Biochem Technology

Bradykinin play different roles in different species

Bradykinin is the final product of the kallikrein–kinin system in the mammalian blood system, and is liberated from three types of kininogens: high molecular weight kininogens and low molecular weight kininogens encoded by a single gene. All three types consist of a heavy chain and light chain, connecting through a disulphide bridge[1]. kallikrein-kinin system is a complex multi-enzyme system composed of circulating and tissue kallikrein and kinin. It is well established that tissue kallikrein and kinin play crucial and diverse roles in cardiovascular and renal homeostasis. Bradykinin is a principal active agent of KKS, protects endothelial cells from oxidative stress-induced senescence through the release of nitric oxide, which is mediated by B2 receptor activation, a previous research shows that BK B2 receptor knockout in diabetic mice leads to an accelerating aging phenotype, due to an increase of oxidative stress. they suggest that bradykinin and its receptor dysfunction is associated with aging. But the mechanism is unclear[2]

However, BK in amphibian shows extreme differences. Bradykinin is a kind peptide of amphibian skin, which including a large amount of antimicrobial peptides, physiological active peptides and neurotransmitter. BK and BRPs are produced from amphibian skin glands as immune defence peptides. BRPs from amphibians are widely studied not only for their diversity of BK homologues which are displayed as N-terminal, C-terminal extension, insertion and amino acid substitution[1,3].

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Reference: [1]Xi X, Li B, Chen T,ea al. A review on bradykinin-related peptides isolated from amphibian skin secretion. Toxins (Basel). 2015, 7(3):951-970 [2] Ruolan Dong, Xizhen Xu, Geng Li, et al. Bradykinin Inhibits Oxidative Stress-Induced Cardiomyocytes Senescence via Regulating Redox State. PLoS One. 2013; 8(10): e77034 [3] Liu CY, Zhou LL, Cheng Q, et al.Effect of bradykinin on renal mesangial cell proliferation and extracellular matrix secretion. Genet Mol Res. 2014, 13(1):490-498

Cortistatin is a cyclic neuropeptide

Cortistatin (CORT), a neuropeptide able to activate GHS-R, has emerged as an additional link in gut-brain interplay. which is the product of an enzymatically processed precursor. CORT precursors are encoded by two different genes that evolved from a common ancestral gene by a duplication mechanism. processing of CORT precursor generates diverse mature peptides as CORT-14 and -29 in rodents and CORT-17 and -29 in humans.

Although CORT was initially discovered in the brain and it is especially abundant in the cortex (where its name comes from), further reports showed that this neuropeptide is also widely distributed at peripheral tissues including gastrointestinal tract and pancreas. Based on its ability to activate ssts, CORT exhibits almost endocrine and most non-endocrine actions of SST. Actually, their main functional divergences, reside in the ability of CORT to promote sleep functions, modulate locomotor activity, exert potent anti-inflammatory actions in experimental models of inflammatory and autoimmune disorders and, its influence on atherogenesis[1].

Cortistatin (CORT) shares high structural and functional similarities with somatostatin (SST)They share some biological activities, some distinct biological activities that are not shared between them, for example some central actions. This evidence suggested the existence of a specific CORT receptor; indeed, differently from SST, CORT is able to bind to Mas-related gene X (MrgX)-2 receptor in various central and peripheral as well as in some neoplastic tissues. Moreover, CORT but not SST is also able to bind the GH secretagogs receptor (GHS-R) that mediates endocrine and non-endocrine actions of ghrelin, its natural ligand. However, the physiological relevance, if any, of CORT binding to these receptors is still unknown[2].

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[1]Chanclón B, Martínez-Fuentes AJ, Gracia-Navarro F. Role of SST, CORT and ghrelin and its receptors at the endocrine pancreas. Front Endocrinol (Lausanne). 2012, 3:114

[2]Giordano R, Picu A, Bonelli L. The activation of somatostatinergic receptors by either somatostatin-14 or cortistatin-17 often inhibits ACTH hypersecretion in patients with Cushing’s disease. Eur J Endocrinol. 2007,157(4):393-398.

The adipokinetic hormone family is neuropeptides

AKH is an insect neurohormone that is synthesized in the corpora cardiaca (CC), a neurohemal organ that is considered the functional equivalent of the vertebrate pituitary gland. AKH is normally 8–10 amino acids long with a pyroglutamate at the N-terminus and an amidated C-terminus. In addition to the essential role of mobilization of metabolites during energy-expensive activities such as flight and locomotion, AKH is involved in the control of carbohydrate homeostasis in the haemolymph of Drosophila and Bombyx larvae[1]. AKH consist of three kinds of peptide: Lom- AKH-I sequence is < Glu-Leu- Asn-Phe-Thr-Pro-Asn-Trp-Gly-Thr-NH and Lom-AKH- 11 in Locusta sequence is Glu-Leu-Asn-Phe-Ser-Ala-Gly-Trp-NH,) differs in only one amino acid from that in Schistocerca (Scg-AKH-11) ( < Glu-Leu-Asn-Phe-Ser-Thr-Gly-Trp-NH2). The three peptides is Lom- AKH-III, sequence is Glu-Leu- Asn-Phe-Thr-Pro-Trp-Trp-NH2[2].

Some researches demonstrated that the primary action of adipokinetic hormone (AKH) is to stimulate calcium ion uptake into the fat body cell, subsequently causing the formation of diacylglycerol from triacylglycerol. Furthermore, it was also shown that AKH is not directly responsible for increased diacylglycerol uptake by lipophorin from the fat body. The diacylglycerol level of the fat body was found to increase by an average of 2.4-fold after 90 min of incubation in the presence of AKH[3].

A gene sequence encoding the neuropeptide adipokinetic hormone (AKH) was isolated from a genomic library of the tobacco hornworm.One clone was obtained from which we deduced an intronless gene encoding the AKH precursor (prepro-AKH). From NH2 to COOH terminus, prepro-AKH consists of a signal peptide, a single AKH peptide block followed by a Gly-Lys-Arg processing site, and a 34-residue sequence that appears unrelated to known peptides[4].

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Reference: [1]Chenggang Zhu, Haishan Huang, Rongsheng Hua, et al. Molecular and functional characterization of adipokinetic hormone receptor and its peptide ligands in Bombyx mori. FEBS Lett. 2009, 583(9): 1463–1468. [2]Oudejans RC, Kooiman FP, Heerma W, et al. Isolation and structure elucidation of a novel adipokinetic hormone (Lom-AKH-III) from the glandular lobes of the corpus cardiacum of the migratory locust, Locusta migratoria. Eur J Biochem. 1991, 195(2): 351-359. [3]Lum PY, Chino H. Primary role of adipokinetic hormone in the formation of low density lipophorin in locusts. J Lipid Res. 1990, 31(11):2039-2044. [4]Bradfield JY1, Keeley LL. Adipokinetic hormone gene sequence from Manduca sexta. J Biol Chem. 1989, 264(22):12791-12793.

Orexins is kind of hypothalamic neuropeptides

Orexins A and B are hypothalamic neuropeptides, in the regulation of food intake, metabolic rate, cardiovascular function, body temperature, locomotor activity, sleep-wake cycle and stress response. These peptides derive from the prepro-orexin (preprohypocretin) gene, which encodes a precursor that is cleaved into orexin-A and orexin-B

Orexins A and B, also known as hypocretin 1 and 2, are neuropeptides derived from a common 130-amino acid precursor peptide, prepro-orexin (PPO), by proteolytic cleavage. Orexin A is a 33-amino acid residue peptide with two intramolecular disulphide bonds in the N-terminal region, whereas orexin B is a linear 28-amino acid residue peptide. The discussed peptides have a 46% sequence identity. Both orexins act via two closely related G-protein coupled receptors, orexin type 1 receptor (OX1R) and orexin type 2 receptor (OX2R). OX1R appears to be selective for orexin A, while OX2R binds both orexin A and orexin B[1].

Orexin-A controls glucose production and utilization in the peripheral tissues via the autonomic nervous system. In addition it has been shown that orexins A and B differentially regulate glucagon release from pancreas. In addition, the presence of orexin receptors in other cerebral areas suggests that orexin-A plays additional functions. It has been demonstrated that the orexins play a role in sleep regulation[2]

Some reports show that Orexin B (ORXB) modulates the function of peritoneal macrophages through activation of calcium-dependent potassium channels and induces enhancement of phagocytosis in mouse peritoneal macrophages. it is plausible that ORXB may function as an anti-infective molecule. However, it has not been reported whether ORXB has antimicrobial properties[3].

[1]Maleszka A, Smolinska N, Nitkiewicz A, et al. Expression of orexin A and B in the porcine hypothalamus during the oestrous cycle. J Physiol Pharmacol. 2013,64(1):55-63. [2]Giovanni Messina, Carmine Dalia,Domenico Tafuri,ea al.Orexin-A controls sympathetic activity and eating behavior. Front Psychol. 2014, 5: 997. [3]Kouji Ohta, Mikihiko Kajiya,Tongbo Zhu, et al.Additive effects of Orexin B and vasoactive intestinal polypeptide on LL-37-mediated antimicrobial activities. J Neuroimmunol. 2011,233(1-2): 37–45.

Human β-defensin 1 is an antimicrobial peptide

Human beta defensins are 3–5 kDa polycationic peptides that are known for their antimicrobial activity against bacteria, fungi and viruses. defensins are chemotactic attractants for immature dendritic cells and memory T cells[1]. Human β-defensin 1 (hBD-1) is an antimicrobial peptide expressed by epithelia and hematopoietic cells.The role of human β defensin-1 (hBD-1) is notable because its gene (beta-defensin 1 (DEFB1)) is constitutively expressed and its antimicrobial activity is potentiated in the low-oxygen environment that characterizes the intestinal mucosa[2].

Defensins can act as direct effectors of the innate immune system through their ability to disrupt the cellular membrane integrity kill via electrostatic interaction which leads to pore formation.

In addition to its role in innate immunity, hBD1 contributes to adaptive immunity by possessing chemotactic activity to recruit immature dendritic cells (DC) and memory T-cells through the CCR6 chemokine receptor. hBD1 may play an important role in tumor suppression via an anti-tumor response involving the immune system[3].Human beta defensin-1 (hBD-1) is a potent “microchemokine” that attracts immature dendritic cells and memory T cells via a specific interaction with the chemokine receptor CCR6. It is through this action that β-defensins are thought to play an important role in both innate and adaptive immune responses, but their role in prostate tumor progression remains unclear. We have previously shown that the expression of hBD-1 is lost or suppressed in 82% of malignant prostate tissue sections analyzed, whereas benign tissues generally expressed moderate to high levels of this peptide. Although hBD-1 expression is lost at high frequency in prostate cancer, little is known about its function or whether this phenomenon contributes to prostate tumor progression[4].Recent studies support its role as a tumor suppressor gene for urological cancers suggesting that decreased HBD-1 levels may play a role in the development of cancers associated with As exposure[5].

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Reference: [1]Kimberley Kallsen, Ellen Andresen, Holger Heine, et al. Histone Deacetylase (HDAC) 1 Controls the Expression of Beta Defensin 1 in Human Lung Epithelial Cells. Published online 2012 Nov 20. doi: 10.1371/journal.pone.0050000 [2]Kelly CJ, Glover LE, Campbell EL,ea al.Fundamental role for HIF-1α in constitutive expression of human β defensin-1. Mucosal Immunol. 2013,6(6):1110-1118

[3]Sudeep K. Bose, Willietta Gibson, Rebecca S. Bullard, et al. PAX2 Oncogene Negatively Regulates the Expression of the Host Defense Peptide Human Beta Defensin-1 in Prostate Cancer. Mol Immunol. 2009,46(6): 1140–1148. [4]Rebecca S. Bullard, Willietta Gibson, Sudeep Bose. Functional Analysis of the Host Defense Peptide Human Beta Defensin-1: New Insight into Its Potential Role in Cancer. Mol Immunol. 2008,45(3): 839–848. [5]Christine M. Hegedus, Christine F. Skibola, Marcella Warner.et al. Decreased Urinary Beta-Defensin-1 Expression as a Biomarker of Response to Arsenic. Toxicol Sci. 2008,106(1): 74–82.

Secretin, a neuropeptide hormone in the brain

In mammals, the gastrointestinal peptide hormone, secretin is a 27-amino acid peptide that was first studied in 1902 by Bayliss and Starling from the extracts of the jejunal mucosa for its ability to stimulate pancreatic secretion[1]. In human, 10 members exist and sequence and functional homologues and ligand-receptor pairs have been characterised in representatives of most vertebrate classes. Secretin-like family GPCR homologues have also been isolated in non-vertebrate genomes however their corresponding ligands have not been convincingly identified and their evolution remains enigmatic[2]. The physiological roles of secretin and its receptor is as follows.

(1)Secretin is a member of the secretin-glucagon family and is secreted by S cells of the duodenum in the crypts of Lieberkühn.

(2) Secretin affects the function of a number of organ systems and cell types.

(3) Secretin exerts its biological effects through G-protein coupled secretin receptors (SR), which are expressed in the basolateral domain of several cells. In addition to regulating the pH of the duodenal content by the control of gastric acid secretion, secretin regulates the secretion of bicarbonate ions into the duodenum from the epithelia lining the pancreatic and biliary ducts. In addition to regulating water homeostasis.

(4) secretin has been considered as a neuropeptide hormone since it is also expressed in the central nervous system (CNS).

Recent evidence has indicated that secretin has pleiotropic effects in several organ systems (including the biliary epithelium) and has been termed a neuroendocrine hormone.

[1] Zhang L, Chow BK. The central mechanisms of secretin in regulating multiple behaviors. Front Endocrinol (Lausanne). 2014, 21(5):77 [2] João CR Cardoso, Florbela A Vieira, Ana S Gomes. The serendipitous origin of chordate secretin peptide family members. BMC Evol Biol. 2010,10: 135. [3] Afroze S, Meng F, Jensen K. The physiological roles of secretin and its receptor. Ann Transl Med. 2013,1(3):29

Kisspeptins is a kind of Melanoma peptides

Kisspeptins are a family of peptides encoded by the KISS1 gene.The KISS-1 gene encodes a 145-amino acid protein, which is cleaved into various forms including kisspeptin-54, kisspeptin-14, kisspeptin-13 and kisspeptin-10, named with respect to their length in amino acids. [1]The Kiss-1 gene has been suggested as a suppressor of metastasis in a various types of cancer, including gastric cancer, oesophageal carcinoma, pancreatic, ovarian, bladder and prostate cancer, through the regulation of cellular migration and invasion[2].

Some researches have recently demonstrated the presence of kisspeptin and GPR54 mRNAs in both pancreatic B and A cells and GPR54 expression in MIN6 and αTC1 pancreatic cell lines. Kisspeptin-54 has been shown to stimulate the late phase of glucose-induced insulin secretion in mouse and human islets and to inhibit insulin secretion from MIN6 cells.kisspeptin-13 is tempting to speculate that the kisspeptin family may be implicated in the regulation of B-cell secretion. The lack of effect of kisspeptin-13 on both glucagon and somatostatin secretion would indicate that it influences the B cell directly, rather than through an A- or D-cell paracrine effect. Both kisspeptin-10 and kisspeptin-13, which is an extension of kisspeptin-10 by three amino acids, act directly at islet β-cells of various species to potentiate insulin secretion, and suggest that inhibitory effects reported in earlier studies may reflect differences in experimental protocols[3].

Kisspeptins has recently been identified by three different groups as endogenous ligands of the Kiss 1 receptor (Kiss-1R), a G protein-coupled receptor (GPR) also known as hOT7T175, AXOR12 or GPR54.

Reference:

[1] R A Silvestre, E M Egido, R Hernández, et al. Kisspeptin-13 inhibits insulin secretion without affecting glucagon or somatostatin release: study in the perfused rat pancreas.J Endocrinol February 1. 2008,196,283-290 [2] Ji K, Ye L, Mason MD, Jiang WG.The Kiss-1/Kiss-1R complex as a negative regulator of cell motility and cancer metastasis. Int J Mol Med. 2013, 32(4):747-754 [3] Bowe JE, Foot VL, Amiel SA, ea al.GPR54 peptide agonists stimulate insulin secretion from murine, porcine and human islets. Islets. 2012, 4(1):20-23.

GLP-1 secretion inhibits weight gain

A new research is published by American researcher in Diabetes online, They found that GLP-1(32-36)amide inhibited weight gain, derived from the glucoincretin hormone GLP-1,that increases basal energy expenditure, curtails the development of obesity, insulin resistance, diabetes, and hepatic steatosis in a diet-induced obese mice. It might be a usefull product to treat human obesity and associated metabolic disorders

The peptapeptide inhibited weight gain, reduced fat mass without change in energy intake, and increased basal energy expenditure independent of physical activity. In the research, They found that as UCP-1 and UCP-3 in brown adipose tissue expressed increased, UCP-3 incresed and of acetylCoA carboxylase was inhbited in skeletal muscle,They found the mechanism of GLP-1(32-36) regulating the metabolism is that GLP-1(32-36)amide activated AMP kinase and inhibited acetyl CoA carboxylase[1].

Another lastest research showed that GLP-1 secretion was pronounced different between men and women. a higher GLP-1 response among women than men, but when glucose tolerance worsens, the decline in GLP-1 secretion is more pronounced in women than in men[2].

These findings may have important clinical implications for human obesity and associated metabolic disorders

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Reference: [1]EvaTomas, Violeta Stanojevic, Karen McManus, GLP-1(32-36)amide Pentapeptide Increases Basal Energy Expenditure and Inhibits Weight Gain In Obese Mice. Diabetes. 2015 Apr 9. pii: db141708 doi:10.2337/db14-1708 [2]Kristine Færch, Signe S. Torekov, Dorte Vistisen,ea al. Glucagon-Like Peptide-1 (GLP-1) Response to Oral Glucose is Reduced in Pre-diabetes, Screen-detected Type 2 Diabetes and Obesity, and Influenced by Sex: The ADDITION-PRO Study. Diabetes, 2015, db141751 DOI: 10.2337/db14-1751

PDK1 – a peptide about melanomas

In the field of biochemistry, 3-phosphoinositide dependent protein kinase-1, also known as PDPK1 is a protein which in humans is encoded by the PDPK1 gene. [1] It is implicated in the development and progression of melanomas.

The structure of PDPK1 can be divided into two domains; the kinase or catalytic domain and the PH domain. The PH domain functions mainly in the interaction of PDPK1 with phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate which is important in localization and activation of some of membrane associated PDPK1′s substrates including AKT.

The kinase domain has three ligand binding sites; the substrate binding site, the ATP binding site, and the docking site (also known as PIF pocket). Several PDPK1 substrates including S6K and Protein kinase C, require the binding at this docking site. Small molecule allosteric activators of PDPK1 were shown to selectively inhibit activation of substrates that require docking site interaction. These compounds do not bind to the active site and allow PDPK1 to activate other substrates that do not require docking site interaction. PDPK1 is constitutively active and at present, there are no known inhibitor proteins for PDPK1.

The activation of PDPK1′s main effector, AKT, is believed to require a proper orientation of the kinase and PH domains of PDPK1 and AKT at the membrane.

PDPK1 is a master kinase, which is crucial for the activation of AKT/PKB and many other AGC kinases including PKC, S6K, SGK. An important role for PDPK1 is in the signalling pathways activated by several growth factors and hormones including insulin signaling. [2]

Mice lacking PDPK1 die during early embryonic development, indicating that this enzyme is critical for transmitting the growth-promoting signals nescessary for normal mammalian development.

Mice that are deficient in PDPK1 have a ≈40% decrease in body mass, mild glucose intolerance, and are resistant to cancer brought about by hyperactivation of the PI3K pathway (PTEN+/-).[3]

PDPK1 stands for 3-phosphoinositide-dependent protein kinase 1. PDPK1 functions downstream of PI3K through PDPK1′s interaction with membrane phospholipids including phosphatidylinositols, phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. PI3K indirectly regulates PDPK1 by phosphorylating phosphatidylinositols which in turn generates phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. However, PDPK1 is believed to be constitutively active and does not always require phosphatidylinositols for its activities.

Phosphatidylinositols are only required for the activation at the membrane of some substrates including AKT. PDPK1 however does not require membrane lipid binding for the efficient phosphorylation of most of its substrates in the cytosol (not at the cell membrane).

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Reference [1] Scortegagna M, Ruller C, Feng Y, Lazova R, Kluger H, Li JL et al. (2014). “Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma”. Oncogene 33 (34): 4330–9. [2] Mora A, Komander D, van Aalten DM, Alessi DR (April 2004). “PDK1, the master regulator of AGC kinase signal transduction”. Semin. Cell Dev. Biol. 15 (2): 161–70. [3] Frödin M, Antal TL, Dümmler BA, Jensen CJ, Deak M, Gammeltoft S et al. (October 2002). “A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation”. EMBO J. 21 (20): 5396–407.

Characterization of motilin from different species

Motilin is an intestinal peptide hormone that binds to a membrane bound receptor located in the gut tissue. Some reports have demonstrated that the motilins from different species has different amino acid and their function is not the same.

Some reports displayed the difference of motilin among mammalians. species-related structural alterations in motilin molecules generate different bioactive capacities in some animal species, suggests that the middle portion of the motilin molecule is important for its bioactive expression, suggests the presence of motilin receptors on canine duodenal muscle, and suggests that an influx of extracellular calcium is involved in the canine duodenal muscle contraction elicited by canine motilin. The experiment motilins purified from porcine and canine intestine differ in their amino acid composition in positions 7-8-12-13-14. The researcher studied in vitro the contractile response of longitudinal duodenal muscles from various animals (guinea pig, rabbit, dog) to porcine and canine synthetic motilins. Both substances failed to elicit contraction of the guinea pig duodenum but were active and equally potent on rabbit muscle[1]. Another report is between rat and porcine.Rat intestinal immunoreactive motilin did not co-elute with natural porcine motilin following high pressure liquid chromatography on a Waters microBondapak C18 reversed-phase column using a linear gradient of water-acetonitrile (10-45%) over 30 min. Although of similar molecular size, rat motilin is probably structurally dissimilar to other mammalian motilins[2].

Some another reports shows the difference between viviparous species and mammalian. motilin was isolated from acid extracts of the small intestine of chickens, The sequence is FVPFFTQSDIQKMQEK-ERNKGQ. Although the six residues differing from porcine motilin (4, 7-10, and 12) are mostly in the pharmacophore of porcine motilin, the affinity of chicken motilin and of the (1-14) fragment of chicken motilin for the motilin receptor of rabbit antral smooth muscle is not much reduced .With smooth muscle tissue of the chicken, however, receptors could not be demonstrated with binding studies. In the tissue bath chicken motilin induced a dose-dependent tonic contraction, which was most pronounced with muscle strips prepared from chicken jejunum. This response was blocked by the Ca2+ antagonist verapamil, but atropine, TTX, L-NNA, guanethidine, prazosin, and yohimbine had no effect. The pEC50 for chicken motilin in the chicken jejunum was 7.41. Motilins from other species had lower potencies, and [Phe3, Leu13]porcine motilin, an antagonist in the rabbit, was an agonist in the chicken. The motilin agonists erythromycin A and EM-523 were almost without effect. Tested against rabbit duodenum, chicken motilin had a smaller potency than mammalian motilins. Thus, chicken motilin and the chicken motilin receptor differ from their mammalian counterparts[3].

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Reference: [1]Poitras P, Lahaie RG, St-Pierre S, et al. Comparative stimulation of motilin duodenal receptor by porcine or canine motilin. Gastroenterology. 1987,92(3):658-662. [2]Vogel LB, Brown JC. Characterization of immunoreactive motilin from the rat small intestine. Can J Physiol Pharmacol. 1990,68(8):1124-1130. [3] Peeters TL, Bormans V, Matthijs G, et.al. Comparison of the biological activity of canine and porcine motilin in rabbit. Regul Pept. 1986,15(4):333-339.

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