Kicking off sphingolipid biosynthesis: structures of the serine palmitoyltransferase complex

Wattenberg, Binks W.

doi:10.1038/s41594-021-00562-0

Cited by 20 publications

(15 citation statements)

References 24 publications

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“…The resultant non-canonical sphingolipid bases, 1-deoxysphinganine and 1deoxymethylsphinganine, form 'dead end' ceramides, which due to the missing C1-OH moiety cannot be further modified [46]. The inability to progress in the sphingolipid metabolic pathway means that deoxysphingolipids cannot be degraded and accumulate to the point of inducing toxicity, as seen in hereditary sensory autonomic neuropathy-1 (HSAN1) [47][48][49][50][51][52][53].…”

Section: Biosynthesis Of Sphingoid Bases and Ceramide Via The De Novo Synthetic Pathwaymentioning

confidence: 99%

A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis

Quinville

Deschenes

Ryckman

et al. 2021

IJMS

115

119

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Sphingolipids are a specialized group of lipids essential to the composition of the plasma membrane of many cell types; however, they are primarily localized within the nervous system. The amphipathic properties of sphingolipids enable their participation in a variety of intricate metabolic pathways. Sphingoid bases are the building blocks for all sphingolipid derivatives, comprising a complex class of lipids. The biosynthesis and catabolism of these lipids play an integral role in small- and large-scale body functions, including participation in membrane domains and signalling; cell proliferation, death, migration, and invasiveness; inflammation; and central nervous system development. Recently, sphingolipids have become the focus of several fields of research in the medical and biological sciences, as these bioactive lipids have been identified as potent signalling and messenger molecules. Sphingolipids are now being exploited as therapeutic targets for several pathologies. Here we present a comprehensive review of the structure and metabolism of sphingolipids and their many functional roles within the cell. In addition, we highlight the role of sphingolipids in several pathologies, including inflammatory disease, cystic fibrosis, cancer, Alzheimer’s and Parkinson’s disease, and lysosomal storage disorders.

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Section: Biosynthesis Of Sphingoid Bases and Ceramide Via The De Novo Synthetic Pathwaymentioning

confidence: 99%

A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis

Quinville

Deschenes

Ryckman

et al. 2021

IJMS

115

119

View full text Add to dashboard Cite

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“…The pathway begins with the condensation of palmitate and serine to give rise 3-keto-dihydrosphingosine (also called 3-ketosphinganine) by serine palmitoyltransferase (SPT), a rate-limiting enzyme for de novo pathway. The SPT is a complex formed by SPTLC1, SPTLC2, ssSPTa/b and a negative regulatory subunit ORMDLs (homologs of the yeast and plant Orms) ( Davis et al, 2019 ; Wattenberg, 2021 ). It should be noted that sphingolipids can be made up of chains of different lengths.…”

Section: Stroke and Ceramide Metabolismmentioning

confidence: 99%

Involvement of Ceramide Metabolism in Cerebral Ischemia

Ouro

Correa-Paz²,

Maqueda³

et al. 2022

Front. Mol. Biosci.

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Ischemic stroke, caused by the interruption of blood flow to the brain and subsequent neuronal death, represents one of the main causes of disability in worldwide. Although reperfusion therapies have shown efficacy in a limited number of patients with acute ischemic stroke, neuroprotective drugs and recovery strategies have been widely assessed, but none of them have been successful in clinical practice. Therefore, the search for new therapeutic approaches is still necessary. Sphingolipids consist of a family of lipidic molecules with both structural and cell signaling functions. Regulation of sphingolipid metabolism is crucial for cell fate and homeostasis in the body. Different works have emphasized the implication of its metabolism in different pathologies, such as diabetes, cancer, neurodegeneration, or atherosclerosis. Other studies have shown its implication in the risk of suffering a stroke and its progression. This review will highlight the implications of sphingolipid metabolism enzymes in acute ischemic stroke.

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“…Recent structural studies on SPT revealed a symmetrical dimer protein anchored to the ER membrane by six α-helices. The complex is formed by a single molecule of SPTLC1, SPTLC2, ssSPTa/b (two small subunits that enhance enzyme activity and also specify acyl-CoA substrate) and four regulatory subunits, ORMDLs (homologs of the yeast and plant Orms) [27]. Then, 3-keto-dihydrosphingosine reductase (KDR) produces sphinganine.…”

Section: The De Novo Pathwaymentioning

confidence: 99%

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

et al. 2021

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Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second messengers, especially when they are generated at the plasma membrane of cells. Its metabolic dysfunction may lead to or be a consequence of an underlying disease. Recent reports on transcriptomics and electrospray ionization mass spectrometry analysis have demonstrated the variation of specific levels of sphingolipids and enzymes involved in their metabolism in different neurodegenerative diseases. In the present review, we highlight the most relevant discoveries related to ceramide and neurodegeneration, with a special focus on Parkinson’s disease.

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Kicking off sphingolipid biosynthesis: structures of the serine palmitoyltransferase complex

Abstract: Kicking off sphingolipid biosynthesis: structures of the serine palmitoyltransferase complex Structures of the human serine palmitoyltransferase complex reveal the overall assembly, regulatory mechanisms and substrate selectivity of this key enzyme in sphingolipid synthesis.

Cited by 20 publications

References 24 publications

A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis

A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis

Involvement of Ceramide Metabolism in Cerebral Ischemia

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

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