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Structural determination of the kidney type glutaminase and the search for its binding partners

Grant number: 10/05987-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2010
Effective date (End): August 31, 2012
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Sandra Martha Gomes Dias
Grantee:Alexandre Cassago
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil
Associated research grant:09/10875-9 - Cellular and biochemical studies of the glutaminase enzyme and its relation with cancer, AP.JP

Abstract

Besides aerobic glycolysis, the increased levels in glutamine comsuption is also a hallmark exhibited in tumors and both phenomena are required in order to maintain its highly proliferative phenotype. With recent publications showing that previously known oncogenes also regulate these metabolic pathways, we anticipate that the better understanding of both structural organization and mechanisms of activation and inhibition of key-proteins underlying the nowadays called metabolic adaptation has the potential to generate high-value therapeutic options for cancer treatment in the future. Of special interest on the glutaminolysis branch of the metabolic adaptation process is the Kidney-type glutaminase (KGA). In mammals, KGA is one of the three known isozymes of the glutaminases, the other two being Glutaminase C (GAC) and LGA (Liver-type Glutaminase). They have been described as mitochondrial enzymes, with their individual prevalences being highly dependent on the tissue studied. Besides a well-know catalytic core, these enzymes are predicted to have different domains that mediate protein:protein interactions. KGA presents ankyrin repeats and, more importantly, two consensus sequences found only in nuclear receptor co-regulator proteins. Moreover, KGA is likely the enzyme of choice in quiescent cells and understanding its regulation modes and binding partners can give us clues on how the metabolic adaptation process happens, culminating with an increase on the cell`s glutaminolytic capability. The goals of this project is to determine the crystallographic structure of KGA, conduct biochemical studies to understand its regulation by phosphate and glutamate and search for binding partners by co-immunoprecipitation and pull-down assays. Further functional characterization of such complexes can be conduct provided that time will be available.

Scientific publications
(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)
SCOTA FERREIRA, AMANDA PETRINA; CASSAGO, ALEXANDRE; GONCALVES, KALIANDRA DE ALMEIDA; DIAS, MARILIA MEIRA; ADAMOSKI, DOUGLAS; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; HONORATO, RODRIGO VARGAS; DE OLIVEIRA, JULIANA FERREIRA; FERREIRA, IGOR MONTEZE; FORNEZARI, CAMILA; BETTINI, JEFFERSON; LOPES OLIVEIRA, PAULO SERGIO; PAES LEME, ADRIANA FRANCO; PORTUGAL, RODRIGO VILLARES; BERTELI AMBROSIO, ANDRE LUIS; GOMES DIAS, SANDRA MARTHA. Active Glutaminase C Self-assembles into a Supratetrameric Oligomer That Can Be Disrupted by an Allosteric Inhibitor. Journal of Biological Chemistry, v. 288, n. 39, p. 28009-28020, SEP 27 2013. Web of Science Citations: 30.
CASSAGO, ALEXANDRE; FERREIRA, AMANDA P. S.; FERREIRA, IGOR M.; FORNEZARI, CAMILA; GOMES, EMERSON R. M.; GREENE, KAI SU; PEREIRA, HUMBERTO M.; GARRATT, RICHARD C.; DIAS, SANDRA M. G.; AMBROSIO, ANDRE L. B. Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 109, n. 4, p. 1092-1097, JAN 24 2012. Web of Science Citations: 108.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.