Lolitrem B
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Basic Info
| Common Name | Lolitrem B(F05010) |
| 2D Structure | |
| Description | Paspalinine is a tremorgenic mycotoxin that is produced by the fungi Neotyphodium lolii and Acremonium lolii. It may be found in contaminated cereal crops such as oats, barley, millet, corn and rice. Tremorgenic mycotoxins affect central nervous system activity and have been implicated in a number of neurologic diseases of cattle collectively known as "staggers syndromes" or “ryegrass staggers”. (A2976, A3066, A3068) |
| FRCD ID | F05010 |
| CAS Number | 81771-19-9 |
| PubChem CID | 3086140 |
| Formula | C42H55NO7 |
| IUPAC Name | None |
| InChI Key | HGBZMCXKHKZYBF-LIHFUKCQSA-N |
| InChI | InChI=1S/C42H55NO7/c1-20(2)17-28-47-32-34(38(7,8)48-28)46-27-14-15-39(9)40(10)21(13-16-41(39,45)42(27)35(32)49-42)18-24-29-23-19-25-30(37(5,6)50-36(25,3)4)31(44)22(23)11-12-26(29)43-33(24)40/h11-12,17,21,25,27-28,30,32,34-35,43,45H,13-16,18-19H2,1-10H3/t21?,25?,27-,28-,30?,32+,34-,35+,39?,40+,41-,42-/m0/s1 |
| Canonical SMILES | CC(=CC1OC2C(C(O1)(C)C)OC3CCC4(C5(C(CCC4(C36C2O6)O)CC7=C5NC8=C7C9=C(C=C8)C(=O)C1C(C9)C(OC1(C)C)(C)C)C)C)C |
| Isomeric SMILES | CC(=C[C@H]1O[C@H]2[C@@H]3[C@@]4(O3)[C@H](CCC5([C@]4(CCC6[C@@]5(C7=C(C6)C8=C(N7)C=CC9=C8CC3C(C9=O)C(OC3(C)C)(C)C)C)O)C)O[C@@H]2C(O1)(C)C)C |
| Synonyms |
7H-(1,3)Dioxino(5'',4'':3'3')oxireno(4',4'a)(1)benzopyrano(5',6':6,7)indeno(1,2-b)isobenzofuro(5,6-e)indol-13(8H)-one, 1,4a,4b,5b,6,7a,9,9a,10,12,12a,16,16b,16c,17,18,18a,19a-octadecahydro-5b-hydroxy-1,1,10,10,12,12,16b,16c-octamethyl-3-(2-methyl-1-propenyl)-
AC1MJ5NM
UNII-4M63MT6W6M
4M63MT6W6M
|
| Classifies |
Fungal Toxin
|
| Update Date | Nov 13, 2018 17:07 |
Chemical Taxonomy
| Kingdom | Organic compounds |
| Superclass | Organoheterocyclic compounds |
| Class | Naphthopyrans |
| Subclass | Not available |
| Intermediate Tree Nodes | Not available |
| Direct Parent | Naphthopyrans |
| Alternative Parents |
|
| Molecular Framework | Aromatic heteropolycyclic compounds |
| Substituents | Naphthopyran - Naphthofuran - Naphthalene - Tetralin - 3-alkylindole - Indole - Indole or derivatives - Aryl alkyl ketone - Aryl ketone - 1,4-dioxepane - Dioxepane - Meta-dioxane - Monosaccharide - Oxane - Pyran - Benzenoid - Cyclic alcohol - Pyrrole - Tertiary alcohol - Tetrahydrofuran - Heteroaromatic compound - Ketone - Acetal - Dialkyl ether - Oxirane - Ether - Oxacycle - Azacycle - Organic nitrogen compound - Organic oxide - Organic oxygen compound - Alcohol - Hydrocarbon derivative - Organopnictogen compound - Organooxygen compound - Organonitrogen compound - Aromatic heteropolycyclic compound |
| Description | This compound belongs to the class of organic compounds known as naphthopyrans. These are compounds containing a pyran ring fused to a naphthalene moiety. Furan is a 6 membered-ring non-aromatic ring with five carbon and one oxygen atoms. Naphthalene is a polycyclic aromatic hydrocarbon made up of two fused benzene rings. |
Properties
| Property Name | Property Value |
|---|---|
| Molecular Weight | 685.902 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 1 |
| Complexity | 1530 |
| Monoisotopic Mass | 685.398 |
| Exact Mass | 685.398 |
| XLogP | 5.8 |
| Formal Charge | 0 |
| Heavy Atom Count | 50 |
| Defined Atom Stereocenter Count | 8 |
| Undefined Atom Stereocenter Count | 4 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| Isotope Atom Count | 0 |
| Covalently-Bonded Unit Count | 1 |
ADMET
| Model | Result | Probability |
|---|---|---|
| Absorption | ||
| Blood-Brain Barrier | BBB+ | 0.7009 |
| Human Intestinal Absorption | HIA+ | 0.9907 |
| Caco-2 Permeability | Caco2- | 0.5581 |
| P-glycoprotein Substrate | Substrate | 0.8588 |
| P-glycoprotein Inhibitor | Non-inhibitor | 0.7477 |
| Non-inhibitor | 0.9582 | |
| Renal Organic Cation Transporter | Non-inhibitor | 0.8559 |
| Distribution | ||
| Subcellular localization | Mitochondria | 0.3981 |
| Metabolism | ||
| CYP450 2C9 Substrate | Non-substrate | 0.8272 |
| CYP450 2D6 Substrate | Non-substrate | 0.8065 |
| CYP450 3A4 Substrate | Substrate | 0.7384 |
| CYP450 1A2 Inhibitor | Inhibitor | 0.6940 |
| CYP450 2C9 Inhibitor | Non-inhibitor | 0.8227 |
| CYP450 2D6 Inhibitor | Non-inhibitor | 0.9138 |
| CYP450 2C19 Inhibitor | Non-inhibitor | 0.8117 |
| CYP450 3A4 Inhibitor | Non-inhibitor | 0.7347 |
| CYP Inhibitory Promiscuity | Low CYP Inhibitory Promiscuity | 0.7827 |
| Excretion | ||
| Toxicity | ||
| Human Ether-a-go-go-Related Gene Inhibition | Weak inhibitor | 0.9930 |
| Non-inhibitor | 0.8735 | |
| AMES Toxicity | Non AMES toxic | 0.5372 |
| Carcinogens | Non-carcinogens | 0.9647 |
| Fish Toxicity | High FHMT | 0.9952 |
| Tetrahymena Pyriformis Toxicity | High TPT | 0.9954 |
| Honey Bee Toxicity | High HBT | 0.6546 |
| Biodegradation | Not ready biodegradable | 0.9941 |
| Acute Oral Toxicity | III | 0.5201 |
| Carcinogenicity (Three-class) | Non-required | 0.5138 |
| Model | Value | Unit |
|---|---|---|
| Absorption | ||
| Aqueous solubility | -4.3784 | LogS |
| Caco-2 Permeability | 1.0424 | LogPapp, cm/s |
| Distribution | ||
| Metabolism | ||
| Excretion | ||
| Toxicity | ||
| Rat Acute Toxicity | 2.9078 | LD50, mol/kg |
| Fish Toxicity | 0.5967 | pLC50, mg/L |
| Tetrahymena Pyriformis Toxicity | 0.8402 | pIGC50, ug/L |
References
| Title | Journal | Date | Pubmed ID |
|---|---|---|---|
| Ergovaline does not alter the severity of ryegrass staggers induced by lolitrem B. | N Z Vet J | 2018 Mar | 29241023 |
| Co-exposure of the Mycotoxins Lolitrem B and Ergovaline in Steers Fed Perennial Ryegrass ( Lolium perenne) Straw: Metabolic Characterization of Excreta. | J Agric Food Chem | 2018 Jun 27 | 29847929 |
| Development and validation of an ultrahigh performance liquid chromatography-high resolution tandem mass spectrometry assay for nine toxic alkaloids from endophyte-infected pasture grasses in horse serum. | J Chromatogr A | 2018 Jul 27 | 29779692 |
| Immunochemical Analysis of Paxilline and Ergot Alkaloid Mycotoxins in Grass Seeds and Plants. | J Agric Food Chem | 2018 Jan 10 | 29237259 |
| Detection of the tremorgenic mycotoxin paxilline and its desoxy analog in ergot of rye and barley: a new class of mycotoxins added to an old problem. | Anal Bioanal Chem | 2017 Aug | 28674820 |
| Lolitrem B and Indole Diterpene Alkaloids Produced by Endophytic Fungi of the Genus Epichloë and Their Toxic Effects in Livestock. | Toxins (Basel) | 2016 Feb 15 | 26891327 |
| Toxicity of endophyte-infected ryegrass hay containing high ergovaline level in lactating ewes. | J Anim Sci | 2015 Aug | 26440189 |
| The role of the Oregon State University Endophyte Service Laboratory in diagnosing clinical cases of endophyte toxicoses. | J Agric Food Chem | 2014 Jul 30 | 25017309 |
| Ergovaline and lolitrem B concentrations in perennial ryegrass in field culture in southern France: distribution in the plant and impact of climatic factors. | J Agric Food Chem | 2014 Dec 31 | 25526521 |
| Combined effects of fungal alkaloids on intestinal motility in an in vitro rat model. | J Anim Sci | 2013 Nov | 23989880 |
| Flow-mediated K(+) secretion in horses intoxicated with lolitrem B (perennial ryegrass staggers). | N Z Vet J | 2013 May | 23134178 |
| The evaluation of fungal endophyte toxin residues in milk. | N Z Vet J | 2013 Jan | 22984816 |
| Peramine and lolitrem B from endophyte-grass associations cascade up the food chain. | J Chem Ecol | 2013 Dec | 24233445 |
| Toxicological evaluation and bioaccumulation potential of lolitrem B, endophyte mycotoxin in Japanese black steers. | Food Addit Contam Part A Chem Anal Control Expo Risk Assess | 2013 | 23721156 |
| Clinical expression of lolitrem B (perennial ryegrass) intoxication in horses. | Equine Vet J | 2012 May | 21793878 |
| The evaluation of endophyte toxin residues in sheep fat. | N Z Vet J | 2012 Jan | 22175431 |
| Patterns of expression of a lolitrem biosynthetic gene in the Epichloë festucae-perennial ryegrass symbiosis. | Mol Plant Microbe Interact | 2008 Feb | 18184063 |
| [Poisoning in livestock--as reference to human cases]. | Chudoku Kenkyu | 2005 Oct | 16318393 |
| [Young perennial ryegrass staggers in a dairy herd]. | Tijdschr Diergeneeskd | 2004 May 1 | 15156654 |
| Evaluation of perennial ryegrass straw as a forage source for ruminants. | J Anim Sci | 2004 Jul | 15309967 |
Targets
- General Function:
- Voltage-gated potassium channel activity
- Specific Function:
- Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). It is also activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+) concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key role in controlling excitability in a number of systems, such as regulation of the contraction of smooth muscle, the tuning of hair cells in the cochlea, regulation of transmitter release, and innate immunity. In smooth muscles, its activation by high level of Ca(2+), caused by ryanodine receptors in the sarcoplasmic reticulum, regulates the membrane potential. In cochlea cells, its number and kinetic properties partly determine the characteristic frequency of each hair cell and thereby helps to establish a tonotopic map. Kinetics of KCNMA1 channels are determined by alternative splicing, phosphorylation status and its combination with modulating beta subunits. Highly sensitive to both iberiotoxin (IbTx) and charybdotoxin (CTX).
- Gene Name:
- KCNMA1
- Uniprot ID:
- Q12791
- Molecular Weight:
- 137558.115 Da
- Mechanism of Action:
- The neurological effects of Lolitrem B are a result of its ability to inhibit large conductance calcium-activated potassium channels (BK channels). Lolitrem B binds to the alpha subunit of the BK channel, inhibiting channel potassium currents. This causes tremorgenic effects either by directly affecting channels in the muscle or by acting on channels in the central nervous system.
References
- Imlach WL, Finch SC, Dunlop J, Meredith AL, Aldrich RW, Dalziel JE: The molecular mechanism of "ryegrass staggers," a neurological disorder of K+ channels. J Pharmacol Exp Ther. 2008 Dec;327(3):657-64. doi: 10.1124/jpet.108.143933. Epub 2008 Sep 18. [18801945 ]