrocytochrome b5 + O2 + 2 H+
-
 Homo sapiens a (4E)-sphing-4-enine ceramide + 2 ferricytochrome b5 + 2 H2O
-
 ?
N-[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-sphinganine + 2 ferrocytochrome b5 + O2 + 2 H+ fluorescence-lebeld substrate Homo sapiens ?
-
 ?

Synonyms

Synonyms Comment Organism
dihydroceramide desaturase
-
 Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
 assay at Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.4
-
 assay at Homo sapiens

Cofactor

Cofactor Comment Organism Structure
cytochrome b5
-
 Homo sapiens
NADH
-
 Homo sapiens

General Information

General Information Comment Organism
malfunction Des1 inhibition is primarily responsible for the antiproliferative effects of SKI-II and its analogues. The structure-activity relationship of Des1 inhibition correlates to that required for inhibition of PC-3 cell growth, indicating that Des1 inhibition is a key driver of the anticancer effects of SKI-II and it analogues, which is also supported by lipidomic studies in PC-3 cells Homo sapiens
physiological function the de novo synthesis of sphingolipids commences with palmitoyl CoA, which is converted into the central lipid ceramide (Cer) in four steps, the last step being the introduction of the double bond at C4 by dihydroceramide desaturase-1 (Des1) Homo sapiens