DrugBank: Botulinum Toxin Type A (DB00083)

targets (2)

Identification

Name

Botulinum Toxin Type A

Accession Number

DB00083 (BIOD00092, BTD00092)

Type

biotech

Groups

approved

Description

Purified botulinum toxin from Clostridium botulinum, purified from culture via dialysis and acid precipitation.

Protein structure

Display: 3D Structure

Protein chemical formula

C₆₇₆₀H₁₀₄₄₇N₁₇₄₃O₂₀₁₀S₃₂

Protein average weight

149322.7000

Sequences

>DB00083 sequence
PFVNKQFNYKDPVNGVDIAYIKIPNVGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLNP
PPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGS
TIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGYG
STQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPNR
VFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKAK
SIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKVL
NRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTG
LFEFYKLLCVRGIITSKTKSLDKGYNKALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEEI
TSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNGK
KYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEAA
MFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGA
VILLEFIPEIAIPVLGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKV
NTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINKAM
ININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDKV
NNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYESNHLIDLSRYASKINIG
SKVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIRIPKYFNSISLNNE
YTIINCMENNSGWKVSLNYGEIIWTLQDTQEIKQRVVFKYSQMINISDYINRWIFVTITN
NRLNNSKIYINGRLIDQKPISNLGNIHASNNIMFKLDGCRDTHRYIWIKYFNLFDKELNE
KEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPRG
SVMTTNIYLNSSLYRGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRLATNASQAG
VEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAKL
VASNWYNRQIERSSRTLGCSWEFIPVDDGWGERPL

FASTA

Synonyms

BoNT/A
Bontoxilysin A
Botulinum neurotoxin type A precursor
botulinum toxin type A
BTX-A

Brand names

Botox
BOTOX (Allegran Inc)
BOTOX Cosmetic (Allegran Inc)
Dysport

Brand name mixtures

Not Available

Categories

Anti-Wrinkle Agents
Antidystonic Agents
Neuromuscular Blocking Agents

CAS number

93384-43-1

Taxonomy

Kingdom

Not Available

Classes

Not Available

Substructures

Not Available

Pharmacology

Indication

For the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia. Also for the treatment of severe primary axillary hyperhidrosis that is inadequately managed with topical agents and for the treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above. Also used cosmetically to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines) as well as for the treatment of excessive underarm sweating.

Pharmacodynamics

A 150 kDa neurotoxic protein produced from fermentation of Hall strain Clostridium botulinum type A grown in a medium containing casein hydrolysate, glucose and yeast extract. It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin, and several accessory proteins. Botulinum Toxin Type A is not expected to be present in the peripheral blood at measurable levels following IM or intradermal injection at the recommended doses. The recommended quantities of neurotoxin administered at each treatment session are not expected to result in systemic, overt distant clinical effects, i.e. muscle weakness, in patients without other neuromuscular dysfunction. However, sub-clinical systemic effects have been shown by single-fiber electromyography after IM doses of botulinum toxins appropriate to produce clinically observable local muscle weakness.

Mechanism of action

Botulinum Toxin Type A blocks neuromuscular transmission by binding to acceptor sites on motor or sympathetic nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings.

Absorption

The chemical complexity of Botulinum Toxin Type A combined with its extreme potency limits the opportunity to study its pharmacokinetic profile in humans. Therefore, no human pharmacokinetic studies have been performed. Botulinum Toxin Type A is injected directly into the target organ, a skeletal muscle. Thus, bioavailability of the intravenous or oral route is not of clinical relevance.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Route of elimination

Not Available

Half life

Not Available

Clearance

Not Available

Toxicity

Based on toxicological studies, it has been estimated that the human LD50 by injection is approximately 2800 Units, equivalent to 28 individual vials of BOTOX (Botulinum Toxin Type A) Purified Neurotoxin Complex (100 Units) for a 70 kg adult. When injected intramuscularly, Botulinum Toxin Type A has been shown to be teratogenic or to have embryocidal effects in some animal species.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Dosage forms

Form	Route	Strength
Powder, for solution	Intramuscular

Prices

Unit description	Cost	Unit
Botox 200 unit vial	1260.0 USD	vial
Dysport 500 unit vial	852.0 USD	vial
Botox 100 unit	655.2 USD	vial
Botox 100 unit vial	630.0 USD	vial
Botox cosmetic 100 unit vial	630.0 USD	vial
Botox cosmetic 50 unit vial	346.8 USD	vial
Botox (100 - 200 unit/Vial)	3.74 USD	vial

Patents

Country	Patent Number	Approved	Expires
Canada	2280565	2005-11-15	2019-08-20
Canada	2310845	2001-05-15	2014-06-07

Properties

State

solid

Melting point

Not Available

Experimental Properties

Property	Value	Source
water solubility	Soluble	PhysProp
hydrophobicity	-0.368	PhysProp
isoelectric point	6.06	Various sources

References

Synthesis Reference

Not Available

General Reference

Montecucco C, Molgo J: Botulinal neurotoxins: revival of an old killer. Curr Opin Pharmacol. 2005 Jun;5(3):274-9. Pubmed
Brin MF, Lew MF, Adler CH, Comella CL, Factor SA, Jankovic J, O’Brien C, Murray JJ, Wallace JD, Willmer-Hulme A, Koller M: Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology. 1999 Oct 22;53(7):1431-8. Pubmed
Shukla HD, Sharma SK: Clostridium botulinum: a bug with beauty and weapon. Crit Rev Microbiol. 2005;31(1):11-8. Pubmed
Eisenach JH, Atkinson JL, Fealey RD: Hyperhidrosis: evolving therapies for a well-established phenomenon. Mayo Clin Proc. 2005 May;80(5):657-66. Pubmed
Schurch B, Corcos J: Botulinum toxin injections for paediatric incontinence. Curr Opin Urol. 2005 Jul;15(4):264-7. Pubmed

External Links

Resource	Link
UniProt	P10845
Genbank	X52066
PharmGKB	PA448659
Drug Product Database	2243721
RxList	http://www.rxlist.com/cgi/generic/botox.htm
Wikipedia	http://en.wikipedia.org/wiki/Botox

ATC Codes

M03AX01

AHFS Codes

92:00.00

PDB Entries

3BTA

FDA label

show (115.4 KB)

MSDS

Not Available

Interactions

Drug Interactions

Drug	Interaction

Food Interactions

Not Available

Targets
1. Synaptosomal-associated protein 25 Pharmacological action: yes Actions: inhibitor t-SNARE involved in the molecular regulation of neurotransmitter release. May play an important role in the synaptic function of specific neuronal systems. Associates with proteins involved in vesicle docking and membrane fusion Organism class: human UniProt ID: P60880 Gene: SNAP25 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Zhou JY, Wang ZF, Ren XM, Tang MZ, Shi YL: Antagonism of botulinum toxin type A-induced cleavage of SNAP-25 in rat cerebral synaptosome by toosendanin. FEBS Lett. 2003 Dec 4;555(2):375-9. Pubmed Flynn TC: Myobloc. Dermatol Clin. 2004 Apr;22(2):207-11, vii. Pubmed Okada M, Yoshida S, Zhu G, Kaneko S: [Methodological consideration in studying the exocytosis mechanisms using microdialysis] Nihon Shinkei Seishin Yakurigaku Zasshi. 2004 Aug;24(4):165-70. Pubmed Frassoni C, Inverardi F, Coco S, Ortino B, Grumelli C, Pozzi D, Verderio C, Matteoli M: Analysis of SNAP-25 immunoreactivity in hippocampal inhibitory neurons during development in culture and in situ. Neuroscience. 2005;131(4):813-23. Pubmed Straughan D: Progress in applying the Three Rs to the potency testing of Botulinum toxin type A. Altern Lab Anim. 2006 Jun;34(3):305-13. Pubmed Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed 2. Rho-related GTP-binding protein RhoB Pharmacological action: unknown Mediates apoptosis in neoplastically transformed cells after DNA damage. Not essential for development but affects cell adhesion and growth factor signaling in transformed cells. Plays a negative role in tumorigenesis as deletion causes tumor formation. Involved in intracellular protein trafficking of a number of proteins. Targets PKN1 to endosomes and is involved in trafficking of the EGF receptor from late endosomes to lysosomes. Also required for stability and nuclear trafficking of AKT1/AKT which promotes endothelial cell survival during vascular development Organism class: human UniProt ID: P62745 Gene: RHOB Protein Sequence: FASTA SNPs: SNPJam Report References: Ishida H, Zhang X, Erickson K, Ray P: Botulinum toxin type A targets RhoB to inhibit lysophosphatidic acid-stimulated actin reorganization and acetylcholine release in nerve growth factor-treated PC12 cells. J Pharmacol Exp Ther. 2004 Sep;310(3):881-9. Epub 2004 May 12. Pubmed

Targets

1. Synaptosomal-associated protein 25

Pharmacological action: yes
Actions: inhibitor

t-SNARE involved in the molecular regulation of neurotransmitter release. May play an important role in the synaptic function of specific neuronal systems. Associates with proteins involved in vesicle docking and membrane fusion

Organism class: human
UniProt ID: P60880 Link_out

Gene: SNAP25 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Zhou JY, Wang ZF, Ren XM, Tang MZ, Shi YL: Antagonism of botulinum toxin type A-induced cleavage of SNAP-25 in rat cerebral synaptosome by toosendanin. FEBS Lett. 2003 Dec 4;555(2):375-9. Pubmed
Flynn TC: Myobloc. Dermatol Clin. 2004 Apr;22(2):207-11, vii. Pubmed
Okada M, Yoshida S, Zhu G, Kaneko S: [Methodological consideration in studying the exocytosis mechanisms using microdialysis] Nihon Shinkei Seishin Yakurigaku Zasshi. 2004 Aug;24(4):165-70. Pubmed
Frassoni C, Inverardi F, Coco S, Ortino B, Grumelli C, Pozzi D, Verderio C, Matteoli M: Analysis of SNAP-25 immunoreactivity in hippocampal inhibitory neurons during development in culture and in situ. Neuroscience. 2005;131(4):813-23. Pubmed
Straughan D: Progress in applying the Three Rs to the potency testing of Botulinum toxin type A. Altern Lab Anim. 2006 Jun;34(3):305-13. Pubmed
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Pharmacological action: unknown

Mediates apoptosis in neoplastically transformed cells after DNA damage. Not essential for development but affects cell adhesion and growth factor signaling in transformed cells. Plays a negative role in tumorigenesis as deletion causes tumor formation. Involved in intracellular protein trafficking of a number of proteins. Targets PKN1 to endosomes and is involved in trafficking of the EGF receptor from late endosomes to lysosomes. Also required for stability and nuclear trafficking of AKT1/AKT which promotes endothelial cell survival during vascular development

Organism class: human
UniProt ID: P62745 Link_out

Gene: RHOB Link_out

Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Ishida H, Zhang X, Erickson K, Ray P: Botulinum toxin type A targets RhoB to inhibit lysophosphatidic acid-stimulated actin reorganization and acetylcholine release in nerve growth factor-treated PC12 cells. J Pharmacol Exp Ther. 2004 Sep;310(3):881-9. Epub 2004 May 12. Pubmed

Comments

Drug created on June 13, 2005 07:24 / Updated on September 29, 2010 14:34

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.