PEPTIDES
Stephen W. Carmichael, Susan L. Stoddard in The Adrenal Medulla 1986 - 1988, 2017
The ability of human plasma kallikrein to hydrolize several proenkephalin-derived peptides was studied by Metters, Rossier, Paquin et al. (1988) to establish whether this enzyme also displays strict selectivity toward cleavage sites within proenkephalin. Several proenkephalin-derived peptides were purified from bovine adrenal chromaffin vesicles and used as substrates. All of the identified cleavages occurred either on the carboxyl terminal side or between pairs of basic amino acids, with plasma kallikrein recognizing processing signals between lysine and arginine. In addition, plasma kallikrein was found to cleave at the carboxyl terminus of the basic pairs of amino acids preceding enkephalin sequences, thereby releasing the biologically active form of the peptide with the free amino terminal tyrosine needed for receptor recognition.
New treatments for hypertension
H. Gavras in The Year in Hypertension 2004, 2004
Specifically, this study showed that improvement in survival is largely the result of better survival during the first 24 hours of the MI, but is sustained over 38 days. Omapatrilat may exert these beneficial effects by at least three mechanisms that are likely interrelated: reduction in MI size, reduction in ventricular arrhythmias, and an improvement in LV remodelling. The reduction in MI size is probably not the result of haemodynamic effects but rather direct neurohumoral effects of omapatrilat, such as reduction in angiotensin II, increase in natriuretic peptides, and greater availability of bradykinin. In previous studies, improvement in survival after MI and reduction in MI size were observed to the same extent as with ACE inhibitors after intra- coronary administration of bradykinin, an effect that was abolished by a bradykinin receptor antagonist. Bradykinin receptor antagonists also abolished the benefit observed after vasopeptidase inhibitors in animal models of MI. Moreover, in a clinical study, an increase in plasma kallikrein levels was positively correlated with early survival after MI |6|.
Role of Engineered Proteins as Therapeutic Formulations
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Kunitz domain is found in numerous proteases, including bovine pancreatic trypsin inhibitor (BPTI), human pancreatic secretory trypsin inhibitor (PSTI), and ecotin (periplasmic E. coli protease inhibitor). Kunitz domains are also involved as ion channel blockers as they mainly inhibit serine proteases. Structurally, kunitz domains are 60 amino acids long that are arranged in form of a mixture of α-helices and β-sheets. The core structure of the Kunitz domain is stabilized by three disulfide bonds that also make the structure compact and protect it from proteases (Ranasinghe and McManus, 2013). Lehmann et al. engineered small protein known as Ecallantide (DX-88) based on Kunitz domain using phage display technology. It acts as an inhibitor of plasma kallikrein that plays a major role in contact cascade to produce bradykinin (Lehmann, 2008). Dennis et al. designed Kunitz domain variants from Alzheimer’s amyloid beta-protein precursor inhibitor (APPI), to inhibit the association of human tissue factor-Factor VIIa complex (TF.FVIIa) (Dennis and Lazarus, 1994).
Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment
Published in Expert Opinion on Investigational Drugs, 2020
Ashay D. Bhatwadekar, Viral S. Kansara, Thomas A. Ciulla
Plasma kallikrein is a serine protease synthesized mainly in the liver as a proenzyme prekallikrein (PK). The mRNA for plasma kallikrein or PK is expressed in a variety of tissues such as the brain, heart, lung, kidneys, adrenal glands, pancreas, spleen, prostate glands, and ovaries. PK is also known as the Fletcher factor due to its involvement in the fletcher trait, a condition with markedly prolonged activated partial thromboplastin time (aPTT). PK is encoded by a single gene localized on a q34-q35 region of the long arm of chromosome 4 [32]. PK is a single chain gamma-globulin zymogen with a molecular weight of 85–88 kDa, and a plasma concentration of ~490 nM. The N terminal region of PK consists of four contagious repeats composed of 4 groups of 90–91 amino acids arranged in ‘apple domains’ (A1-A4), Figure 1. The N-terminal of the PK lacks intrinsic activity and mainly involved in the recruitment of certain proteins [33]. The majority of PK circulates in plasma as a complex with alpha globulin, high molecular weight kininogen (HK). The apple domains, A1 and A4, serve as binding sites for HK. The proteolytic processing of PK leads to activated plasma kallikrein via activated factor XII (αFXIIa) on the negatively charged surface, factor XII fragment (βFXIIa) in the fluid phase and prolycarboxypeptidase on endothelial cells. Plasma kallikrein then cleaves HK to liberate bradykinin. While bradykinin directly activates the B2 receptor, the cleavage of bradykinin by carboxypeptidase generates des-arg9 bradykinin (DABK) leads to activation of B1 receptors (Figure 2).
Genetic aspects of idiopathic asthenozoospermia as a cause of male infertility
Published in Human Fertility, 2020
Zohreh Heidary, Kioomars Saliminejad, Majid Zaki-Dizaji, Hamid Reza Khorram Khorshid
Hyperviscosity, or the persistence over time of a homogeneous semen stickiness and adherence, is a less explored infertility-related phenotype that has been thought to negatively impact spermatozoa motility, count and progression in the female reproductive tract, often impairing fertilization (Du Plessis, Gokul, & Agarwal, 2013). Several proteins are known to play key roles in the cascade of semen coagulation and liquefaction including the kallikrein (KLK) family, that was found on chromosome 19q13.3–13.4, and the whey-acidic-protein four-disulfide core domain (WFDC) cluster, located at chromosome 20q13 (Clauss, Lilja, & Lundwall, 2002). Human Kallikreins are a subgroup of serine proteases which are divided into the tissue and plasma kallikreins. The tissue Kallikrein loci encode a family of fifteen closely related serine proteases with pervasive activities in diverse proteolytic cascades; while the plasma kallikrein has no known paralogue and encode only one serine protease (KLKB1). Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation (Michael et al., 2006; Pathak, Wong, Dreveny, & Emsley, 2013).
The discovery and development of transmembrane serine protease 2 (TMPRSS2) inhibitors as candidate drugs for the treatment of COVID-19
Published in Expert Opinion on Drug Discovery, 2022
Christiana Mantzourani, Sofia Vasilakaki, Velisaria-Eleni Gerogianni, George Kokotos
Kishk et al. identified proteins with known X-ray structure and high homology for TMPRSS2 using SWISS-MODEL and NCBI blastp [102]. These proteins included transmembrane protease serine 1 and 13 and a group of human plasma kallikrein. Homology models were built with SWISS-MODEL, evaluated, and subjected to molecular dynamics simulations to measure their energetic stability. Docking of nafamostat in the TMPRSS2 active site with MOE program revealed the position of the phenyl guanidine group in the S1 pocket and its hydrogen bond interactions with residues Asp435, Ser436, Ser463 and Gly462. The hydrophobic pocket, which consists of Thr459, Ser460, Trp461 and Val473, accommodates the phenyl ring. The active site was determined by site finder and positioned to contain the catalytic Ser441 and S1 pocket amino acids, including Glu389, Tyr416, Asp435, Ser436, Cys437, Gln438, Thr459, Ser460, Trp461, Gly462, Ser463, Gly464, Cys465, Ala466, Arg470, Pro471, Gly472 and Val473.
Related Knowledge Centers
- Bradykinin
- Catalysis
- Chemical Reaction
- Enzyme
- Kallikrein
- Lysine
- Arginine
- Kininogen
- Gene
- Prekallikrein