Dept. of Biochemistry & Organic Chemistry
Research
Functional genomics and enzymology of glutathione
All cellular processes involve proteins encoded in the genome. The sequencing of a complete genome is just a prerequisite for the understanding of the functions of proteins in biological systems. Our research is focused on the abundant proteins that use glutathione as a substrate or cofactor. Genomic DNA sequences, cDNA, and ESTs will be examined for structures with similarities to known glutathione-linked proteins and analyzed by means of the Structure-Function Data Base developed at UCSF. Coding sequences will be expressed and the purified proteins functionally characterized. Higher eukaryotes harbor ca. 40 putative glutathione transferases (GSTs) genes, but in mammals only ca. 20 genes have so far been studied. GSTs are prominent detoxication enzymes, but also have functions in hormone biosynthesis and cellular signaling pathways. Thus, homologous proteins can be expected to have additional biological roles yet to be discovered. Potential substrates and diverse libraries of chemical probes will be used for catalytic and binding studies of the expressed proteins in order to identify and characterize functional binding sites in novel proteins.
References:
Usama M. Hegazy, Bengt Mannervik and Gun Stenberg (2004) Functional role of the lock and key motif at the subunit interface of glutathione transferase P1-1, J. Biol. Chem. 279, 9586-9596.
Maryam Edalat, Mats A.A. Persson and Bengt Mannervik (2003) Selective recognition of peptide sequences by glutathione transferases: a possible mechanism for modulation of cellular stress-induced signaling pathways, Biol. Chem., 384 , 645-651.
Ylva Ivarsson, Aaron J. Mackey, Maryam Edalat, William R. Pearson and Bengt Mannervik (2003) Identification of residues in glutathione transferase capable of driving functional diversification in evolution - A novel approach to protein redesign, J. Biol. Chem. 278 , 8733-8738.
Ina Hubatsch, Bengt Mannervik, Ling Gao, L. Jackson Roberts, Yan Chen and Jason D. Morrow (2002) The cyclopentenone product of lipid peroxidation, 15-A 2t -isoprostane (8-iso-prostaglandin A 2 ), is efficiently conjugated with glutathione by human and rat glutathione transferase A4-4, Chem. Res. Toxicol. 15 , 1114-1118.
Samantha Lien, Ann Gustafsson, Anna-Karin Andersson and Bengt Mannervik (2001) Human glutathione transferase A1-1 demonstrates both half-of-the-sites and all-of-the-sites reactivity, J. Biol. Chem. 276 , 35599-35605.