ArticleThe Journal of biological chemistry2009
The external aldimine form of serine palmitoyltransferase: structural, kinetic, and spectroscopic analysis of the wild-type enzyme and HSAN1 mutant mimics.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 67 citations in OpenAlex.
- Substrate-bound structures of yeast ALA synthase reveal protein dynamics initiating heme biosynthesis.Science advances · 2026Article
- Evolution, structure and function of the putative biosynthetic gene cluster of the fungal secondary metabolite myriocin, a potent inhibitory sphingolipid.Communications biology · 2026Article
- Electrostatic tuning of the pyridoxal-5'-phosphate cofactor site defines pH dependence in type I cystathionine β-lyases.The Journal of biological chemistry · 2026Article
- An Integrated Engineering Approach to Intensify the Biocatalytic Metaraminol Synthesis.ChemSusChem · 2026Article
- Polyketide synthase-derived sphingolipids mediate microbiota protection against a bacterial pathogen in C. elegans.Nature communications · 2025Article
- Intestinal permeability of N-acetylcysteine is driven by gut microbiota-dependent cysteine palmitoylation.Nature communications · 2025Article
- Rational engineering of a thermostable α-oxoamine synthase biocatalyst expands the substrate scope and synthetic applicability.Communications chemistry · 2025Article
- Atypical sphingosine-1-phosphate metabolites-biological implications of alkyl chain length.Pflugers Archiv : European journal of physiology · 2024Review
- Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.Journal of neuromuscular diseases · 2024Review
- Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.Nature communications · 2023Article
- Versatile Chemo-Biocatalytic Cascade Driven by a Thermophilic and Irreversible C-C Bond-Forming α-Oxoamine Synthase.ACS sustainable chemistry & engineering · 2023Article
- Mechanism of sphingolipid homeostasis revealed by structural analysis ofScience advances · 2023Article
- Time-resolved multiparameter analytics on a cell-free production platform for acyl-CoA precursors.Analytical science advances · 2022Article
- Crystal structure of Sphingobacterium multivorum serine palmitoyltransferase complexed with tris(hydroxymethyl)aminomethane.Acta crystallographica. Section F, Structural biology communications · 2022Article
- Desaturation of the Sphingofungin Polyketide Tail Results in Increased Serine Palmitoyltransferase Inhibition.Microbiology spectrum · 2022Article
- Understanding and Circumventing the Requirement for Native Thioester Substrates for α-Oxoamine Synthase Reactions.ACS chemical biology · 2022Article
- Identification and Biosynthesis of Pro-Inflammatory Sulfonolipids from an Opportunistic PathogenACS chemical biology · 2022Article
- Convergent evolution of bacterial ceramide synthesis.Nature chemical biology · 2022Article
- Specialized acyl carrier protein used by serine palmitoyltransferase to synthesize sphingolipids inFrontiers in microbiology · 2022Article
- Genetic and lipidomic analyses suggest thatAccess microbiology · 2022Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Sphingolipid biosynthesis begins with the condensation of L-serine and palmitoyl-CoA catalyzed by the PLP-dependent enzyme serine palmitoyltransferase (SPT). Mutations in human SPT cause hereditary sensory autonomic neuropathy type 1, a disease characterized by loss of feeling in extremities and severe pain. The human enzyme is a membrane-bound hetereodimer, and the most common mutations are located in the enzymatically incompetent monomer, suggesting a "dominant" or regulatory effect. The molecular basis of how these mutations perturb SPT activity is subtle and is not simply loss of activity. To further explore the structure and mechanism of SPT, we have studied the homodimeric bacterial enzyme from Sphingomonas paucimobilis. We have analyzed two mutants (N100Y and N100W) engineered to mimic the mutations seen in hereditary sensory autonomic neuropathy type 1 as well as a third mutant N100C designed to mimic the wild-type human SPT. The N100C mutant appears fully active, whereas both N100Y and N100W are significantly compromised. The structures of the holoenzymes reveal differences around the active site and in neighboring secondary structure that transmit across the dimeric interface in both N100Y and N100W. Comparison of the l-Ser external aldimine structures of both native and N100Y reveals significant differences that hinder the movement of a catalytically important Arg(378) residue into the active site. Spectroscopic analysis confirms that both N100Y and N100W mutants subtly affect the chemistry of the PLP. Furthermore, the N100Y and R378A mutants appear less able to stabilize a quinonoid intermediate. These data provide the first experimental insight into how the most common disease-associated mutations of human SPT may lead to perturbation of enzyme activity.
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