sphingolipid biosynthesis
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2022 ◽  
Author(s):  
Christian Metallo ◽  
Michal Handzlik ◽  
Jivani Gengatharan ◽  
Katie Frizzi ◽  
Grace McGregor ◽  
...  

Abstract Type 2 diabetes represents a disease spectrum in which chronic metabolic dysfunction damages multiple organ systems including liver, kidneys, and peripheral nerves1,2. While onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidemia3-7, aberrant amino acid metabolism also contributes to pathogenesis of diabetes and potentially its complications8-10. Serine and glycine are closely related non-essential amino acids11,12 that are consistently reduced in patients with metabolic syndrome10,13-16, but the mechanistic drivers of serine deficiency and the downstream metabolic and phenotypic consequences remain unclear. Low systemic serine, a serine-opathy, is also emerging as a hallmark of macular and peripheral nerve disorders. Specifically, serine deficiency correlates positively with impaired visual acuity and peripheral neuropathy (PN)17-19. Here we demonstrate that aberrant serine homeostasis in the liver drives serine and glycine deficiencies in genetically obese and hyperglycaemic mice. This serine-opathy can be diagnosed with a serine tolerance test that quantifies systemic serine disposal. Mimicking these metabolic alterations via dietary serine/glycine restriction together with high fat intake dramatically accelerates thermal hypoalgesia in mice and reduces epidermal sensory nerve density, which are accompanied by extensive sciatic nerve lipid remodeling. These phenotypes were subsequently normalized by myriocin, linking serine-associated PN with sphingolipid biosynthesis. These findings identify systemic serine deficiency and dyslipidemia as novel risk factors for PN that may be exploited therapeutically.


2021 ◽  
Author(s):  
Jakub Zahumensky ◽  
Caroline Mota Fernandes ◽  
Petra Vesela ◽  
Maurizio Del Poeta ◽  
James Bernard Konopka ◽  
...  

Sphingolipids are essential building blocks of eukaryotic membranes and important signalling molecules, tightly regulated in response to environmental and physiological inputs. Mechanism of sphingolipid level perception at the plasma membrane remains unclear. In Saccharomyces cerevisiae, Nce102 protein has been proposed to function as sphingolipid sensor as it changes its plasma membrane distribution in response to sphingolipid biosynthesis inhibition. We show that Nce102 redistributes specifically in regions of increased sphingolipid demand, e.g., membranes of nascent buds. Furthermore, we report that production of Nce102 increases following sphingolipid biosynthesis inhibition and Nce102 is internalized when excess sphingolipid precursors are supplied. This suggests that the total amount of Nce102 in the plasma membrane is a measure of the current need for sphingolipids, whereas its local distribution marks sites of high sphingolipid demand. Physiological role of Nce102 in regulation of sphingolipid synthesis is demonstrated by mass spectrometry analysis showing reduced levels of complex sphingolipids and long-chain bases in nce102? deletion mutant. Nce102 behaves analogously in human fungal pathogen Candida albicans, suggesting a conserved principle of local sphingolipid control across species.


2021 ◽  
Author(s):  
Nao Komatsu ◽  
Yuko Ishino ◽  
Rina Shirai ◽  
Ken-taro Sakata ◽  
Motohiro Tani ◽  
...  

Global control for the synthesis of lipids constituting a bilayer of cell membranes is known to be with a small number of transcription factors called master transcriptional regulators, which target a wide range of genes encoding lipid metabolism enzymes and/or their regulators. Although master transcriptional regulators of glycerophospholipids and sterols have been identified in both yeast and mammals, this aspect of sphingolipid metabolism is not yet understood. In the present study, we identified the C2H2-type zinc finger transcription factor, Com2, as a master transcriptional regulator of sphingolipid metabolism in the budding yeast, Saccharomyces cerevisiae. The target of rapamycin complex 2 (TORC2)-activated protein kinase Ypk1 is known to regulate sphingolipid metabolism. Activated Ypk1 stimulates the activity of serine palmitoyl transferase (SPT), the first-step enzyme in sphingolipid biosynthesis, by phosphorylating and inhibiting Orm1/2, a negative regulator of SPT. This regulation of SPT activity is thought to be a major pathway in the regulation of sphingolipid metabolism. In the present study, we found that inhibition of sphingolipid synthesis upregulates the expression of Com2, which in turn leads to the concomitant expression of Ypk1. The upregulation of Ypk1 expression was found to be dependent on a putative Com2-binding site in the YPK1 promoter. Our results also suggested that Com2 senses intracellular sphingolipid levels through a pathway independent of TORC2-Ypk1-mediated sensing of sphingolipids. Our results revealed an additional layer of mechanistic regulation that allows cells to maintain appropriate levels of sphingolipid biosynthesis and to rapidly induce this process in response to environmental stresses.


2021 ◽  
pp. 1-16
Author(s):  
I.B. Molina-Pintor ◽  
A.E. Rojas-García ◽  
I.M. Medina-Díaz ◽  
B.S. Barrón-Vivanco ◽  
Y.Y. Bernal-Hernández ◽  
...  

Fumonisins (FBs), a widespread group of mycotoxins produced by Fusarium spp., are natural contaminants in cereals and foodstuffs. Fumonisin B1 (FB1) is the most toxic and prevalent mycotoxin of this group, and it has been reported that FB1 accounts for 70-80% of FBs produced by the mycotoxigenic strains. The mode of action of FB1 depends on the structural similarity with sphinganine/sphingosine N-acyltransferase. This fact causes an accumulation of sphingoid bases and blocks the sphingolipid biosynthesis or the function of sphingolipids. Diverse toxic effects and diseases such as hepatocarcinogenicity, hepatotoxicity, nephrotoxicity, and cytotoxicity have been reported, and diseases like leukoencephalomalacia in horses and pulmonary oedema in horses and swine have been described. In humans, FBs have been associated with oesophageal cancer, liver cancer, neural tube defects, and infantile growth delay. However, despite the International Agency for Research on Cancer designated FB1 as a possibly carcinogenic to humans, its genotoxicity and epigenetic properties have not been clearly elucidated. This review aims to summarise the progress in research about the genotoxic and epigenetics effects of FB1.


FEBS Journal ◽  
2021 ◽  
Author(s):  
Yuko Ishino ◽  
Nao Komatsu ◽  
Ken‐taro Sakata ◽  
Daichi Yoshikawa ◽  
Motohiro Tani ◽  
...  

Author(s):  
Songuigama Coulibaly ◽  
Jean-Paul D. U. N'guessan ◽  
Alain Kacou ◽  
Jean-Fabrice K. Koffi ◽  
Amelanh S. Diakité ◽  
...  

Antifungal therapeutics is confronted today with the challenge of drug resistance of most fungal germs to current antifungal drugs. Faced with this situation, the search for new and more efficient antifungal molecules that avoid the phenomenon of drug resistance becomes an urgent task. The design of new antifungal drugs acting on new biological targets and/or by innovative mechanisms of action is essential in the fight against fungal infections. Current advances in molecular biology have identified new targets for the development of new antifungal therapy. Several biological targets for the development of new antifungal agents are currently being explored. Amongst these, the most promising are BET (Bromodomain and Extra-Terminal) proteins, Homoserine transacetylase (HTA), mannan cell wall, Glycosylphosphatidylinositols (GPI) anchor biosynthesis, Histone deacetylases, Sphingolipid biosynthesis, D9 fatty acid desaturase and Chitin biosynthesis. This review summarizes the new biological targets and their inhibitors under development as potential new antifungal drugs.


2021 ◽  
Author(s):  
Shahan Mamoor

Gynecologic cancers including cancers of the endometrium are a clinical problem (1-4). We mined published and public microarray data (5, 6) to discover genes associated with endometrial cancers by comparing transcriptomes of the normal endometrium and endometrial tumors from humans. We identified ORMDL sphingolipid biosynthesis regulator 2, encoded by ORMDL2, as among the most differentially expressed genes, transcriptome-wide, in cancers of the endometrium. ORMDL2 was expressed at significantly higher levels in endometrial tumor tissues as compared to the endometrium. Importantly, in human endometrial cancer, primary tumor expression of ORMDL2 was correlated with overall survival in white patients with low mutational burden. ORMDL2 may be a molecule of interest in understanding the etiology or progression of human endometrial cancer.


Science ◽  
2021 ◽  
Vol 371 (6526) ◽  
pp. 255-260
Author(s):  
Jiancai Li ◽  
Rayko Halitschke ◽  
Dapeng Li ◽  
Christian Paetz ◽  
Haichao Su ◽  
...  

Many plant specialized metabolites function in herbivore defense, and abrogating particular steps in their biosynthetic pathways frequently causes autotoxicity. However, the molecular mechanisms underlying their defense and autotoxicity remain unclear. Here, we show that silencing two cytochrome P450s involved in diterpene biosynthesis in the wild tobacco Nicotiana attenuata causes severe autotoxicity symptoms that result from the inhibition of sphingolipid biosynthesis by noncontrolled hydroxylated diterpene derivatives. Moreover, the diterpenes’ defensive function is achieved by inhibiting herbivore sphingolipid biosynthesis through postingestive backbone hydroxylation products. Thus, by regulating metabolic modifications, tobacco plants avoid autotoxicity and gain herbivore defense. The postdigestive duet that occurs between plants and their insect herbivores can reflect the plant’s solutions to the “toxic waste dump” problem of using potent chemical defenses.


2021 ◽  
Author(s):  
Shahan Mamoor

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with brain metastasis in humans with metastatic breast cancer. We found that ORMDL sphingolipid biosynthesis regulator 3, encoded by ORMDL3, was among the genes whose expression was most different in the brain metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. ORMDL3 mRNA was present at increased quantities in brain metastatic tissues as compared to primary tumors of the breast. Importantly, expression of ORMDL3 in primary tumors was significantly correlated with patient overall survival. Modulation of ORMDL3 expression may be relevant to the biology by which tumor cells metastasize from the breast to the brain in humans with metastatic breast cancer.


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