Nematode Sterol Biochemistry

Chitwood, David J.; Patterson, Glenn W.; Nes, W. David

doi:10.1201/9781439821831.ch9

Cited by 6 publications

(10 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2A). Consistent with previous reports (21), cholesterol fed to the nematode generated cholesterol (cholest-5-enol) [1], 7-dehydrocholesterol (cholesta-5,7-dienol) [2], lathosterol (cholest-7-enol) [12], lophenol [17], and  8 (14) lophenol [4-methyl cholest-8(14)-enol] [18]. However, quite surprisingly, the D 6 -cholesterol supplement generated a disrupted sterol composition that was presumably due to a kinetic isotope effect on an intermediate enzyme that led to marked depletion in lathosterol and C4-methyl sterol metabolites ( Fig.…”

Section: Discovery Of Coordinately Branching Pathways In C Elegans Csupporting

confidence: 94%

“…14). Careful inspection of the GC trace showed, as reported previously (21), a trace metabolite eluting at RRTc 1.27 with M + 414, and its mass spectrum was consistent with the previously identified 24-methyl lophanol. However, within our limits of detection there was no GC/MS evidence for 3-oxo sterols.…”

Section: Demonstration For An Ancient C4-sterol Metabolism Pathway Casupporting

confidence: 84%

“…Although there is much research in C. elegans sterol metabolism, the rationale for how the reported sterol complement generated in nematodes from cholesterol metabolism specifies the metabolite order, what enzyme(s) controls the flux to  8(14) -lophenol, and where stanols originate in an otherwise stenol metabolic pathway is poorly defined. In a preliminary study, to confirm previous sterol metabolism results (21), we characterized the sterol content of C. elegans fed with cholesterol and D 6 -cholesterol ( Fig. 2A).…”

Section: Discovery Of Coordinately Branching Pathways In C Elegans Csupporting

confidence: 62%

“…Once it became clear to us that nematodes can synthesize a novel route to lophanol involving 3-oxo sterol intermediates we considered the observation by Chitwood that 24-methyl lophanol is likely a trace product of campesterol (24-methyl cholesterol) fed to C. elegans and not necessarily an artifact (21). Consequently, we sought to verify this finding.…”

Section: Demonstration For An Ancient C4-sterol Metabolism Pathway Camentioning

confidence: 99%

See 3 more Smart Citations

A nematode sterol C4α-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity

Zhou

Fisher

Vanderloop

et al. 2020

Journal of Lipid Research

View full text Add to dashboard Cite

Primitive sterol evolution plays an important role in fossil record interpretation and offers potential therapeutic avenues for human disease resulting from nematode infections. Recognizing that C4-methyl stenol products [8(14)-lophenol] can be synthesized in bacteria while C4-methyl stanol products (dinosterol) can be synthesized in dinoflagellates and preserved as sterane biomarkers in ancient sedimentary rock is key to eukaryotic sterol evolution. In this regard, nematodes have been proposed to convert dietary cholesterol to 8(14)-lophenol by a secondary metabolism pathway that could involve sterol C4 methylation analogous to the C2 methylation of hopanoids (radicle-type mechanism) or C24 methylation of sterols (carbocation-type mechanism). Here, we characterized dichotomous cholesterol metabolic pathways in Caenorhabditis elegans that generate 3-oxo sterol intermediates in separate paths to lophanol (4-methyl stanol) and 8(14)-lophenol (4-methyl stenol). We uncovered alternate C3-sterol oxidation and Δ7 desaturation steps that regulate sterol flux from which branching metabolite networks arise, while lophanol/8(14)-lophenol formation is shown to be dependent on a sterol C4α-methyltransferse (4-SMT) that requires 3-oxo sterol substrates and catalyzes a newly discovered 3-keto-enol tautomerism mechanism linked to S-adenosyl-l-methionine-dependent methylation. Alignment-specific substrate-binding domains similarly conserved in 4-SMT and 24-SMT enzymes, despite minimal amino acid sequence identity, suggests divergence from a common, primordial ancestor in the evolution of methyl sterols. The combination of these results provides evolutionary leads to sterol diversity and points to cryptic C4-methyl steroidogenic pathways of targeted convergence that mediate lineage-specific adaptations.

show abstract

Section: Discovery Of Coordinately Branching Pathways In C Elegans Csupporting

confidence: 94%

Section: Demonstration For An Ancient C4-sterol Metabolism Pathway Casupporting

confidence: 84%

Section: Discovery Of Coordinately Branching Pathways In C Elegans Csupporting

confidence: 62%

Section: Demonstration For An Ancient C4-sterol Metabolism Pathway Camentioning

confidence: 99%

See 2 more Smart Citations

A nematode sterol C4α-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity

Zhou

Fisher

Vanderloop

et al. 2020

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…More directly, both sterol starvation and mutations in a megalinrelated protein LRP-1, which presumably mediates sterol endocytosis by hyp7 hypodermis, have been shown to prevent the shedding and degradation of the old cuticle at all C. elegans moults (Yochem et al 1999). Whether ecdysteroids are required for nematode moulting is not clear, as their synthesis from cholesterol has not been demonstrated (Chitwood 1992).…”

Section: Nhr-25 As a Core Regulator Of Moultingmentioning

confidence: 99%

The conserved nuclear receptor Ftz‐F1 is required for embryogenesis, moulting and reproduction in Caenorhabditis elegans

Ishihara²,

et al. 2000

View full text Add to dashboard Cite

Background: Nuclear receptors are essential players in the development of all metazoans. The nematode Caenorhabditis elegans possesses more than 200 putative nuclear receptor genes, several times more than the number known in any other organism. Very few of these transcription factors are conserved with components of the steroid response pathways in vertebrates and arthropods. Ftz-F1, one of the evolutionarily oldest nuclear receptor types, is required for steroidogenesis and sexual differentiation in mice and for segmentation and metamorphosis in Drosophila.

show abstract

A model for Niemann–Pick type C disease in the nematode Caenorhabditis elegans

2000

View full text Add to dashboard Cite

Niemann-Pick type C (NP-C) disease is a progressive neurodegenerative disorder characterized by the inappropriate accumulation of unesterified cholesterol in lysosomes [1]. NP-C patients show various defects including hepatosplenomegaly, ataxia, dystonia and dementia. Most cases of NP-C are associated with inactivating mutations of the NPC1 gene [2], which encodes a protein implicated in the retrograde transport of sterols and other cargo from lysosomes [3]. Furthermore, localization of the NPC1 protein to lysosomal/endosomal compartments is essential for proper transport [4]. To create a model of NP-C disease in a simple, genetically tractable organism, we generated deletion mutations in two Caenorhabditis elegans homologs of the human NPC1 gene, designated npc-1 and npc-2. Animals mutant for npc-1 developed slowly, laid eggs prematurely, and were hypersensitive to cholesterol deprivation. Furthermore, npc-1; npc-2 double-mutant animals inappropriately formed dauer larvae under favorable growth conditions. These phenotypes in C. elegans provide a model system for both genetic and chemical suppressor screening that could identify promising drug targets and leads for NP-C disease.

show abstract

Nematode Sterol Biochemistry

Cited by 6 publications

References 55 publications

A nematode sterol C4α-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity

A nematode sterol C4α-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity

The conserved nuclear receptor Ftz‐F1 is required for embryogenesis, moulting and reproduction in Caenorhabditis elegans

A model for Niemann–Pick type C disease in the nematode Caenorhabditis elegans

Contact Info

Product

Resources

About