Schistosoma mansoni is a parasitic helminth that lives in the blood vessels of humans. It infects 220 million persons in 76 different countries including Puerto Rico and the Santa Lucia Islands, US territories. Although the parasite lives in the host in an aerobic millieu, it depends for its survival on anaerobic glycolysis. Our philosophy is that the better our understanding of the physiology and biochemistry of the parasite, the better our chance of identifying unique targets that can be selectively influenced by prospective chemotherapeutic agents. In order to survive, S. mansoni must metabolize every 6 hours an amount of glucose equivalent to its dry weight. Inhibition of a rate limiting enzyme in glycolysis, such as phosphofructokinase, by chemotherapeutic agents (e.g., organic antimonial) is lethal to the parasites. This research focuses on a hormonal/transduction system discovered in our laboratory in S. mansoni and other trematodes that regulates glycolysis in these parasites. Serotonin is a hormone-like agent in S. mansoni. It stimulates glycolysis and glycogenolysis and activates adenylate cyclase, glycogen phosphorylase and phosphofructokinase. It has many of the same functions that epinephrine has in mammals. The transmembrane signalling system for serotonin is composed of serotonin receptors that are unique to the parasite; a GTP binding protein; adenylate cyclase, a c-AMP-dependent protein kinase and signal and target proteins(e.g., phosphofructokinase). In this proposal we plan to study in depth three components of the serotonin signalling system: phosphofructokinase, GTP binding proteins, and serotonin receptors. Since our first attempt to renew this grant, we have succeeded in cloning two components of the signalling system, the Gsa protein and phosphofructokinase. We will complete the structural and functional analysis of the Gsa clone. We will express the PFK gene in bacterial or insect cells and study the biochemical nature of the recombinant protein. We plan to continue our work on cloning the serotonin receptor from the parasites and on characterizing its molecular and biochemical properties. Our studies have more significance than their possible use for drug development. Characterization of the molecular components of this """"""""primitive"""""""" signalling system contribute to our basic knowledge of transmembrane signal transduction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI016501-12A3
Application #
2060366
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1980-04-01
Project End
1996-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
12
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Mansour, J M; McCrossan, M V; Bickle, Q D et al. (2000) Schistosoma mansoni phosphofructokinase: immunolocalization in the tegument and immunogenicity. Parasitology 120 ( Pt 5):501-11
Su, J G; Mansour, J M; Mansour, T E (1996) Purification, kinetics and inhibition by antimonials of recombinant phosphofructokinase from Schistosoma mansoni. Mol Biochem Parasitol 81:171-8
Ding, J; Su, J G; Mansour, T E (1994) Cloning and characterization of a cDNA encoding phosphofructokinase from Schistosoma mansoni. Mol Biochem Parasitol 66:105-10
Iltzsch, M H; Bieber, D; Vijayasarathy, S et al. (1992) Cloning and characterization of a cDNA coding for the alpha-subunit of a stimulatory G protein from Schistosoma mansoni. J Biol Chem 267:14504-8
Webster, P J; Mansour, T E (1992) Conserved classes of homeodomains in Schistosoma mansoni, an early bilateral metazoan. Mech Dev 38:25-32
Webster, P J; Seta, K A; Chung, S C et al. (1992) A cDNA encoding an alpha-tubulin from Schistosoma mansoni. Mol Biochem Parasitol 51:169-70
Mahrenholz, A M; Hefta, S A; Mansour, T E (1991) Phosphofructokinase from Fasciola hepatica: sequence of the cAMP-dependent protein kinase phosphorylation site. Arch Biochem Biophys 288:463-7
Conner, D A; Mansour, T E (1990) Serotonin receptor-mediated activation of adenylate cyclase in the neuroblastoma NCB.20: a novel 5-hydroxytryptamine receptor. Mol Pharmacol 37:742-51
Zurita, M; Bieber, D; Mansour, T E (1989) Identification, expression and in situ hybridization of an eggshell protein gene from Fasciola hepatica. Mol Biochem Parasitol 37:11-7
Mansour, J M; Mansour, T E (1989) Identification of GTP-binding proteins in Fasciola hepatica and Schistosoma mansoni by immunoblotting. Mol Biochem Parasitol 36:11-8

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