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112 | 2013
Annuaire du Collège de France 2011-2012
Résumé des cours et travaux 112e année
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Glutathione transferases, detoxication, cancer and longevity

Résumé des conférences du Collège de France (2011-2012)
Bengt Mannervik
p. 853-854

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Lecture 1: Glutathione transferases, detoxication, cancer and longevity

1Glutathione transferases (GSTs) were discovered 50 years ago as enzymes capable of conjugating electrophilic organic substances with the thiol group of glutathione. Early on GSTs were identified as prominent detoxication enzymes that protect cells against mutagens and carcinogens. Our research established that products of lipid peroxidation and other oxidative processes are natural substrates of the enzymes. In humans GST A4-4 and GST M2-2 appear to have evolved specifically for inactivation of 4-hydroxynonenal and ortho-quinones of catecholamines, respectively, as evidenced by their distinctive high activities with the substrates. It would appear that GSTs counter the effects of oxidative stress associated with numerous degenerative conditions such as Parkinson and Alzheimer disease, cataract, atherosclerosis, diabetes, and cancer. In tumor cells GSTs can cause resistance against alkylating anti-cancer drugs. Engineered GSTs with enhanced activity against cytostatic drugs may find medical applications in gene therapy and in the activation of prodrugs. Long-lived strains of eukaryotes are characterized by overexpression of a subset of GSTs. It is possible that longevity of humans is also correlated with the expression of certain GSTs and that pharmacological interventions may influence health and life-span by enhanced detoxication capacity of toxic compounds occurring in tissues.

Lecture 2: Tiselius – pioneer in separation science and the first professor of biochemistry in Sweden

2Arne Tiselius was recruited as an assistant to Prof. Theodor (The) Svedberg at Uppsala University in 1926. Svedberg was engaged in studies on colloidal particles and their sedimentation in a field of gravity, which led to the design of the ultra-centrifuge. Tiselius’ assignment was to study colloidal particles in a field of electricity, which led to the development of electrophoresis. This was the subject of his PhD thesis (1930). After obtaining his degree Tiselius became interested in adsorption phenomena, and following a period of research at Princeton University Tiselius engaged in studies of zeolites. Tiselius had no permanent employment but by Svedberg’ initiative Karin and Herbert Jacobsson made a donation to Uppsala University in order to create a professorship for Tiselius. In 1938 Tiselius was appointed to the Chair of Biochemistry at Uppsala University endowed by the Jacobsson’s. This was the first professorship in biochemistry in Sweden. Tiselius improved the electrophoresis technique and demonstrated that the human serum contained several separable components in the globulin fraction. These studies led to the Nobel Prize in chemistry in 1948. A building was created for the new Institute of Biochemistry and the discipline of biochemistry flourished. Several of Tiselius’ students continued the development of biochemical separation techniques involving electrophoresis and various chromatographic techniques. This led to the formation of several companies manufacturing equipment for biochemical applications that became used world wide. In addition, research on aspects of biochemistry other than separation science was initiated in the department. Examples include enzymology, microbiology, nucleic acid chemistry, polymer science, and peptide synthesis.

Lecture 3: Molecular quasi-species in evolution applied to the engineering of promiscuous glutathione transferases

3Glutathione transferases (GSTs) provide an excellent platform for investigations of redesign of proteins for novel functions. In Nature higher eukaryotes display numerous active genes. Humans have up to 17 different genes, Drosophila melanogaster 37, and poplars have 81. Sequence homologies indicate that the genes have divergently evolved from a common ancestor. The significance of the multiple forms is that they shared different substrate selectivities, even though some of them display overlapping activities. Evidently, the redesign of a given enzyme can give rise to multiple variants with different activities. Our laboratory has demonstrated that mutations of a small number of amino acid residues by protein engineering can give rise to GSTs that have gained novel catalytic properties. The stochastic approach of generating mutant libraries by shuffling of DNA encoding different GSTs has also given rise to large numbers of catalytically competent GSTs. In some instances the mutants form clusters of functionally related variants similar to isoenzymes of an extant GST. In other cases clusters display functional properties that distinguish them significantly from the parental forms. We have adopted the notion of quasi-species to designate such clusters and we propose that a cluster should be subjected to directed evolution rather than the single most active variant.

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Cours et travaux du Collège de France. Annuaire 112e année, Collège de France, Paris, avril 2013, p. 853-854. ISBN 978-2-7226-0198-7

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Bengt Mannervik, « Glutathione transferases, detoxication, cancer and longevity », L’annuaire du Collège de France [En ligne], 112 | 2013, mis en ligne le 28 août 2013, consulté le 23 février 2018. URL : http://journals.openedition.org/annuaire-cdf/1128

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Auteur

Bengt Mannervik

Professeur à l’université d’Uppsala (Suède)

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Droits d’auteur

Collège de France

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