Bradykinin

Source: Wikipedia, the free encyclopedia.
Bradykinin
Names
IUPAC name
Bradykinin
Systematic IUPAC name
(2S)-2-{(12S,32S,9S,12S,142S,17S)-11-[(2S)-2-Amino-5-(carbamimidoylamino)pentanoyl]-9-benzyl-12-(hydroxymethyl)-2,4,7,10,13,15-hexaoxo-5,8,11,16-tetraaza-1(2),3,14(1,2)-tripyrrolidina-19-benzenanonadecaphane-17-carboxamido}-5-(carbamimidoylamino)pentanoic acid
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard
 100.000.362 Edit this at Wikidata
IUPHAR/BPS
MeSH Bradykinin
UNII
  • InChI=1S/C50H73N15O11/c51-32(16-7-21-56-49(52)53)45(72)65-25-11-20-39(65)47(74)64-24-9-18-37(64)43(70)58-28-40(67)59-34(26-30-12-3-1-4-13-30)41(68)62-36(29-66)46(73)63-23-10-19-38(63)44(71)61-35(27-31-14-5-2-6-15-31)42(69)60-33(48(75)76)17-8-22-57-50(54)55/h1-6,12-15,32-39,66H,7-11,16-29,51H2,(H,58,70)(H,59,67)(H,60,69)(H,61,71)(H,62,68)(H,75,76)(H4,52,53,56)(H4,54,55,57)/t32-,33-,34-,35-,36-,37-,38-,39-/m0/s1 checkY
    Key: QXZGBUJJYSLZLT-FDISYFBBSA-N checkY
  • InChI=1/C50H73N15O11/c51-32(16-7-21-56-49(52)53)45(72)65-25-11-20-39(65)47(74)64-24-9-18-37(64)43(70)58-28-40(67)59-34(26-30-12-3-1-4-13-30)41(68)62-36(29-66)46(73)63-23-10-19-38(63)44(71)61-35(27-31-14-5-2-6-15-31)42(69)60-33(48(75)76)17-8-22-57-50(54)55/h1-6,12-15,32-39,66H,7-11,16-29,51H2,(H,58,70)(H,59,67)(H,60,69)(H,61,71)(H,62,68)(H,75,76)(H4,52,53,56)(H4,54,55,57)/t32-,33-,34-,35-,36-,37-,38-,39-/m0/s1
    Key: QXZGBUJJYSLZLT-FDISYFBBBG
  • O=C(N[C@H](C(=O)N[C@H](C(=O)O)CCC/N=C(\N)N)Cc1ccccc1)[C@H]5N(C(=O)[C@@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@H]3N(C(=O)[C@H]2N(C(=O)[C@@H](N)CCC/N=C(\N)N)CCC2)CCC3)Cc4ccccc4)CO)CCC5
Properties
C50H73N15O11
Molar mass 1060.228 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)
Chr. 3 q21-qter
Search for
StructuresSwiss-model
DomainsInterPro
Bradykinin
Identifiers
SymbolBradykinin
PfamPF06753
InterProIPR009608
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a

prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin consists of nine amino acids, and is a physiologically and pharmacologically active peptide of the kinin group of proteins
.

A class of drugs called

angiotensin-converting-enzyme inhibitors (ACE inhibitors) increase bradykinin levels by inhibiting its degradation, thereby increasing its blood pressure lowering effect. ACE inhibitors are FDA approved for the treatment of hypertension and heart failure
.

Structure

Bradykinin, sometimes referred to as BK, is a 9–amino acid

peptide chain. The amino acid sequence of bradykinin is: Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (RPPGFSPFR).[1]
Its empirical formula is therefore C
50H
73N
15O
11.

Metabolism

The kinin–kallikrein system makes bradykinin by proteolytic cleavage of its kininogen precursor, high-molecular-weight kininogen (HMWK or HK), by the enzyme kallikrein. Moreover, there is compelling evidence that plasmin, a fibrinolytic enzyme, is able to generate bradykinin after HMWK cleavage.[2]

In humans, bradykinin is broken down by many different kininases: angiotensin-converting enzyme (ACE, kininase II), neprilysin,[3] NEP2, aminopeptidase P (APP), carboxypeptidase N (CPN, kininase I), Carboxypeptidase M, Neutral endopeptidase 24.15, Endothelin converting enzyme-1, Endothelin converting enzyme-2.[4]

Function

Effects

Bradykinin is a potent endothelium-dependent vasodilator and mild diuretic, which may cause a lowering of the 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.[5]

During inflammation, it is released locally from mast cells and basophils during tissue damage.[6] Specifically in relation to pain, bradykinin has been shown to sensitize TRPV1 receptors, thus lowering the temperature threshold at which they activate, thus presumably contributing to allodynia.[7]

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. It also plays a role in the constriction and eventual occlusion of a number of other fetal vessels, including the umbilical arteries and vein. The differential vasoconstriction of these fetal vessels compared to the vasodilator response of other vessels suggests that the walls of these fetal vessels are different from other vessels.[8]

Receptors

Main article: Bradykinin receptor
  • The B1 receptor (also called
    endothelial cells have been described as a potential source for this B1 receptor-CXCL5 pathway.[10]
  • 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.

Disorders

Bradykinin is also thought to be the cause of the dry cough in some patients on widely prescribed 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; increased bradykinin sensitizes somatosensory fibers and thus causes hyperalgesia. Bradykinin may mediate this via pro-inflammatory peptides (e.g. substance P, neuropeptide Y) and a local release of histamine.[11][12]

In severe cases, the elevation of bradykinin may result in angioedema, a medical emergency.[13] People of African descent have up to five times increased risk of ACE inhibitor induced angioedema due to hereditary predisposing risk factors such as hereditary angioedema.[14] This refractory cough is a common cause for stopping ACE inhibitor therapy.

Overactivation of bradykinin is thought to play a role in a rare disease called hereditary angioedema.[15]

Low levels of bradykinin in the body correlate to with obesity in adolescents; it has been proposed that bradykinin can be used as a biomarker for metabolic syndrome.[16]

Bradykinins have been implicated in a number of cancer progression processes.[17] Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks.[18] Bradykinins have been implicated in cell proliferation and migration in gastric cancers,[19] and bradykinin antagonists have been investigated as anti-cancer agents.[20]

Bradykinin has been proposed as an explanation for many symptoms associated with COVID-19, including dry coughs, myalgia, fatigue, nausea, vomiting, diarrhea, anorexia, headaches, decreased cognitive function, arrhythmia and sudden cardiac death.[21]

Therapeutic implications

A

angiotensin converting enzyme inhibitor captopril. [citation needed] It was approved by the FDA for the treatment of hypertension in 1981.[citation needed
]

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.[23] Other substances that act as bradykinin inhibitors include aloe[24][25] and polyphenols, substances found in red wine and green tea.[26]

History

Bradykinin was discovered in 1948 by three

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."

See also

Look up bradykinin in Wiktionary, the free dictionary.

References

  1. PMID 35252738
    .
  2. PMID 27531677
    .
  3. ^ "MME membrane metalloendopeptidase [Homo sapiens (human)]". www.ncbi.nlm.nih.gov. Retrieved 2022-02-06.
  4. PMID 30283782
    .
  5. ISBN 978-3-8047-1377-2
    .
  6. S2CID 4061940
    .
  7. PMID 27445816
    .
  8. OCLC 920806541
    .
  9. PMID 10934225
    .
  10. PMID 17878384
    .
  11. S2CID 6040673
    .
  12. PMID 8315520
    .
  13. ^ Li HH (2018-05-22). "Angioedema: Practice Essentials, Background, Pathophysiology". Medscape.
  14. ^ Guyer AC, Banerji A. "ACE inhibitor-induced angioedema". UpToDate. Retrieved 2018-06-03.
  15. S2CID 22772933
    .
  16. S2CID 235206108
    .
  17. PMID 12025961
    .
  18. S2CID 53024740
    .
  19. S2CID 3954713
    .
  20. PMID 14529414
    .
  21. PMID 32633718
    .
  22. PMID 14302350
    .
  23. PMID 2203073
    .
  24. PMID 15182910
    .
  25. PMID 7143219
    .
  26. S2CID 24807751
    .
  27. PMID 18127230
    .
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