Quantum Mechanics/Molecular Mechanics Study of the Reaction Mechanism of Glyoxalase I
(2020) In Inorganic Chemistry 59. p.2594-2603- Abstract
- Glyoxalase I (GlxI) is a member of the glyoxalase
system, which is important in cell detoxification and converts
hemithioacetals of methylglyoxal (a cytotoxic byproduct of sugar
metabolism that may react with DNA or proteins and introduce
nucleic acid strand breaks, elevated mutation frequencies, and
structural or functional changes of the proteins) and glutathione
into D-lactate. GlxI accepts both the S and R enantiomers of
hemithioacetal, but converts them to only the S-D enantiomer of
lactoylglutathione. Interestingly, the enzyme shows this unusual
specificity with a rather symmetric active site (a Zn ion
coordinated to two glutamate residues; Glu-99 and Glu-172),
making the investigation of... (More) - Glyoxalase I (GlxI) is a member of the glyoxalase
system, which is important in cell detoxification and converts
hemithioacetals of methylglyoxal (a cytotoxic byproduct of sugar
metabolism that may react with DNA or proteins and introduce
nucleic acid strand breaks, elevated mutation frequencies, and
structural or functional changes of the proteins) and glutathione
into D-lactate. GlxI accepts both the S and R enantiomers of
hemithioacetal, but converts them to only the S-D enantiomer of
lactoylglutathione. Interestingly, the enzyme shows this unusual
specificity with a rather symmetric active site (a Zn ion
coordinated to two glutamate residues; Glu-99 and Glu-172),
making the investigation of its reaction mechanism challenging.
Herein, we have performed a series of combined quantum
mechanics and molecular mechanics calculations to study the reaction mechanism of GlxI. The substrate can bind to the enzyme in two different modes, depending on the direction of its alcoholic proton (H2; toward Glu-99 or Glu-172). Our results show that the S substrate can react only if H2 is directed toward Glu-99 and the R substrate only if H2 is directed toward Glu-172. In both cases, the reactions lead to the experimentally observed S-D enantiomer of the product. In addition, the results do not show any low- energy paths to the wrong enantiomer of the product from neither the S nor the R substrate. Previous studies have presented several opposing mechanisms for the conversion of R and S enantiomers of the substrate to the correct enantiomer of the product. Our results confirm one of them for the S substrate, but propose a new one for the R substrate. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/5c3343ab-d727-4b55-af6f-7df9f684e8ec
- author
- Jafari, Sonia ; Ryde, Ulf LU ; Fouda, Adam Emad Ahmed ; Alavi, Fatemeh Sadat ; Dong, Geng LU and Irani, Mehdi LU
- organization
- publishing date
- 2020-02-03
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Inorganic Chemistry
- volume
- 59
- pages
- 2594 - 2603
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:32011880
- scopus:85079563430
- ISSN
- 1520-510X
- DOI
- 10.1021/acs.inorgchem.9b03621
- language
- English
- LU publication?
- yes
- id
- 5c3343ab-d727-4b55-af6f-7df9f684e8ec
- date added to LUP
- 2020-09-26 10:20:47
- date last changed
- 2023-04-10 20:36:12
@article{5c3343ab-d727-4b55-af6f-7df9f684e8ec, abstract = {{Glyoxalase I (GlxI) is a member of the glyoxalase<br/>system, which is important in cell detoxification and converts<br/>hemithioacetals of methylglyoxal (a cytotoxic byproduct of sugar<br/>metabolism that may react with DNA or proteins and introduce<br/>nucleic acid strand breaks, elevated mutation frequencies, and<br/>structural or functional changes of the proteins) and glutathione<br/>into D-lactate. GlxI accepts both the S and R enantiomers of<br/>hemithioacetal, but converts them to only the S-D enantiomer of<br/>lactoylglutathione. Interestingly, the enzyme shows this unusual<br/>specificity with a rather symmetric active site (a Zn ion<br/>coordinated to two glutamate residues; Glu-99 and Glu-172),<br/>making the investigation of its reaction mechanism challenging.<br/>Herein, we have performed a series of combined quantum<br/>mechanics and molecular mechanics calculations to study the reaction mechanism of GlxI. The substrate can bind to the enzyme in two different modes, depending on the direction of its alcoholic proton (H2; toward Glu-99 or Glu-172). Our results show that the S substrate can react only if H2 is directed toward Glu-99 and the R substrate only if H2 is directed toward Glu-172. In both cases, the reactions lead to the experimentally observed S-D enantiomer of the product. In addition, the results do not show any low- energy paths to the wrong enantiomer of the product from neither the S nor the R substrate. Previous studies have presented several opposing mechanisms for the conversion of R and S enantiomers of the substrate to the correct enantiomer of the product. Our results confirm one of them for the S substrate, but propose a new one for the R substrate.}}, author = {{Jafari, Sonia and Ryde, Ulf and Fouda, Adam Emad Ahmed and Alavi, Fatemeh Sadat and Dong, Geng and Irani, Mehdi}}, issn = {{1520-510X}}, language = {{eng}}, month = {{02}}, pages = {{2594--2603}}, publisher = {{The American Chemical Society (ACS)}}, series = {{Inorganic Chemistry}}, title = {{Quantum Mechanics/Molecular Mechanics Study of the Reaction Mechanism of Glyoxalase I}}, url = {{https://lup.lub.lu.se/search/files/84188066/261_cq_glxi.pdf}}, doi = {{10.1021/acs.inorgchem.9b03621}}, volume = {{59}}, year = {{2020}}, }