Inhibition of serine palmitoyl-transferase activity by lipoxamycin.

Abstract

Serine palmitoyltransferase condenses serine with a fatty acyl-CoA to form ketodihydrosphingosine in the first committed step of sphingolipid biosynthesis. A family of novel compounds, called the sphingofungins, have recently been discovered to be the first specific inhibitors of this enzyme1~3). Initially identified as antifungal agents, the sphingofungins resemble the long chain base intermediates in the sphingolipid pathway and inhibit the serine Liquid production medium C consisted of 10 g of beta-cyclodextrin, 40 g of dextrin, 7 g of distillers solubles and 5 g of yeast extract per liter of distilled water. Forty four ml of this mediumwas distributed into 250-ml unbaffled Erlenmeyer flasks. Production of antifungal activity was accomplished by adding 2ml of the seed culture described above to each production flask. Production cultures were incubated at 28°C for 4 days. Antifungal activity was produced in the culture filtrate and could conveniently be detected using the formation of zones of inhibition against Candida and Penicillium.Twoliters of the fermentation described above

Limonoid Compounds Inhibit Sphingomyelin Biosynthesis by Preventing CERT Protein-dependent Extraction of Ceramides from the Endoplasmic Reticulum

“…This lipid-specific protein-based cell screening appears to be a very efficient technique for high throughput analysis of small compounds affecting lipid metabolism (18). In the present screen performed in the presence of DHS, we focused on SM biosynthesis and excluded serine palmitoyltransferase inhibitors because a number of them such as ISP-1/myriocin, sphingofungins, lipoxamycin, and sulfamisterine have been reported (25,(63)(64)(65)(66). Out of a library of 2011 natural products and derivatives, we identified 3-chloro-8␤-hydroxycarapin, CHC, a limonoid derivative.…”

The Transposon impala Is Activated by Low Temperatures: Use of a Controlled Transposition System To Identify Genes Critical for Viability of Aspergillus fumigatus

“…For example, Afua_4g07800 is the homologue of S. cerevisiae RAM2, which encodes the common alpha subunit of both the farnesyltransferase and geranylgeranyltransferase, for which a number of inhibitors have been identified (27). Also, Afua_6g12390 encodes Lcb1, a component of serine palmitoyltransferase, and sphingofungins B and C (isolated from A. fumigatus) and lipoxamycin (isolated from Streptomyces) all specifically target serine palmitoyltransferase and are potent antifungal agents (33,52). The mutant bank identified here also contains a number of potentially novel targets.…”

Human and Murine Serine‐Palmitoyl‐CoA Transferase

“…pchloro-L-alanine 1271, L-cycloserine [27-301, sphingofungins [31], myriocin (ISP1) [32] and lipoxamycin [33], the latter being structurally related to sphingosine bases. We tested the inhibition of endogenous SPT in the lysate of untransfected HEK 293 cells and of SPT in the lysate of overexpressing cell clones in vitro by two of its most common inhibitors, L-cycloserine and 8-chloro-L-alanine (summarized in Fig.…”