Definition
Annexins are calcium-dependent phospholipid-binding proteins. More than a thousand proteins of the annexin superfamily have been identified in major eukaryotic phyla, but annexins are absent from yeasts and prokaryotes.
Discovery
The first annexin to be identified was annexin VII (synexin) from the bovine adrenal medulla by creutz and team in 19781.
Classification
Annexins are grouped under 5 major classes (A-E), the 12 annexins which are commonly found in vertebrates are classified under annexin A family and named as annexins A1-A13 (or ANXA1-ANXA13), leaving A12 not assigned in the official nomenclature. Annexins outside vertebrates are classified under family B (in invertebrates), C (in fungi and under groups of unicellular eukaryotes), D (in plants), and E (in protists).
Structural Characteristics
Each annexin is composed of two principal domains: the divergent NH2-terminal “head” and the conserved COOH-terminal protein core. The COOH-terminal protein core harbors the Ca2+ and membrane binding sites and is responsible for mediating the canonical membrane binding properties. An annexin core comprises four (in annexin A6 eight) segments of internal and interannexin homology that are easily identified in a linear sequence alignment. It forms a highly alpha helical and tightly packed disk with a slight curvature and two principle sides. The more convex side contains Ca2+ binding sites, the so-called type II and type III sites, and faces the membrane when an annexin is associated peripherally with phospholipids2. Many annexins undergo posttranslational modifications viz., phosphorylation and myristoylation1.
Mode of action
The process of membrane aggreagation requires the self association of annexin molecules where Ca2+ plays an important role. In case of synexin (annexin VII) at lower concentration of Ca2+ level it is soluble, if the concentration of Ca2+ increase it results in binding of annexins to membrane further increase in Ca2+ levels results in membrane aggregation and fusion.
Function
Annexins interact with various cell-membrane components that are involved in the structural organization of the cell, intracellular signaling by enzyme modulation and ion fluxes, growth control, and they can act as atypical calcium channels1.
References
1.Moss SE, Morgan RO (2004). The Annexins. Genome Biol., 5(4): 219.
Wednesday, June 17, 2009
Calcineurin (PP2B)
Definition
Calcineurin also known as protein phosphatase 2B (PP2B), is a phosphoprotein serine/threonine phosphatase, activated physiologically by Ca2+–calmodulin.
Discovery
It was identified and characterized by Claude Klee and Philip Cohen in the late 1970s.
Structural Characteristics
Calcineurin is a dimer of an A catalytic subunit and a B subunit. Calmodulin becomes tightly associated with calcineurin only in the presence of elevated, but physiological, levels of Ca2+ 1.
Classification
In mammals three isoforms of calcineurin A (Aa, Aß and A?) and two isoforms of calcineurin B (B1, and B2) are expressed from separate genes1.
Mode of action
In resting cells, nuclear factor of activated T-cells (NFAT) proteins are phosphorylated, and in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin. On dephosphorylation NFAT translocate to the nucleus whereon, it binds to consensus DNA sites and controls gene transcription2.
Functions
Calcineurin plan an important role in intracellular signaling. In budding yeast, calcineurin has a role in coordinating adaptation to environmental stress both through the calcineurin–Crz1p transcriptional pathway and through post-translational mechanisms. Calcineurin signaling is involved in the long-term adaptation after chronic drug treatment in a way that may parallel its role during memory formation3.
References
1.Hogan PG, Li H (2005). Calcineurin. Curr Biol., 15(12):442-443.
2.Valerie Horsley and Grace K. Pavlath (2002). Nfat: ubiquitous regulator of cell differentiation and adaptation. J Cell Biol., 156(5): 771–774.
3.Biala G (2007). Memory processes and addiction: involvement of the calcineurin signaling pathway. Postepy Hig Med Dosw (Online)., 61:199-203.
Calcineurin also known as protein phosphatase 2B (PP2B), is a phosphoprotein serine/threonine phosphatase, activated physiologically by Ca2+–calmodulin.
Discovery
It was identified and characterized by Claude Klee and Philip Cohen in the late 1970s.
Structural Characteristics
Calcineurin is a dimer of an A catalytic subunit and a B subunit. Calmodulin becomes tightly associated with calcineurin only in the presence of elevated, but physiological, levels of Ca2+ 1.
Classification
In mammals three isoforms of calcineurin A (Aa, Aß and A?) and two isoforms of calcineurin B (B1, and B2) are expressed from separate genes1.
Mode of action
In resting cells, nuclear factor of activated T-cells (NFAT) proteins are phosphorylated, and in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin. On dephosphorylation NFAT translocate to the nucleus whereon, it binds to consensus DNA sites and controls gene transcription2.
Functions
Calcineurin plan an important role in intracellular signaling. In budding yeast, calcineurin has a role in coordinating adaptation to environmental stress both through the calcineurin–Crz1p transcriptional pathway and through post-translational mechanisms. Calcineurin signaling is involved in the long-term adaptation after chronic drug treatment in a way that may parallel its role during memory formation3.
References
1.Hogan PG, Li H (2005). Calcineurin. Curr Biol., 15(12):442-443.
2.Valerie Horsley and Grace K. Pavlath (2002). Nfat: ubiquitous regulator of cell differentiation and adaptation. J Cell Biol., 156(5): 771–774.
3.Biala G (2007). Memory processes and addiction: involvement of the calcineurin signaling pathway. Postepy Hig Med Dosw (Online)., 61:199-203.
Bombesin and Analogs
Definition
Bombesin is a polypeptide that is found in the brain and gastrointestinal tract. Experimentally it has shown to cause the secretion of various substances (as gastrin and cholecystokinin) and to inhibit intestinal motility.
Discovery
Bombesin was isolated from the skin of the frog Bombina bonmina by Anastasi and team in 19711.
Classification
Bombesin-like peptides are grouped into three families - 1) Bombesin group, viz., bombesin and alytesin, 2) Ranatensin group viz., ranatensins, litorin, and Rohdei litorin, 3) Phyllolitorin group viz., Leu(8)- and Phe(8)-phyllolitorins.
Structural characteristics
Bombesin is a small peptide of 14 amino acids.
Mode of action
The biological activity of bombesin is mediated by binding to specific receptors viz., gastrin releasing peptide receptor (GRPR; called also BB2 receptor), neuromedin B receptor (NMBR; called also BB1 receptor) and bombesin receptor subtype 3 (BRS-3; called also BB3 receptor). Bombesin induce Ca2+ release from intracellular stores2.
Functions
Bombesin and bombesin-like factors show a wide spectrum of biological activities. It regulates the contraction of smooth muscle cells, induction of the secretion of neuropeptides and hormones. It is one of the most powerful substances showing anorexic effects in the hypothalamus. It induces the release of gastrin and cholecystokinin in the intestines and the pancreas. They also posses activities of cytokines.
References
1.Anastasi A, Erspamer V, Bucci M (1971). Isolation and structure of bombesin and alytesin, 2 analogous active peptides from the skin of the European amphibians Bombina and Alytes. Experientia., 27(2):166-167.
2. Wang JL, Kalyanaraman S, Vivo MD, Gautam N (1996). Bombesin and thrombin affect discrete pools of intracellular calcium through different G-proteins. Biochem J., 320:87-91.
Bombesin is a polypeptide that is found in the brain and gastrointestinal tract. Experimentally it has shown to cause the secretion of various substances (as gastrin and cholecystokinin) and to inhibit intestinal motility.
Discovery
Bombesin was isolated from the skin of the frog Bombina bonmina by Anastasi and team in 19711.
Classification
Bombesin-like peptides are grouped into three families - 1) Bombesin group, viz., bombesin and alytesin, 2) Ranatensin group viz., ranatensins, litorin, and Rohdei litorin, 3) Phyllolitorin group viz., Leu(8)- and Phe(8)-phyllolitorins.
Structural characteristics
Bombesin is a small peptide of 14 amino acids.
Mode of action
The biological activity of bombesin is mediated by binding to specific receptors viz., gastrin releasing peptide receptor (GRPR; called also BB2 receptor), neuromedin B receptor (NMBR; called also BB1 receptor) and bombesin receptor subtype 3 (BRS-3; called also BB3 receptor). Bombesin induce Ca2+ release from intracellular stores2.
Functions
Bombesin and bombesin-like factors show a wide spectrum of biological activities. It regulates the contraction of smooth muscle cells, induction of the secretion of neuropeptides and hormones. It is one of the most powerful substances showing anorexic effects in the hypothalamus. It induces the release of gastrin and cholecystokinin in the intestines and the pancreas. They also posses activities of cytokines.
References
1.Anastasi A, Erspamer V, Bucci M (1971). Isolation and structure of bombesin and alytesin, 2 analogous active peptides from the skin of the European amphibians Bombina and Alytes. Experientia., 27(2):166-167.
2. Wang JL, Kalyanaraman S, Vivo MD, Gautam N (1996). Bombesin and thrombin affect discrete pools of intracellular calcium through different G-proteins. Biochem J., 320:87-91.
Tuesday, June 16, 2009
BAD Peptides
Definition
BAD is a member of the BCl-2 family of proteins and acts to promote apoptosis by forming heterodimers with the survival proteins BCL-2 and BCLXL, thus preventing them from binding with BAX1.
Discovery
BAD was originally identified in a yeast two hybrid system that was used to screen for BCL-2 interacting proteins1.
Classification
BAD belongs to the BH3 sub-family of proteins that also includes other pro-apoptotic proteins; BH3 BID, BIK, BLK, HRK, BNIP3 and BIML2.
Structural Characteristics
BAD peptides contain a highly conserved alpha-helical BH3 domain through which they form heterodimers with BCL-2 and BCLXL3. The BH3 domain is structurally defined as four-turn amphipathic a-helices, containing the sequence motif: Hy-X-X-X-Hy-X-X-X-Sm-D/E-X-Hy4. This domain is sufficient for pro-apoptotic functions of BAD.
Mode of action
BAD peptides are located on the outer-mitochondrail membrane. Activation of NGF or IL-3 receptors on the mitochondrial membrane mediates the activation of AKT or PKA holoenzyme respectively that result in the phosphorylation of BAD at Ser-136 and 1122,5. Phosphorylated BAD is translocated to the cytosol by phosphoserine binding protein. Following a death signal BAD is dephosporylated and found in association with BCL-XL-BCL-2 in which form BAD can exert its functions6.
Functions
BCL-2 family proteins that includes BAD play a pivotal role in deciding whether a cell will live or die by apoptosis. Pro-apoptotic function of BAD is triggered by growth factor deprivation in the cell that results in its dephosphorylation and activation7. Activated BAD binds to BCL-2-BCL-XL and releases BAK and BAX that initiate apoptosis. Increased BAD protein levels have been found in diseases like myocardial ischemia-reperfusion7. BAD is also implicated in cancer. In mouse models it has been found that decrease in BAD levels leads to malignancy8. Interestingly recent studies have shown that the tumor suppressor protein, p53 binds to BAD in response to DNA damage and in turn BAD triggers apoptosis of such cells thus maintaining cell physiology9.
References
1. Elizabeth Y, Jiping Z, Jennifer J, Boise LH, Craig B, Thompson and Stanley JK, (1995). Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces bax and promotes cell death. Cell, 80, Issue 2, 285-91.
2. Atan G, James M.M, Stanley J.K (1999). BCL-2 family members and the mitochondria in apoptosis. Genes and Development, 13; 1899-1911.
3. Sabine O, Jose-L D, William H, Julia C, Yan W, Gary W, Steve C, Suzanne W, Lawrence CF, and Tilman O (1997). Structural properties of Human BAD. J Biol. Chem., 372, 49, 30866-892.
4. Beth L, Sangita S and Guido K (2008). Bcl-2 family members; Dual regulators of apoptosis and autophagy. Autophagy, 4:5, 600-606.
5. Zha J, Harada H, Yang E, Jockel J, Kormeyer SJ (1996c). Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell, 87:619–628.
6. Zha J, Harada H, Osipov K, Jockel J, Waksman G, Korsmeyer SJ (1997). BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity. J. Biol. Chem., 272:24101–24104.
7. Åsa BG and Roberta AG (2007). Bcl-2 family members and apoptosis, taken to heart. Am J Physiol Cell Physiol., 292:45-51.
8. Zinkel S, Gross A and Yang E (2006). BCL2 family in DNA damage and cell cycle control. Cell Death and Differentiation, 13, 1351–1359.
9. Peng J, Wenjing D and Mian W (2007). p53 and BAD: Remote strangers become close friends, Cell Research, 17: 283–285.
BAD is a member of the BCl-2 family of proteins and acts to promote apoptosis by forming heterodimers with the survival proteins BCL-2 and BCLXL, thus preventing them from binding with BAX1.
Discovery
BAD was originally identified in a yeast two hybrid system that was used to screen for BCL-2 interacting proteins1.
Classification
BAD belongs to the BH3 sub-family of proteins that also includes other pro-apoptotic proteins; BH3 BID, BIK, BLK, HRK, BNIP3 and BIML2.
Structural Characteristics
BAD peptides contain a highly conserved alpha-helical BH3 domain through which they form heterodimers with BCL-2 and BCLXL3. The BH3 domain is structurally defined as four-turn amphipathic a-helices, containing the sequence motif: Hy-X-X-X-Hy-X-X-X-Sm-D/E-X-Hy4. This domain is sufficient for pro-apoptotic functions of BAD.
Mode of action
BAD peptides are located on the outer-mitochondrail membrane. Activation of NGF or IL-3 receptors on the mitochondrial membrane mediates the activation of AKT or PKA holoenzyme respectively that result in the phosphorylation of BAD at Ser-136 and 1122,5. Phosphorylated BAD is translocated to the cytosol by phosphoserine binding protein. Following a death signal BAD is dephosporylated and found in association with BCL-XL-BCL-2 in which form BAD can exert its functions6.
Functions
BCL-2 family proteins that includes BAD play a pivotal role in deciding whether a cell will live or die by apoptosis. Pro-apoptotic function of BAD is triggered by growth factor deprivation in the cell that results in its dephosphorylation and activation7. Activated BAD binds to BCL-2-BCL-XL and releases BAK and BAX that initiate apoptosis. Increased BAD protein levels have been found in diseases like myocardial ischemia-reperfusion7. BAD is also implicated in cancer. In mouse models it has been found that decrease in BAD levels leads to malignancy8. Interestingly recent studies have shown that the tumor suppressor protein, p53 binds to BAD in response to DNA damage and in turn BAD triggers apoptosis of such cells thus maintaining cell physiology9.
References
1. Elizabeth Y, Jiping Z, Jennifer J, Boise LH, Craig B, Thompson and Stanley JK, (1995). Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces bax and promotes cell death. Cell, 80, Issue 2, 285-91.
2. Atan G, James M.M, Stanley J.K (1999). BCL-2 family members and the mitochondria in apoptosis. Genes and Development, 13; 1899-1911.
3. Sabine O, Jose-L D, William H, Julia C, Yan W, Gary W, Steve C, Suzanne W, Lawrence CF, and Tilman O (1997). Structural properties of Human BAD. J Biol. Chem., 372, 49, 30866-892.
4. Beth L, Sangita S and Guido K (2008). Bcl-2 family members; Dual regulators of apoptosis and autophagy. Autophagy, 4:5, 600-606.
5. Zha J, Harada H, Yang E, Jockel J, Kormeyer SJ (1996c). Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell, 87:619–628.
6. Zha J, Harada H, Osipov K, Jockel J, Waksman G, Korsmeyer SJ (1997). BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity. J. Biol. Chem., 272:24101–24104.
7. Åsa BG and Roberta AG (2007). Bcl-2 family members and apoptosis, taken to heart. Am J Physiol Cell Physiol., 292:45-51.
8. Zinkel S, Gross A and Yang E (2006). BCL2 family in DNA damage and cell cycle control. Cell Death and Differentiation, 13, 1351–1359.
9. Peng J, Wenjing D and Mian W (2007). p53 and BAD: Remote strangers become close friends, Cell Research, 17: 283–285.
Antimicrobial and Related Peptides
Definition
Antimicrobial peptides (AMPs) are as widespread as bacterial inactivator molecules in the innate immune systems of insects, fungi, plants, and mammals. These peptides are also known as host defense peptides (HDPs) as they have other immuno-modulatory functions besides the direct antimicrobial actions and are even capable of killing cancerous cells 1,2.
Classification
Three broad categories of HDPs have been identified: 1) the linear peptides with helical structures, 2) the cysteine stabilized peptides with beta-sheet, and 3) a group of linear peptides rich in proline and arginine that primarily have been identified in non-mammalian species.
Structural characteristics
In mammals, cathelicidins and defensins are the two principal AMP families. Cathelicidins are peptides with a conserved proregion and a variable C-terminal antimicrobial domain. Defensins are the best-characterized AMPs, they have six invariant cysteines, forming three intramolecular cystine-disulfide bonds.
Mode of action
The mode of action of AMPs elucidated to date include inhibition of cell wall formation, formation of pores in the cell membrane resulting in the disruption of membrane potential with eventual lysis of the cell. These peptides also inhibit nuclease activity of both RNase and DNase.
Functions
They have a broad ability to kill microbes. AMPs form an important means of host defense in eukaryotes. Large AMPs (>100 amino acids), are often lytic, nutrient-binding proteins or specifically target microbial macromolecules. Small AMPs act by disrupting the structure of microbial cell membranes. It plays an active role in wound repair and regulation of the adaptive immune system. They have multiple roles as mediators of inflammation with impact on epithelial and inflammatory cells, influencing diverse processes such as cell proliferation, wound healing, cytokine release, chemotaxis, immune induction 3.
References
1. Gottlieb CT, Thomsen LE, Ingmer H, Mygind PH, Kristensen HH, Gram L(2008). Antimicrobial peptides effectively kill a broad spectrum of Listeria monocytogenes and Staphylococcus aureus strains independently of origin, sub-type, or virulence factor expression. BMC Microbiol., 8:205.
2. Yeaman MR and Yount NY (2003). Mechanisms of Antimicrobial Peptide Action and Resistance. Pharmocological Reviews, 55(1).
3. Hanna Galkowska H and Olszewski WL (2003). Antimicrobial peptides – their role in immunity and therapeutic potential. Centr Eur J Immunol., 28 (3):138–141.
Antimicrobial peptides (AMPs) are as widespread as bacterial inactivator molecules in the innate immune systems of insects, fungi, plants, and mammals. These peptides are also known as host defense peptides (HDPs) as they have other immuno-modulatory functions besides the direct antimicrobial actions and are even capable of killing cancerous cells 1,2.
Classification
Three broad categories of HDPs have been identified: 1) the linear peptides with helical structures, 2) the cysteine stabilized peptides with beta-sheet, and 3) a group of linear peptides rich in proline and arginine that primarily have been identified in non-mammalian species.
Structural characteristics
In mammals, cathelicidins and defensins are the two principal AMP families. Cathelicidins are peptides with a conserved proregion and a variable C-terminal antimicrobial domain. Defensins are the best-characterized AMPs, they have six invariant cysteines, forming three intramolecular cystine-disulfide bonds.
Mode of action
The mode of action of AMPs elucidated to date include inhibition of cell wall formation, formation of pores in the cell membrane resulting in the disruption of membrane potential with eventual lysis of the cell. These peptides also inhibit nuclease activity of both RNase and DNase.
Functions
They have a broad ability to kill microbes. AMPs form an important means of host defense in eukaryotes. Large AMPs (>100 amino acids), are often lytic, nutrient-binding proteins or specifically target microbial macromolecules. Small AMPs act by disrupting the structure of microbial cell membranes. It plays an active role in wound repair and regulation of the adaptive immune system. They have multiple roles as mediators of inflammation with impact on epithelial and inflammatory cells, influencing diverse processes such as cell proliferation, wound healing, cytokine release, chemotaxis, immune induction 3.
References
1. Gottlieb CT, Thomsen LE, Ingmer H, Mygind PH, Kristensen HH, Gram L(2008). Antimicrobial peptides effectively kill a broad spectrum of Listeria monocytogenes and Staphylococcus aureus strains independently of origin, sub-type, or virulence factor expression. BMC Microbiol., 8:205.
2. Yeaman MR and Yount NY (2003). Mechanisms of Antimicrobial Peptide Action and Resistance. Pharmocological Reviews, 55(1).
3. Hanna Galkowska H and Olszewski WL (2003). Antimicrobial peptides – their role in immunity and therapeutic potential. Centr Eur J Immunol., 28 (3):138–141.
Wednesday, June 3, 2009
Amastatin and Analogs
Definition
Amastatin is a oligopeptide antibiotic complex that is a competitive inhibitor of aminopeptidases and also has antitumor property.
Discovery
Amastatin was isolated from the culture filtrate of Streptomyces spME98-M31.
Analog of Amastatin
Epiamastatin is a diastereoepimer of the effective peptidase inhibitor amastatin and differs structurally by a single transposition of the OH group with H atom at C2. Compared with amastatin, epiamastatin is pharmacologically inactive.
Structure
The structure of amastatin is (2S, 3R)-3-Amino-2-hydroxy-5-methyl-hexanoyl]-Val-Val-Asp. There are three kinds of functional group NH2, OH and COOH, in the amastatin molecule.
Functions
It is a competitive inhibitor of the aminopeptidases A and M2. It inhibits cytosolic leucine aminopeptidase, microsomal aminopeptidase M and bacterial leucine aminopeptidase3.
References
1.Tobe H, Morishima H, Aoyagi T, Umezawa H, Isshiki K, Nakamura K, Yoshioka T, Shimauchi Y, Inui T. (!982). Synthesis and structure-activity relationships of amastatin analogues, inhibitors of aminopeptidase A. Agric. Biol. Chem., 46:1865-1872.
2.Rich DH, Moon BJ, Harbeson S (1984). Inhibition of aminopeptidases by amastatin and bestatin derivatives. Effect of inhibitor structure on slow-binding processes. J Med Chem., 27(4):417-22.
3.Wilkes SH, Prescott JM. (1985). The slow, tight binding of bestatin and amastatin to aminopeptidases. J Biol Chem., 260(24):13154-62.
Amastatin is a oligopeptide antibiotic complex that is a competitive inhibitor of aminopeptidases and also has antitumor property.
Discovery
Amastatin was isolated from the culture filtrate of Streptomyces spME98-M31.
Analog of Amastatin
Epiamastatin is a diastereoepimer of the effective peptidase inhibitor amastatin and differs structurally by a single transposition of the OH group with H atom at C2. Compared with amastatin, epiamastatin is pharmacologically inactive.
Structure
The structure of amastatin is (2S, 3R)-3-Amino-2-hydroxy-5-methyl-hexanoyl]-Val-Val-Asp. There are three kinds of functional group NH2, OH and COOH, in the amastatin molecule.
Functions
It is a competitive inhibitor of the aminopeptidases A and M2. It inhibits cytosolic leucine aminopeptidase, microsomal aminopeptidase M and bacterial leucine aminopeptidase3.
References
1.Tobe H, Morishima H, Aoyagi T, Umezawa H, Isshiki K, Nakamura K, Yoshioka T, Shimauchi Y, Inui T. (!982). Synthesis and structure-activity relationships of amastatin analogues, inhibitors of aminopeptidase A. Agric. Biol. Chem., 46:1865-1872.
2.Rich DH, Moon BJ, Harbeson S (1984). Inhibition of aminopeptidases by amastatin and bestatin derivatives. Effect of inhibitor structure on slow-binding processes. J Med Chem., 27(4):417-22.
3.Wilkes SH, Prescott JM. (1985). The slow, tight binding of bestatin and amastatin to aminopeptidases. J Biol Chem., 260(24):13154-62.
Allatostatins
Definition
Allatostatins (ASTs) are pleiotropic neuropeptide hormones in insects and crustacean. There major function in the insect is the inhibition of juvenile hormone synthesis by the corpora allata and reduce their food intake1.
Discovery
The first identified ASTs were isolated from brain-retro cerebral complexes of the cockroach Diploptera punctata2.
Classification
ASTs encompass a group of three families determined by consensus sequences, the cockroach type representing the FGLa family, the cricket type representing the W(X)6 Wa family and the PISCF family1.
Structural Characteristics
AST’s are 8-13 amino acids long, are amidated, and show sequence similarity, including a 3-amino acid sequence at the C-terminal end that is common to all four peptides. The peptide sequences are as follows: allatostatin-1, Ala-Pro-Ser-Gly-Ala-Gln-Arg-Leu-Tyr-Gly-Phe-Gly-Leu-NH2; allatostatin-2, Gly-Asp-Gly-Arg-Leu-Tyr-Ala-Phe-Gly-Leu-NH2; allatostatin-3, Gly-Gly-Ser-Leu-Tyr-Ser-Phe-Gly-Leu-NH2; and allatostatin-4, Asp-Arg-Leu-Tyr-Ser-Phe-Gly-Leu-NH23.
Mode of action
In mammalian cells, allatostatin bind to AST receptors to open G-protein coupled inward rectifying potassium channels, resulting in reduced membrane potential and input resistance4.
Function
The action of ASTs have been largely defined in individual species, in the case of the FGLamide family, such actions include (1) the inhibition of vitellogenin production by fat body in cockroaches, (2) the inhibition of myotropic activity, particularly in gut tissue of Dictyoptera and Orthoptera, (3) regulation of release of digestive enzymes in the midgut of cockroaches, (4) neurotransmission in crab stomatogastric ganglion and possibly cockroach CNS.The biological action of the W(x) 6 Wamide family include (1) Inhibition of ectysteroid biosynthesis (prothoracicostatic activity) by prothoracic glands in silk moth and ovaries of crickets, (2) Inhibition of locust oviduct muscle, (3) Inhibition of spontaneous muscle contraction in foregut of the cockroach. The PISCF family display biological effect similar to the two AST families inhibiting contraction in larval drosophila heart muscle. This peptide family plays a role in the regulation of migratory flight in Lepidoptera.
References
1.Stay B and Tobe SS (2007). "The role of allatostatins in juvenile hormone synthesis in insects and crustaceans". Annu. Rev. Entomo., 52: 277–99.
2.Pratt GE, Farnsworth DE, Fok KF, Siegel NR, McCormack AL, Shabanowitz J, Hunt DF, Feyereisen R (1991). Identity of a second type of allatostatin from cockroach brains: an octadecapeptide amide with a tyrosine-rich address sequence. Proc Natl Acad Sci., 88(6): 2412–2416.
3.Woodhead AP, Stay B, Seidel SL, Khan MA, Tobe SS (1989). Primary structure of four allatostatins: neuropeptide inhibitors of juvenile hormone synthesis. Proc Natl Acad Sci., 86(15):5997-6001.
4.Tan EM, Yamaguchi Y, Horwitz GD, Gosgnach S, Lein ES, Goulding M, Albright TD, Callaway EM (2006). Selective and quickly reversible inactivation of mammalian neurons in vivo uses the Drosophila allatostatin receptor. Neuron, 1:57–170.
Allatostatins (ASTs) are pleiotropic neuropeptide hormones in insects and crustacean. There major function in the insect is the inhibition of juvenile hormone synthesis by the corpora allata and reduce their food intake1.
Discovery
The first identified ASTs were isolated from brain-retro cerebral complexes of the cockroach Diploptera punctata2.
Classification
ASTs encompass a group of three families determined by consensus sequences, the cockroach type representing the FGLa family, the cricket type representing the W(X)6 Wa family and the PISCF family1.
Structural Characteristics
AST’s are 8-13 amino acids long, are amidated, and show sequence similarity, including a 3-amino acid sequence at the C-terminal end that is common to all four peptides. The peptide sequences are as follows: allatostatin-1, Ala-Pro-Ser-Gly-Ala-Gln-Arg-Leu-Tyr-Gly-Phe-Gly-Leu-NH2; allatostatin-2, Gly-Asp-Gly-Arg-Leu-Tyr-Ala-Phe-Gly-Leu-NH2; allatostatin-3, Gly-Gly-Ser-Leu-Tyr-Ser-Phe-Gly-Leu-NH2; and allatostatin-4, Asp-Arg-Leu-Tyr-Ser-Phe-Gly-Leu-NH23.
Mode of action
In mammalian cells, allatostatin bind to AST receptors to open G-protein coupled inward rectifying potassium channels, resulting in reduced membrane potential and input resistance4.
Function
The action of ASTs have been largely defined in individual species, in the case of the FGLamide family, such actions include (1) the inhibition of vitellogenin production by fat body in cockroaches, (2) the inhibition of myotropic activity, particularly in gut tissue of Dictyoptera and Orthoptera, (3) regulation of release of digestive enzymes in the midgut of cockroaches, (4) neurotransmission in crab stomatogastric ganglion and possibly cockroach CNS.The biological action of the W(x) 6 Wamide family include (1) Inhibition of ectysteroid biosynthesis (prothoracicostatic activity) by prothoracic glands in silk moth and ovaries of crickets, (2) Inhibition of locust oviduct muscle, (3) Inhibition of spontaneous muscle contraction in foregut of the cockroach. The PISCF family display biological effect similar to the two AST families inhibiting contraction in larval drosophila heart muscle. This peptide family plays a role in the regulation of migratory flight in Lepidoptera.
References
1.Stay B and Tobe SS (2007). "The role of allatostatins in juvenile hormone synthesis in insects and crustaceans". Annu. Rev. Entomo., 52: 277–99.
2.Pratt GE, Farnsworth DE, Fok KF, Siegel NR, McCormack AL, Shabanowitz J, Hunt DF, Feyereisen R (1991). Identity of a second type of allatostatin from cockroach brains: an octadecapeptide amide with a tyrosine-rich address sequence. Proc Natl Acad Sci., 88(6): 2412–2416.
3.Woodhead AP, Stay B, Seidel SL, Khan MA, Tobe SS (1989). Primary structure of four allatostatins: neuropeptide inhibitors of juvenile hormone synthesis. Proc Natl Acad Sci., 86(15):5997-6001.
4.Tan EM, Yamaguchi Y, Horwitz GD, Gosgnach S, Lein ES, Goulding M, Albright TD, Callaway EM (2006). Selective and quickly reversible inactivation of mammalian neurons in vivo uses the Drosophila allatostatin receptor. Neuron, 1:57–170.
Agouti Related Peptides
Definition
Agouti-related peptide (AgRP) is a neuropeptide produced in the brain in the arcuate nucleus of the hypothalamus. It is an endogenous antagonist of melanocortin receptors (MC3-R and MC4-R) which plays a critical role in energy balance.
Discovery
It was identified independently by two teams based on sequence similarity with Agouti signalling peptide, a protein synthesized in the skin that controls coat color1,2.
Classification
There are 3 synthetic AgRP fragments in humans, viz AgRP (25-51), AgRP (54-82) and AgRP (83-132). Amino-terminal fragments AgRP (25-51) and (54-82) were devoid of significant antagonist activity, whereas the amidated carboxyl-terminal AGRP fragment (83-132)-NH2 is potently active3.
Structural characteristics
The human AgRP is 132 amino acids in length, and is about 25 percent identical to agouti polypeptide. It contains 11 cysteines, the majority of which are located at the carboxyl terminal end of the polypeptide, and form 5 disulfide bridges4. The C-terminal portion of the peptide (87-132) is believed to be necessary for optimal binding and contains a five fingered spider-toxin motif with an eight amino acid portion mimicking alpha -MSH.
Mode of action
AgRP binds specifically to MC3-R and MC4-R as an inverse agonist. This inverse agonism antagonizes the action of alpha-MSH and also brings down the level of cAMP (secondary messanger) produced in the affected cells.
Functions
The major function of AgRP is to increase appetite and decrease metabolism. It is one of the most potent and longest appetite stimulator. It can used in treatment of obesity and is particularly beneficial in the prevention and treatment of type 2 diabetes5.
References
1.Shutter JR, Graham M, Kinsey AC, Scully S, Lüthy R, Stark KL (March 1997). "Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice". Genes & Development 11 (5): 593–602.
2.Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS (October 1997). "Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein". Science (New York, N.Y.) 278 (5335): 135–8.
3.Quillan JM, Sadée W, Wei ET, Jimenez C, Ji L, Chang JK (1998). A synthetic human Agouti-related protein-(83-132)-NH2 fragment is a potent inhibitor of melanocortin receptor function. FEBS Lett, 428(1-2):59-62.
4.Bures EJ, Hui JO, Young Y, Chow DT, Katta V, Rohde MF, Zeni L, Rosenfeld RD, Stark KL, Haniu M (1998). Determination of disulfide structure in agouti-related protein (AGRP) by stepwise reduction and alkylation. Biochemistry, 37(35):12172-12177.
5.Wilding JP (2002). Neuropeptides and appetite control. Diabet Med, 19(8):619-627
Agouti-related peptide (AgRP) is a neuropeptide produced in the brain in the arcuate nucleus of the hypothalamus. It is an endogenous antagonist of melanocortin receptors (MC3-R and MC4-R) which plays a critical role in energy balance.
Discovery
It was identified independently by two teams based on sequence similarity with Agouti signalling peptide, a protein synthesized in the skin that controls coat color1,2.
Classification
There are 3 synthetic AgRP fragments in humans, viz AgRP (25-51), AgRP (54-82) and AgRP (83-132). Amino-terminal fragments AgRP (25-51) and (54-82) were devoid of significant antagonist activity, whereas the amidated carboxyl-terminal AGRP fragment (83-132)-NH2 is potently active3.
Structural characteristics
The human AgRP is 132 amino acids in length, and is about 25 percent identical to agouti polypeptide. It contains 11 cysteines, the majority of which are located at the carboxyl terminal end of the polypeptide, and form 5 disulfide bridges4. The C-terminal portion of the peptide (87-132) is believed to be necessary for optimal binding and contains a five fingered spider-toxin motif with an eight amino acid portion mimicking alpha -MSH.
Mode of action
AgRP binds specifically to MC3-R and MC4-R as an inverse agonist. This inverse agonism antagonizes the action of alpha-MSH and also brings down the level of cAMP (secondary messanger) produced in the affected cells.
Functions
The major function of AgRP is to increase appetite and decrease metabolism. It is one of the most potent and longest appetite stimulator. It can used in treatment of obesity and is particularly beneficial in the prevention and treatment of type 2 diabetes5.
References
1.Shutter JR, Graham M, Kinsey AC, Scully S, Lüthy R, Stark KL (March 1997). "Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice". Genes & Development 11 (5): 593–602.
2.Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS (October 1997). "Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein". Science (New York, N.Y.) 278 (5335): 135–8.
3.Quillan JM, Sadée W, Wei ET, Jimenez C, Ji L, Chang JK (1998). A synthetic human Agouti-related protein-(83-132)-NH2 fragment is a potent inhibitor of melanocortin receptor function. FEBS Lett, 428(1-2):59-62.
4.Bures EJ, Hui JO, Young Y, Chow DT, Katta V, Rohde MF, Zeni L, Rosenfeld RD, Stark KL, Haniu M (1998). Determination of disulfide structure in agouti-related protein (AGRP) by stepwise reduction and alkylation. Biochemistry, 37(35):12172-12177.
5.Wilding JP (2002). Neuropeptides and appetite control. Diabet Med, 19(8):619-627
Monday, June 1, 2009
ACTH and Related Peptide Sequences
Definition
Adrenocorticotropic hormone (ACTH) or corticotropin is a hormone produced by the anterior pituitary gland that stimulates the adrenal cortex.
Related peptides
The six related peptides include smaller biologically active fragments (hormones) which are derived from a common precursor by differential processing of the pro-opiomelanocortin polyprotein (POMC) viz. ACTH, corticotrophin like intermediate lobe protein [CLIP], ß-endorphin, gamma-lipotropin [yLPH], met-encephalin and alpha-melanotropin [aMSH]1.
Discovery
The properties of ACTH were first investigated in the 1930s. In 1933, research groups headed by James Collip, Herbert Evans and Bemardo Houssay used pituitary extracts to stimulate the adrenal cortex. American biochemist Choh Hao Li was one of several scientists who isolated ACTH in 1943 and synthesized it in 1963.
Structural characteristics
ACTH has a molecular weight of 4541.3 K Da2. It is a straight-chain peptide molecule consisting of 39 amino. The first 24 and last 7 amino acids are identical and there are minor differences in amino acids 25 through 32. Only the first 20 amino acids are required for full activity, referred as active centre.
Mechanism of action
ACTH enters the systemic circulation and binds to specific high affinity receptors located on the surface of adrenal cortical cells and the skin. ACTH receptor is a seven membrane-spanning G-protein coupled receptor3, which upon ligand binding undergoes conformation changes that stimulate the enzyme adenylate cyclase, which leads to an increase in intracellular cAMP and subsequent activation of protein kinase A. The activation of protein kinase A ultimately results in stimulation of steroidogenesis.
Function
ACTH's principal function is to stimulate the cortex of the adrenal glands to secrete a group of steroid hormones called glucocorticoids, mineralocorticoids and androgens steroids. Glucocorticoid hormones control the body's use of sugar and also help regulate biological functions during stressful moments. It stimulates the conversion of cholesterol into pregnenolone, the precursor of all steroid hormones. It is used in the treatment of rheumatoid arthritis, ulcerative colitis, hepatitis and to relieve pain. They play a major role in memory processing, by facilitating essential protein synthesis at sites specific for the memory4.
References
1. Funkelstein L, Toneff T, Mosier C, Hwang SR, Beuschlein F, Lichtenauer UD, Reinheckel T, Peters C, Hook V (2008). Major role of cathepsin L for producing the peptide hormones ACTH, beta-endorphin, and alpha-MSH, illustrated by protease gene knockout and expression. J Biol Chem., 283(51):35652-35659.
2.Lee TH, Lerner AB, Buettner-Janusch V (1961). On the structure of human corticotropin (adrenocorticotropic hormone). J. Biol. Chem., 236:2970-2974.
3.Mountjoy KG, Robbins LS, Mortrud MT, Cone RD (1992). The cloning of a family of genes that encode the melanocortin receptors. Science, 257:248–1251
4.Flood JF, Jarvik ME, Bennett EL, Orme AE (1976). Effects of ACTH peptide fragments on memory formation. Pharmacol Biochem Behav., 5:41-51.
Adrenocorticotropic hormone (ACTH) or corticotropin is a hormone produced by the anterior pituitary gland that stimulates the adrenal cortex.
Related peptides
The six related peptides include smaller biologically active fragments (hormones) which are derived from a common precursor by differential processing of the pro-opiomelanocortin polyprotein (POMC) viz. ACTH, corticotrophin like intermediate lobe protein [CLIP], ß-endorphin, gamma-lipotropin [yLPH], met-encephalin and alpha-melanotropin [aMSH]1.
Discovery
The properties of ACTH were first investigated in the 1930s. In 1933, research groups headed by James Collip, Herbert Evans and Bemardo Houssay used pituitary extracts to stimulate the adrenal cortex. American biochemist Choh Hao Li was one of several scientists who isolated ACTH in 1943 and synthesized it in 1963.
Structural characteristics
ACTH has a molecular weight of 4541.3 K Da2. It is a straight-chain peptide molecule consisting of 39 amino. The first 24 and last 7 amino acids are identical and there are minor differences in amino acids 25 through 32. Only the first 20 amino acids are required for full activity, referred as active centre.
Mechanism of action
ACTH enters the systemic circulation and binds to specific high affinity receptors located on the surface of adrenal cortical cells and the skin. ACTH receptor is a seven membrane-spanning G-protein coupled receptor3, which upon ligand binding undergoes conformation changes that stimulate the enzyme adenylate cyclase, which leads to an increase in intracellular cAMP and subsequent activation of protein kinase A. The activation of protein kinase A ultimately results in stimulation of steroidogenesis.
Function
ACTH's principal function is to stimulate the cortex of the adrenal glands to secrete a group of steroid hormones called glucocorticoids, mineralocorticoids and androgens steroids. Glucocorticoid hormones control the body's use of sugar and also help regulate biological functions during stressful moments. It stimulates the conversion of cholesterol into pregnenolone, the precursor of all steroid hormones. It is used in the treatment of rheumatoid arthritis, ulcerative colitis, hepatitis and to relieve pain. They play a major role in memory processing, by facilitating essential protein synthesis at sites specific for the memory4.
References
1. Funkelstein L, Toneff T, Mosier C, Hwang SR, Beuschlein F, Lichtenauer UD, Reinheckel T, Peters C, Hook V (2008). Major role of cathepsin L for producing the peptide hormones ACTH, beta-endorphin, and alpha-MSH, illustrated by protease gene knockout and expression. J Biol Chem., 283(51):35652-35659.
2.Lee TH, Lerner AB, Buettner-Janusch V (1961). On the structure of human corticotropin (adrenocorticotropic hormone). J. Biol. Chem., 236:2970-2974.
3.Mountjoy KG, Robbins LS, Mortrud MT, Cone RD (1992). The cloning of a family of genes that encode the melanocortin receptors. Science, 257:248–1251
4.Flood JF, Jarvik ME, Bennett EL, Orme AE (1976). Effects of ACTH peptide fragments on memory formation. Pharmacol Biochem Behav., 5:41-51.
Atrial Natriuretic Peptides (ANP/ANF) and Related Peptides
Definition
Atrial natriuretic peptide (ANP), atrial natriuretic factor (ANF), or atriopeptin, is a hormone secreted by heart muscle cells. It is involved in the homeostatic control of body water, sodium, potassium and fat. It is released by muscle cells in the upper chambers (atria) of the heart (atrial myocytes), in response to high blood pressure. It is closely related to brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP).
Discovery
ANP was discovered in 1981 by a team in Ottawa led by Adolfo J. de Bold after they made the seminal observation that injection of atrial tissue extracts into rats caused copious natriuresis1.
Structural characteristics
ANP is a 28-amino acid peptide with a 17-amino acid ring in the middle of the molecule. The ring is formed by a disulfide bond between two cysteine residues at positions 7 and 23. BNP and CNP also share the same amino acid ring. The ANP receptor occurs as a dimer of a single span transmembrane polypeptide, each containing an extracellular hormone-binding domain and an intracellular domain consisting of a protein kinase-like, ATP-dependent regulatory domain and a GC catalytic domain2.
Mode of action
The activities of ANP are mediated by the ANP receptor or the A-type natriuretic peptide receptor carrying intrinsic guanylate cyclase (GC) catalytic activity. Binding of the hormone to the receptor stimulates GC catalytic activity, thereby elevating intracellular cGMP levels. cGMP in turn, mediates the hormonal actions through cGMP-regulated ion channels, protein kinases and phosphodiesterases.
Functions
ANP stimulates vasodilatation, fluid egress, increases glomerular filtration and salt and water excretion. It also blocks the release and actions of several hormones, including angiotensin II, aldosterone and vasopressin. ANP levels are commonly elevated when there is excessive fluid volume or hypertension, and the hormone may be important in combating these states. It shows promise as an agent to treat heart failure, renal failure and fluid excess states3.
References
1.Mebazaa A and Payen D (1990). Atrial natriuretic factor. Ann Fr Anesth Reanim., 9(2):153-168.
2.Ogawa H, Qiu Y, Ogata CM, Misono KS (2004). Crystal structure of hormone-bound atrial natriuretic peptide receptor extracellular domain: rotation mechanism for transmembrane signal transduction. J Biol Chem., 279(27):28625-28631.
3.Baxter JD, Lewicki JA, Gardner DG (1988). Atrial Natriuretic Peptide. Nature BioTechnology, 6: 529 – 546.
Atrial natriuretic peptide (ANP), atrial natriuretic factor (ANF), or atriopeptin, is a hormone secreted by heart muscle cells. It is involved in the homeostatic control of body water, sodium, potassium and fat. It is released by muscle cells in the upper chambers (atria) of the heart (atrial myocytes), in response to high blood pressure. It is closely related to brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP).
Discovery
ANP was discovered in 1981 by a team in Ottawa led by Adolfo J. de Bold after they made the seminal observation that injection of atrial tissue extracts into rats caused copious natriuresis1.
Structural characteristics
ANP is a 28-amino acid peptide with a 17-amino acid ring in the middle of the molecule. The ring is formed by a disulfide bond between two cysteine residues at positions 7 and 23. BNP and CNP also share the same amino acid ring. The ANP receptor occurs as a dimer of a single span transmembrane polypeptide, each containing an extracellular hormone-binding domain and an intracellular domain consisting of a protein kinase-like, ATP-dependent regulatory domain and a GC catalytic domain2.
Mode of action
The activities of ANP are mediated by the ANP receptor or the A-type natriuretic peptide receptor carrying intrinsic guanylate cyclase (GC) catalytic activity. Binding of the hormone to the receptor stimulates GC catalytic activity, thereby elevating intracellular cGMP levels. cGMP in turn, mediates the hormonal actions through cGMP-regulated ion channels, protein kinases and phosphodiesterases.
Functions
ANP stimulates vasodilatation, fluid egress, increases glomerular filtration and salt and water excretion. It also blocks the release and actions of several hormones, including angiotensin II, aldosterone and vasopressin. ANP levels are commonly elevated when there is excessive fluid volume or hypertension, and the hormone may be important in combating these states. It shows promise as an agent to treat heart failure, renal failure and fluid excess states3.
References
1.Mebazaa A and Payen D (1990). Atrial natriuretic factor. Ann Fr Anesth Reanim., 9(2):153-168.
2.Ogawa H, Qiu Y, Ogata CM, Misono KS (2004). Crystal structure of hormone-bound atrial natriuretic peptide receptor extracellular domain: rotation mechanism for transmembrane signal transduction. J Biol Chem., 279(27):28625-28631.
3.Baxter JD, Lewicki JA, Gardner DG (1988). Atrial Natriuretic Peptide. Nature BioTechnology, 6: 529 – 546.
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