Desaturation of the Sphingofungin Polyketide Tail Results in Increased Serine Palmitoyltransferase Inhibition

Hoefgen, Sandra; Bissell, Alexander U; Huang, Ying; Gherlone, Fabio; Raguž, Luka; Beemelmanns, Christine; Valiante, Vito

doi:10.1128/spectrum.01331-22

Cited by 5 publications

(5 citation statements)

References 34 publications

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“…To ensure the required palmitoyl-CoA for the reaction, we supplied palmitic acid to the reaction mix and additionally incubated the purified Escherichia coli -derived fatty-acid-CoA ligase FadD, together with SphA ( 34 ). Although the production of 3-ketodihydrosphinganine was lower compared to the SPT positive control [isolated from Sphingomonas paucimobilis ( 19 )], we confirmed that SphA has SPT activity and that its dual functionality is driven by the availability of the used substrates ( Fig. 4A ).…”

Section: Resultssupporting

confidence: 67%

“…Analysis of the SphA activity was done with previously purified FadD, SphA, and SPT enzymes and already described protocol ( 18 , 19 ).…”

Section: Methodsmentioning

confidence: 99%

“…These compounds are toxic metabolites that inhibit serine palmitoyl transferase (SPT), a multimeric enzyme responsible for the condensation of palmitoyl-CoA with serine, the first and crucial step in the biosynthesis of sphingolipids (SLs) ( 17 ). Recently, we succeeded in elucidating the biosynthesis of sphingofungin B, C, and D in A. fumigatus ( 18 ) and assayed their potential to inhibit SPTs ( 19 ). In brief, the polyketide synthase (PKS) SphB together with the aminotransferase SphA generate the first intermediate.…”

Section: Introductionmentioning

confidence: 99%

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The spatial organization of sphingofungin biosynthesis in Aspergillus fumigatus and its cross-interaction with sphingolipid metabolism

Jojić,

Gherlone,

Cseresnyés

et al. 2024

mBio

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Sphingofungins are sphinganine analog mycotoxins acting as inhibitors of serine palmitoyl transferases, enzymes responsible for the first step in the sphingolipid biosynthesis. Eukaryotic cells are highly organized with various structures and organelles to facilitate cellular processes and chemical reactions, including the ones occurring as part of the secondary metabolism. We studied how sphingofungin biosynthesis is compartmentalized in the human-pathogenic fungus Aspergillus fumigatus , and we observed that it takes place in the endoplasmic reticulum (ER), ER-derived vesicles, and the cytosol. This implies that sphingofungin and sphingolipid biosynthesis colocalize to some extent. Automated analysis of confocal microscopy images confirmed the colocalization of the fluorescent proteins. Moreover, we demonstrated that the cluster-associated aminotransferase (SphA) and 3-ketoreductase (SphF) play a bifunctional role, supporting sphingolipid biosynthesis, and thereby antagonizing the toxic effects caused by sphingofungin production. IMPORTANCE A balanced sphingolipid homeostasis is critical for the proper functioning of eukaryotic cells. To this end, sphingolipid inhibitors have therapeutic potential against diseases related to the deregulation of sphingolipid balance. In addition, some of them have significant antifungal activity, suggesting that sphingolipid inhibitors-producing fungi have evolved mechanisms to escape self-poisoning. Here, we propose a novel self-defense mechanism, with cluster-associated genes coding for enzymes that play a dual role, being involved in both sphingofungin and sphingolipid production.

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Section: Resultssupporting

confidence: 67%

“…Analysis of the SphA activity was done with previously purified FadD, SphA, and SPT enzymes and already described protocol ( 18 , 19 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The spatial organization of sphingofungin biosynthesis in Aspergillus fumigatus and its cross-interaction with sphingolipid metabolism

Jojić,

Gherlone,

Cseresnyés

et al. 2024

mBio

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“…Sphingofungin is a polyketide-derived compound, which was first isolated from A. fumigatus in 1992 [108]. Sphingofungin is known to inhibit serine palmitoyl transferase (SPT) [109], which plays a crucial role in the biosynthesis of sphingolipids (SLs) [110]. Recently, using confocal microscopy, it was shown that the synthesis of sphingofungins and SLs was partially co-compartmentalized in the ER and ER-derived vesicles [111].…”

Section: Timeline Of Linkage Of Natural Products To Specific Bgcsmentioning

confidence: 99%

A Timeline of Biosynthetic Gene Cluster Discovery in Aspergillus fumigatus: From Characterization to Future Perspectives

Seo,

Wassano,

Amir Rawa

et al. 2024

JoF

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In 1999, the first biosynthetic gene cluster (BGC), synthesizing the virulence factor DHN melanin, was characterized in Aspergillus fumigatus. Since then, 19 additional BGCs have been linked to specific secondary metabolites (SMs) in this species. Here, we provide a comprehensive timeline of A. fumigatus BGC discovery and find that initial advances centered around the commonly expressed SMs where chemical structure informed rationale identification of the producing BGC (e.g., gliotoxin, fumigaclavine, fumitremorgin, pseurotin A, helvolic acid, fumiquinazoline). Further advances followed the transcriptional profiling of a ΔlaeA mutant, which aided in the identification of endocrocin, fumagillin, hexadehydroastechrome, trypacidin, and fumisoquin BGCs. These SMs and their precursors are the commonly produced metabolites in most A. fumigatus studies. Characterization of other BGC/SM pairs required additional efforts, such as induction treatments, including co-culture with bacteria (fumicycline/neosartoricin, fumigermin) or growth under copper starvation (fumivaline, fumicicolin). Finally, four BGC/SM pairs were discovered via overexpression technologies, including the use of heterologous hosts (fumicycline/neosartoricin, fumihopaside, sphingofungin, and sartorypyrone). Initial analysis of the two most studied A. fumigatus isolates, Af293 and A1160, suggested that both harbored ca. 34–36 BGCs. However, an examination of 264 available genomes of A. fumigatus shows up to 20 additional BGCs, with some strains showing considerable variations in BGC number and composition. These new BGCs present a new frontier in the future of secondary metabolism characterization in this important species.

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“…For example, motif 1 was the only one present in CarAGT2, Aminotransferases and other enzymes display some structural domains that are highly conserved throughout evolution. Aminotran_5 (PF00266), which encodes a protein that is a phosphoserine aminotransferase, regulates immune function and is involved in oxidative stress [29] including CarSPTa, CarSPTb, and CarKBL. Transmembrane domains may function as membrane receptors, membrane-anchored proteins, or ion channel proteins localized on the membrane [30,31].…”

Section: Discussionmentioning

confidence: 99%

Aminotransferase Class I and II Gene Family in the Jinjiang Oyster (Crassostrea ariakensis): Genomewide Identification, Phylogenetic Analysis and Expression Profiles after Salinity Stress

Ge,

Liu,

et al. 2023

Fishes

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Aminotransferases are enzymes found in living organisms that catalyze transfer reactions between amino acids and keto acids, crucial for amino acid metabolism and synthesis. Aminotransferase classes I and II play a vital role in regulating osmolarity, protecting cells, and improving metabolic homeostasis and cellular fitness. To investigate the characteristics of the aminotransferase class I and II gene family and their roles in osmotic pressure regulation in the Jinjiang oyster (Crassostrea ariakensis), the gene structure, chromosomal localization, and phylogeny were characterized and the genes’ expression in the gill under high-salt stress was analyzed. In this study, eighteen Aminotransferase class I and II genes, including SPTLCa and SPTLCb, SPTa and SPTb, ALAT2a and ALAT2b, KAT3a and KAT3b, and ASTa, ASTb and ASTc, were identified. The physicochemical properties of 11 family members were stable, with their instability factors less than 40. Subcellular localization prediction showed that aminotransferase classes I and II were localized in the cytoplasm or mitochondria. Chromosomal localization results showed that the 18 aminotransferase class I and II genes were located on eight chromosomes. All members of this gene family had the Aminotran_1_2 structural domain which is associated with osmotic pressure regulation by adjusting the conversion reaction between amino acids and keto acids. Most gene expressions showed an initial increase followed by a decrease from 0 h to 12 h when the oysters were challenged by acute stress using artificial seawater with a salinity of 40. However, the expression of CarAGT2 and CarKAT3b genes showed an increased trend with increasing stress time. This study systematically investigated the bioinformatics characteristics of the aminotransferase class I and II gene family in C. ariakensis and their role in osmotic pressure regulation, which provides scientific data for understanding the potential functions of these genes in physiological adaptation, thereby expanding the research on osmoregulation in bivalves.

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Desaturation of the Sphingofungin Polyketide Tail Results in Increased Serine Palmitoyltransferase Inhibition

Abstract: Targeting the cellular sphingolipid metabolism is often discussed as a potential approach to treat associated human diseases such as cancer and Alzheimer's disease. Alternatively, it is also a possible target for the development of antifungal compounds, which are direly needed.

Cited by 5 publications

References 34 publications

The spatial organization of sphingofungin biosynthesis in Aspergillus fumigatus and its cross-interaction with sphingolipid metabolism

The spatial organization of sphingofungin biosynthesis in Aspergillus fumigatus and its cross-interaction with sphingolipid metabolism

A Timeline of Biosynthetic Gene Cluster Discovery in Aspergillus fumigatus: From Characterization to Future Perspectives

Aminotransferase Class I and II Gene Family in the Jinjiang Oyster (Crassostrea ariakensis): Genomewide Identification, Phylogenetic Analysis and Expression Profiles after Salinity Stress

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