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PDBsum entry 6rv0
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References listed in PDB file
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Key reference
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Title
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Cycloserine enantiomers are reversible inhibitors of human alanine:glyoxylate aminotransferase: implications for primary hyperoxaluria type 1.
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Authors
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M.Dindo,
S.Grottelli,
G.Annunziato,
G.Giardina,
M.Pieroni,
G.Pampalone,
A.Faccini,
F.Cutruzzolà,
P.Laurino,
G.Costantino,
B.Cellini.
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Ref.
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Biochem J, 2019,
476,
3751-3768.
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PubMed id
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Abstract
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Peroxisomal alanine:glyoxylate aminotransferase (AGT) is responsible for
glyoxylate detoxification in human liver and utilizes pyridoxal 5'-phosphate
(PLP) as coenzyme. The deficit of AGT leads to Primary Hyperoxaluria Type I
(PH1), a rare disease characterized by calcium oxalate stones deposition in the
urinary tract as a consequence of glyoxylate accumulation. Most missense
mutations cause AGT misfolding, as in the case of the G41R, which induces
aggregation and proteolytic degradation. We have investigated the interaction of
wild-type AGT and the pathogenic G41R variant with d-cycloserine (DCS,
commercialized as Seromycin), a natural product used as a second-line treatment
of multidrug-resistant tuberculosis, and its synthetic enantiomer l-cycloserine
(LCS). In contrast with evidences previously reported on other PLP-enzymes, both
ligands are AGT reversible inhibitors showing inhibition constants in the
micromolar range. While LCS undergoes half-transamination generating a ketimine
intermediate and behaves as a classical competitive inhibitor, DCS displays a
time-dependent binding mainly generating an oxime intermediate. Using a
mammalian cellular model, we found that DCS, but not LCS, is able to promote the
correct folding of the G41R variant, as revealed by its increased specific
activity and expression as a soluble protein. This effect also translates into
an increased glyoxylate detoxification ability of cells expressing the variant
upon treatment with DCS. Overall, our findings establish that DCS could play a
role as pharmacological chaperone, thus suggesting a new line of intervention
against PH1 based on a drug repositioning approach. To a widest extent, this
strategy could be applied to other disease-causing mutations leading to AGT
misfolding.
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