2C21

Specificity of the Trypanothione-dependednt Leishmania major Glyoxalase I: Structure and biochemical comparison with the human enzyme

Summary for 2C21

• Entry DOI: 10.2210/pdb2c21/pdb
• Descriptor: TRYPANOTHIONE-DEPENDENT GLYOXALASE I, NICKEL (II) ION, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (6 entities in total)
• Functional Keywords: glyoxalase i, lyase, leishmania major, trypanothione, glutathionylspermidine, methylglyoxal, detoxification
• Biological source: LEISHMANIA MAJOR
• Total number of polymer chains: 6
• Total formula weight: 101074.91

Authors

Ariza, A.,Vickers, T.J.,Greig, N.,Armour, K.A.,Eggleston, I.M.,Fairlamb, A.H.,Bond, C.S. (deposition date: 2005-09-23, release date: 2006-02-01, Last modification date: 2023-12-13)

Primary citation

Ariza, A.,Vickers, T.J.,Greig, N.,Armour, K.A.,Dixon, M.J.,Eggleston, I.M.,Fairlamb, A.H.,Bond, C.S.
Specificity of the Trypanothione-Dependent Leishmania Major Glyoxalase I: Structure and Biochemical Comparison with the Human Enzyme.
Mol.Microbiol., 59:1239-, 2006

PubMed Abstract: Trypanothione replaces glutathione in defence against cellular damage caused by oxidants, xenobiotics and methylglyoxal in the trypanosomatid parasites, which cause trypanosomiasis and leishmaniasis. In Leishmania major, the first step in methylglyoxal detoxification is performed by a trypanothione-dependent glyoxalase I (GLO1) containing a nickel cofactor; all other characterized eukaryotic glyoxalases use zinc. In kinetic studies L. major and human enzymes were active with methylglyoxal derivatives of several thiols, but showed opposite substrate selectivities: N1-glutathionylspermidine hemithioacetal is 40-fold better with L. major GLO1, whereas glutathione hemithioacetal is 300-fold better with human GLO1. Similarly, S-4-bromobenzylglutathionylspermidine is a 24-fold more potent linear competitive inhibitor of L. major than human GLO1 (Kis of 0.54 microM and 12.6 microM, respectively), whereas S-4-bromobenzylglutathione is >4000-fold more active against human than L. major GLO1 (Kis of 0.13 microM and >500 microM respectively). The crystal structure of L. major GLO1 reveals differences in active site architecture to both human GLO1 and the nickel-dependent Escherichia coli GLO1, including increased negative charge and hydrophobic character and truncation of a loop that may regulate catalysis in the human enzyme. These differences correlate with the differential binding of glutathione and trypanothione-based substrates, and thus offer a route to the rational design of L. major-specific GLO1 inhibitors.

PubMed: 16430697
DOI: 10.1111/J.1365-2958.2006.05022.X

Experimental method

X-RAY DIFFRACTION (2 Å)