Functional Relevance of Human Pyruvate Kinase-M2 Mutations: PKM2 Mutations from Bloom Syndrome patients - Couverture souple

Gupta, Vibhor; Bamezai, Rameshwar N.K.

 
9783848408962: Functional Relevance of Human Pyruvate Kinase-M2 Mutations: PKM2 Mutations from Bloom Syndrome patients
Couverture souple
ISBN 10 : 3848408961 ISBN 13 : 9783848408962
Editeur : LAP LAMBERT Academic Publishing, 2012

Synopsis

Out of 4 isoforms of Pyruvate kinase; a glycolytic enzyme, M2 is a prototype isoform expressed in embryonic and adult dividing cells. For the first time, we reported two missense mutations in Pyruvate kinase M2 isozyme (H391Y and K422R) from the cells of Bloom syndrome patients, prone to develop cancer. Results showed that despite the presence of mutations in the inter-subunit contact domain, the K422R and H391Y mutant proteins maintained their homotetrameric structure, similar to the wild-type protein, but showed a loss of activity by 75 and 20%, respectively. Interestingly, H391Y showed a 6-fold increase in affinity for its substrate phosphoenolpyruvate and behaved like a non-allosteric protein with compromised cooperative binding. The co-expression of homotetrameric wild type and mutant PKM2 in the cellular milieu resulted in the interaction between the two at the monomer level, which was substantiated further by in vitro experiments. Interestingly, in a unique observation, hetero-oligomeric populations of PKM2 with an altered activity and affinity led to an increased rate of polyploidy i.e genomic instability.

Les informations fournies dans la section « Synopsis » peuvent faire référence à une autre édition de ce titre.

Présentation de l'éditeur

Out of 4 isoforms of Pyruvate kinase; a glycolytic enzyme, M2 is a prototype isoform expressed in embryonic and adult dividing cells. For the first time, we reported two missense mutations in Pyruvate kinase M2 isozyme (H391Y and K422R) from the cells of Bloom syndrome patients, prone to develop cancer. Results showed that despite the presence of mutations in the inter-subunit contact domain, the K422R and H391Y mutant proteins maintained their homotetrameric structure, similar to the wild-type protein, but showed a loss of activity by 75 and 20%, respectively. Interestingly, H391Y showed a 6-fold increase in affinity for its substrate phosphoenolpyruvate and behaved like a non-allosteric protein with compromised cooperative binding. The co-expression of homotetrameric wild type and mutant PKM2 in the cellular milieu resulted in the interaction between the two at the monomer level, which was substantiated further by in vitro experiments. Interestingly, in a unique observation, hetero-oligomeric populations of PKM2 with an altered activity and affinity led to an increased rate of polyploidy i.e genomic instability.

Biographie de l'auteur

Dr. Gupta graduated as a Gold Medalist from Himachal Pradesh University, in year 2005 and joined Jawaharlal Nehru University for his PhD. He was awarded with the degree of doctor of philosophy in year 2010. At the time of publication of this book, he is working as a Postdoctoral fellow in University of Pennsylvania, USA.

Les informations fournies dans la section « A propos du livre » peuvent faire référence à une autre édition de ce titre.

Éditeur
LAP LAMBERT Academic Publishing
Date d'édition
2012
Langue
anglais
ISBN 10 
3848408961
ISBN 13 
9783848408962
Reliure
Broché
Nombre de pages
100
Coordonnées du fabricant
non disponible
Personne responsable
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