Abstract：
:Human galactokinase (GALK) is the first enzyme in the Leloir pathway, converting α-d-galactose into galactose-1-phosphate (Gal-1-P). Recently, there is increasing interest in targeting GALK as a novel therapy to ameliorate the disease manifestations in patients with Classic Galactosemia as it would, in combination with (ga-)lactose restriction reduce accumulation of Gal-1-P, a cytotoxic agent. Previously, we identified 34 small molecule compounds that inhibited GALK in vitro using experimental high-throughput screening. In order to isolate useful lead compounds, we characterized these hits with regards to their kinase selectivity profiles, potency and capability to reduce Gal-1-P accumulation in patient cell lines, and their modes of action. We found that the majority of these compounds had IC(50)s ranging from 0.7μM to 33.3μM. When tested against other members of the GHMP kinase family, three compounds (1, 4, and 24) selectively inhibited GALK with high potency. Through alignment of GALK and mevalonate kinase (MVK) crystal structures, we identified that eight amino acid residues and an L1 loop were different within the ATP-binding pockets of these two closely related kinases. By site-directed mutagenesis experiments, we identified one amino acid residue required for the inhibitory function of two of the three selective compounds. Based on these results, we generated binding models of these two compounds using a high-precision docking program. Compounds 4 and 24 inhibited GALK in a mixed model, while compound 1 exhibited parabolic competitive inhibition. Most importantly, using cells from galactosemic patients we found that selected compounds lowered Gal-1-P concentrations.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Tang M,Wierenga K,Elsas LJ,Lai Kdoi
10.1016/j.cbi.2010.07.025subject
Has Abstractpub_date
2010-12-05 00:00:00pages
376-85issue
3eissn
0009-2797issn
1872-7786pii
S0009-2797(10)00482-5journal_volume
188pub_type
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journal_title：Chemico-biological interactions
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journal_title：Chemico-biological interactions
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journal_title：Chemico-biological interactions
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journal_title：Chemico-biological interactions
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journal_title：Chemico-biological interactions
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journal_title：Chemico-biological interactions
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journal_title：Chemico-biological interactions
pub_type： 杂志文章,评审
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journal_title：Chemico-biological interactions
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journal_title：Chemico-biological interactions
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更新日期：2017-10-01 00:00:00
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pub_type： 杂志文章
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
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abstract：:The hydrolysis of paraoxon (POX), phenylacetate (PA) and beta-naphthylacetate (BNA) was studied in human serum. Based upon correlations between enzyme activities, upon reversible inhibition by EDTA and upon progressive inhibition by iso-OMPA, tabun, eserine and bis-4 nitrophenylphosphate, the following conclusions wer...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
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更新日期：1993-06-01 00:00:00
