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Mechanisms of saccharopine pathway induction in human cells

Grant number: 12/00235-5
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): March 01, 2012
Effective date (End): June 30, 2015
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Paulo Arruda
Grantee:Izabella Agostinho Pena
Host Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated scholarship(s):13/12271-9 - Expression, purification and structural characterization of human lysine-ketoglutarate reductase/Saccharopine dehydrogenase (LKR/SDH), BE.EP.DD


Saccharopine pathway of lysine degradation is being studied for many decades in a great variety of organisms and there has been convincing evidences that link this pathway to cellular responses to stress conditions. In plants and mammals, superexpression of Saccharopine pathway genes provided protection against osmotic and oxidative stress. In plants there is a significant increase in expression of the pathway genes in several stress conditions. In mammals, the inducibility of this pathway under stress conditions still has not been tested, and the molecular mechanisms that regulate the expression of the Saccharopine pathway were not explored until now. Cellular stresses like oxidative stress are in focus in many research areas and there are many evidences that correlate stresses as causes of many high-prevalence diseases such as cancer, arteriosclerosis, obesity, Alzheimer's and other neurodegenerative diseases. If Saccharopine pathway is really linked to cellular stress responses, and if their induction mechanisms are deciphered, this knowledge can be very useful not only in basic research and understanding of this pathway physiology but also in therapeutic purposes, to create new stress response-modulating methods. This research project aims to decipher the mechanisms which regulate the induction of Saccharopine pathway and also their relation to stress. Complementarily, this project aims to find the putative transcription factors and/or inducer molecules that act on this way. Bioinformatics and experimental procedures using human cell cultures (HEK293 cells) will be used to this project development. Additionally, the study of this pathway in human cells will complement the studies which are being realized in plants and bacteria, enabling a general concept concerning the saccharopine pathway modulation mechanisms in different biological models. (AU)

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Scientific publications (8)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
BARRETO, PEDRO; OKURA, VAGNER; PENA, IZABELLA A.; MAIA, RENATO; MAIA, IVAN G.; ARRUDA, PAULO. Overexpression of mitochondrial uncoupling protein 1 (UCP1) induces a hypoxic response in Nicotiana tabacum leaves. Journal of Experimental Botany, v. 67, n. 1, p. 301-313, . (12/00235-5, 14/17634-5, 14/24183-0)
KIYOTA, EDUARDO; PENA, IZABELLA AGOSTINHO; ARRUDA, PAULO. The saccharopine pathway in seed development and stress response of maize. PLANT CELL AND ENVIRONMENT, v. 38, n. 11, p. 2450-2461, . (12/00235-5, 10/50114-4)
NESHICH, IZABELLA A. P.; KIYOTA, EDUARDO; ARRUDA, PAULO. Genome-wide analysis of lysine catabolism in bacteria reveals new connections with osmotic stress resistance. ISME Journal, v. 7, n. 12, p. 2400-2410, . (12/00235-5, 10/50114-4)
PENA, IZABELLA AGOSTINHO; MARQUES, LYGIA AZEVEDO; LARANJEIRA, ANGELO B. A.; YUNES, JOSE A.; EBERLIN, MARCOS N.; MACKENZIE, ALEX; ARRUDA, PAULO. Mouse lysine catabolism to aminoadipate occurs primarily through the saccharopine pathway; implications for pyridoxine dependent epilepsy (PDE). BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1863, n. 1, p. 121-128, . (13/23920-8, 10/50114-4, 12/00235-5)
ARRUDA, PAULO; NESHICH, IZABELLA PENA. Nutritional-rich and stress-tolerant crops by saccharopine pathway manipulation. FOOD AND ENERGY SECURITY, v. 1, n. 2, p. 141-147, . (12/00235-5, 10/50114-4)
PENA, IZABELLA A.; MARQUES, LYGIA A.; LARANJEIRA, ANGELO B. A.; YUNES, JOSE A.; EBERLIN, MARCOS N.; ARRUDA, PAULO. Simultaneous detection of lysine metabolites by a single LC-MS/MS method: monitoring lysine degradation in mouse plasma. SPRINGERPLUS, v. 5, . (13/23920-8, 10/50114-4, 12/00235-5)
BARRETO, PEDRO; OKURA, VAGNER KATSUMI; PENA NESHICH, IZABELLA AGOSTINHO; MAIA, IVAN DE GODOY; ARRUDA, PAULO. Overexpression of UCP1 in tobacco induces mitochondrial biogenesis and amplifies a broad stress response. BMC PLANT BIOLOGY, v. 14, . (12/00235-5, 12/00126-1)
DIAS-LOPES, CAMILA; NESHICH, IZABELLA A. P.; NESHICH, GORAN; ORTEGA, JOSE MIGUEL; GRANIER, CLAUDE; CHAVEZ-OLORTEGUI, CARLOS; MOLINA, FRANCK; FELICORI, LIZA. Identification of New Sphingomyelinases D in Pathogenic Fungi and Other Pathogenic Organisms. PLoS One, v. 8, n. 11, . (12/00235-5, 09/16376-4)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
PENA, Izabella Agostinho. Aminoadipato-semialdeído sintase (AASS) como um novo alvo terapêutico para epilepsia dependente de piridoxina. 2015. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.

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