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0  structures 8  species 0  interactions 35  sequences 5  architectures

Family: Bradykinin (PF06753)

Summary: Bradykinin

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Bradykinin Edit Wikipedia article

Bradykinin
Bradykinin structure.svg
Bradykinin updated.png
Identifiers
CAS number 58-82-2 YesY
PubChem 439201
ChemSpider 388341 YesY
UNII S8TIM42R2W YesY
MeSH Bradykinin
ChEBI CHEBI:3165 YesY
ChEMBL CHEMBL406291 YesY
IUPHAR ligand 649
Jmol-3D images Image 1
Properties
Molecular formula C50H73N15O11
Molar mass 1060.21 g/mol
 YesY (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references
kininogen 1
Identifiers
Symbol KNG1
Alt. symbols KNG, BDK
Entrez 3827
HUGO 6383
OMIM 612358
RefSeq NM_001102416
UniProt P01042
Other data
Locus Chr. 3 q21-qter
Bradykinin
Identifiers
Symbol Bradykinin
Pfam PF06753
InterPro IPR009608

Bradykinin is a peptide that causes blood vessels to dilate (enlarge), and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin (by inhibiting its degradation) further lowering blood pressure. Bradykinin works on blood vessels through the release of prostacyclin, nitric oxide, and Endothelium-Derived Hyperpolarizing Factor.

Bradykinin is a physiologically and pharmacologically active peptide of the kinin group of proteins, consisting of nine amino acids.

Structure[edit]

Bradykinin is a 9-amino acid peptide chain. The amino acid sequence of bradykinin is: Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg. Its empirical formula is therefore C50H73N15O11.

Synthesis[edit]

The kinin-kallikrein system makes bradykinin by proteolytic cleavage of its kininogen precursor, high-molecular-weight kininogen (HMWK or HK), by the enzyme kallikrein.

Metabolism[edit]

In humans, bradykinin is broken down by three kininases: angiotensin-converting enzyme (ACE), aminopeptidase P (APP), and carboxypeptidase N (CPN), which cleave the 7-8, 1-2, and 8-9 positions, respectively.[1][2]

Physiological Role (Function)[edit]

Effects[edit]

Bradykinin is a potent endothelium-dependent vasodilator, leading to a drop in blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain.[3] Bradykinin also causes natriuresis, contributing to the drop in blood pressure.

Bradykinin raises internal calcium levels in neocortical astrocytes causing them to release glutamate.[4]

Bradykinin is also thought to be the cause of the dry cough in some patients on angiotensin-converting enzyme (ACE) inhibitor drugs. It is thought that bradykinin is converted to inactive metabolites by ACE, therefore inhibition of this enzyme leads to increased levels of bradykinin, which causes a dry cough via bronchoconstriction. This refractory cough is a common cause for stopping ACE inhibitor therapy, in which case angiotensin II receptor antagonists (ARBs) are the next line of treatment.

Overactivation of bradykinin is thought to play a role in a rare disease called hereditary angioedema, formerly known as hereditary angio-neurotic edema.[5]

Initial secretion of bradykinin post-natally causes constriction and eventual atrophy of the ductus arteriosus, forming the ligamentum arteriosum between the pulmonary trunk and aortic arch.

Receptors[edit]

  • The B1 receptor (also called bradykinin receptor B1) is expressed only as a result of tissue injury, and is presumed to play a role in chronic pain. This receptor has been also described to play a role in inflammation.[6] Most recently, it has been shown that the kinin B1 receptor recruits neutrophil via the chemokine CXCL5 production. Moreover, endothelial cells have been described as a potential source for this B1 receptor-CXCL5 pathway.[7]
  • The B2 receptor is constitutively expressed and participates in bradykinin's vasodilatory role.

The kinin B1 and B2 receptors belong to G protein coupled receptor (GPCR) family.

History[edit]

Bradykinin was discovered in 1948 by three Brazilian physiologists and pharmacologists working at the Instituto Biológico, in São Paulo, Brazil, led by Dr. Maurício Rocha e Silva. Together with colleagues Wilson Teixeira Beraldo and Gastão Rosenfeld, they discovered the powerful hypotensive effects of bradykinin in animal preparations. Bradykinin was detected in the blood plasma of animals after the addition of venom extracted from the Bothrops jararaca (Brazilian lancehead snake), brought by Rosenfeld from the Butantan Institute. The discovery was part of a continuing study on circulatory shock and proteolytic enzymes related to the toxicology of snake bites, started by Rocha e Silva as early as 1939. Bradykinin was to prove a new autopharmacological principle, i.e., a substance that is released in the body by a metabolic modification from precursors, which are pharmacologically active. According to B.J. Hagwood, Rocha e Silva's biographer, "The discovery of bradykinin has led to a new understanding of many physiological and pathological phenomena including circulatory shock induced by venoms and toxins." Etymology: brady [Gk] slow, kinin [Gk ] kīn(eîn) to move, set in motion,  ? from the effect of snake venom on intestinal smooth muscle, which was noted to slowly contract.[citation needed]

Therapeutic Implications[edit]

The practical importance of the discovery of bradykinin became apparent when one of his collaborators at the Medical School of Ribeirão Preto at the University of São Paulo, Dr. Sérgio Henrique Ferreira, discovered a bradykinin-potentiating factor (BPF) in the bothropic venom, which increases powerfully both the duration and magnitude of its effects on vasodilation and the consequent fall in blood pressure. On the basis of this finding, Squibb scientists developed the first of a new generation of highly-effective anti-hypertensive drugs, the so-called ACE inhibitors, such as captopril (trademarked Capoten).

Currently, bradykinin inhibitors (antagonists) are being developed as potential therapies for hereditary angioedema. Icatibant is one such inhibitor. Additional bradykinin inhibitors exist. It has long been known in animal studies that bromelain, a substance obtained from the stems and leaves of the pineapple plant, suppresses trauma-induced swelling caused by the release of bradykinin into the bloodstream and tissues.[8] Other substances that act as bradykinin inhibitors include aloe[9][10] and polyphenols, substances found in red wine and green tea.[11]

See also[edit]

References[edit]

  1. ^ Dendorfer A, Wolfrum S, Wagemann M, Qadri F, Dominiak P (May 2001). "Pathways of bradykinin degradation in blood and plasma of normotensive and hypertensive rats". Am. J. Physiol. Heart Circ. Physiol. 280 (5): H2182–8. PMID 11299220. 
  2. ^ Kuoppala A, Lindstedt KA, Saarinen J, Kovanen PT, Kokkonen JO (April 2000). "Inactivation of bradykinin by angiotensin-converting enzyme and by carboxypeptidase N in human plasma". Am. J. Physiol. Heart Circ. Physiol. 278 (4): H1069–74. PMID 10749699. 
  3. ^ Mutschler, Ernst; Schäfer-Korting, Monika (1997). Arzneimittelwirkungen (in German) (7 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. ISBN 3-8047-1377-7. 
  4. ^ Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (June 1994). "Glutamate-mediated astrocyte-neuron signalling". Nature 369 (6483): 744–7. doi:10.1038/369744a0. PMID 7911978. 
  5. ^ Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G (August 2007). "Nonallergic angioedema: role of bradykinin". Allergy 62 (8): 842–56. doi:10.1111/j.1398-9995.2007.01427.x. PMID 17620062. 
  6. ^ McLean PG, Ahluwalia A, Perretti M (August 2000). "Association between Kinin B1 Receptor Expression and Leukocyte Trafficking across Mouse Mesenteric Postcapillary Venules". J. Exp. Med. 192 (3): 367–80. doi:10.1084/jem.192.3.367. PMC 2193221. PMID 10934225. 
  7. ^ Duchene J, Lecomte F, Ahmed S, Cayla C, Pesquero J, Bader M, Perretti M, Ahluwalia A (October 2007). "A novel inflammatory pathway involved in leukocyte recruitment: role for the kinin B1 receptor and the chemokine CXCL5". J. Immunol. 179 (7): 4849–56. PMID 17878384. 
  8. ^ Lotz-Winter H (June 1990). "On the pharmacology of bromelain: an update with special regard to animal studies on dose-dependent effects". Planta Med. 56 (3): 249–53. doi:10.1055/s-2006-960949. PMID 2203073. 
  9. ^ Bautista-Pérez R, Segura-Cobos D, Vázquez-Cruz B (July 2004). "In vitro antibradykinin activity of Aloe barbadensis gel". J Ethnopharmacol 93 (1): 89–92. doi:10.1016/j.jep.2004.03.030. PMID 15182910. 
  10. ^ Yagi A, Harada N, Yamada H, Iwadare S, Nishioka I (October 1982). "Antibradykinin active material in Aloe saponaria". J Pharm Sci 71 (10): 1172–4. doi:10.1002/jps.2600711024. PMID 7143219. 
  11. ^ Richard T, Delaunay JC, Mérillon JM, Monti JP (December 2003). "Is the C-terminal region of bradykinin the binding site of polyphenols?". J. Biomol. Struct. Dyn. 21 (3): 379–85. doi:10.1080/07391102.2003.10506933. PMID 14616033. 

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Bradykinin Provide feedback

This family consists of several bradykinin sequences. The skins of anuran amphibians, in addition to mucus glands, contain highly specialised poison glands, which, in reaction to stress or attack, exude a complex noxious cocktail of biologically active molecules. These secretions often contain a plethora of peptides among which bradykinin or structural variants have been identified [1].

Literature references

  1. Chen T, Orr DF, Bjourson AJ, McClean S, O'Rourke M, Hirst DG, Rao P, Shaw C; , Eur J Biochem 2002;269:4693-4700.: Novel bradykinins and their precursor cDNAs from European yellow-bellied toad (Bombina variegata) skin. PUBMED:12230583 EPMC:12230583


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This tab holds annotation information from the InterPro database.

InterPro entry IPR009608

This family consists of several bradykinin sequences. The skins of anuran amphibians, in addition to mucus glands, contain highly specialised poison glands, which, in reaction to stress or attack, exude a complex noxious cocktail of biologically active molecules. These secretions often contain a plethora of peptides among which bradykinin or structural variants have been identified [PUBMED:12230583].

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Seed source: Pfam-B_7085 (release 10.0)
Previous IDs: none
Type: Family
Author: Moxon SJ
Number in seed: 2
Number in full: 35
Average length of the domain: 16.50 aa
Average identity of full alignment: 85 %
Average coverage of the sequence by the domain: 34.95 %

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Parameter Sequence Domain
Gathering cut-off 20.7 20.7
Trusted cut-off 20.9 20.9
Noise cut-off 20.4 20.4
Model length: 19
Family (HMM) version: 7
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