Structural insights into the assembly and substrate selectivity of human SPT–ORMDL3 complex

Li, Sisi; Xie, Tian; Liu, Peng; Wang, Lei; Gong, Xin

doi:10.1038/s41594-020-00553-7

Cited by 66 publications

(89 citation statements)

References 49 publications

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“…ssSPTa promotes the use of the 16-carbon acyl-CoA; however, the inclusion of ssSPTb in its stead allows 18-carbon and longer acyl-CoAs to serve as SPT substrates 13 . The structures reveal the basis for this 2,3 . From the orientation of the bound 3-ketodihydrosphingosine, as well as that of two inhibitors that mimic the acyl-CoA structure, these groups identified the site of acyl-CoA binding, predominantly contributed by SPTLC2 (Fig.…”

Section: News and Viewsmentioning

confidence: 87%

“…Regulation of sphingolipid production is crucial to cell physiology, and dysregulation underlies a number of devastating pathologies 1 . Two articles, from Lee et al 2 and Gong et al 3 , report a pivotal advance in our understanding of how sphingolipids are synthesized and how synthesis is regulated.…”

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confidence: 99%

“…In addition to establishing the overall shape of the human SPT complex, the newly reported cryo-EM structures 2,3 illuminate the stoichiometry of the subunits, the structural basis of subunit interactions and the substrate binding sites, and they yield important clues about the activation of the enzyme by the small subunits and the control of enzyme activity by the ORMDLs. Both groups determined multiple structures, including a core unit with SPTLC1, SPTLC2 and ssSPTa; the core unit with ORMDL; and structures with the 3-ketodihydrosphingosine product 2 and inhibitors mimicking either substrates 3 or the transition state 2 .…”

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confidence: 99%

“…The new structures reveal a symmetrical dimer of protein assemblies, with each assembly containing a single molecule of SPTLC1, SPTLC2, ssSPTa and, when included, ORMDL3 ( Fig. 2a) 2,3 . The overall structure of the SPTLC1-2 dimer within the assembly is similar to that of the homodimeric bacterial enzymes 2,3 .…”

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confidence: 99%

“…2a) 2,3 . The overall structure of the SPTLC1-2 dimer within the assembly is similar to that of the homodimeric bacterial enzymes 2,3 . The complex is anchored to the membrane by six α-helices, contributed by SPTLC1 and ssSPTa (one each) and by ORMDL (four).…”

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confidence: 99%

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Kicking off sphingolipid biosynthesis: structures of the serine palmitoyltransferase complex

Wattenberg

2021

Nat Struct Mol Biol

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confidence: 87%

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confidence: 99%

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Kicking off sphingolipid biosynthesis: structures of the serine palmitoyltransferase complex

Wattenberg

2021

Nat Struct Mol Biol

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The sphingolipid anteome: implications for evolution of the sphingolipid metabolic pathway

2022

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Modern cell membranes contain a bewildering complexity of lipids, among them sphingolipids (SLs). Advances in mass spectrometry have led to the realization that the number and combinatorial complexity of lipids, including SLs, is much greater than previously appreciated. SLs are generated de novo by four enzymes, namely serine palmitoyltransferase, 3-ketodihydrosphingosine reductase, ceramide synthase and dihydroceramide D4-desaturase 1. Some of these enzymes depend on the availability of specific substrates and cofactors, which are themselves supplied by other complex metabolic pathways. The evolution of these four enzymes is poorly understood and likely depends on the co-evolution of the metabolic pathways that supply the other essential reaction components. Here, we introduce the concept of the 'anteome', from the Latin ante ('before') to describe the network of metabolic ('omic') pathways that must have converged in order for these pathways to co-evolve and permit SL synthesis. We also suggest that the current origin of life and evolutionary models lack appropriate experimental support to explain the appearance of this complex metabolic pathway and its anteome.

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SPTLC2 variants are associated with early‐onset ALS and FTD due to aberrant sphingolipid synthesis

Naruse,

Ishiura,

Esaki

et al. 2024

Ann Clin Transl Neurol

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ObjectiveAmyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early‐onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies.MethodsOur research commenced with an in‐depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early‐onset ALS (onset age of <40 years). This involved whole‐exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early‐onset ALS and further included 440 patients with adult‐onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants.ResultsWe identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early‐onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early‐onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction.InterpretationOur study revealed novel SPTLC2 variants in patients with early‐onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development.

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Structural insights into the assembly and substrate selectivity of human SPT–ORMDL3 complex

Cited by 66 publications

References 49 publications

Kicking off sphingolipid biosynthesis: structures of the serine palmitoyltransferase complex

Kicking off sphingolipid biosynthesis: structures of the serine palmitoyltransferase complex

The sphingolipid anteome: implications for evolution of the sphingolipid metabolic pathway

SPTLC2 variants are associated with early‐onset ALS and FTD due to aberrant sphingolipid synthesis

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