Xanthurenic Acid Provokes Formation of Unfolded Proteins in Endoplasmic Reticulum of the Lens Epithelial Cells

doi:10.1006/bbrc.1999.1716

Biochemical and Biophysical Research Communications

Volume 265, Issue 2, 19 November 1999, Pages 600-605

https://doi.org/10.1006/bbrc.1999.1716 Get rights and content

Abstract

The role of xanthurenic acid in a cell is unknown, but it is suspected to provoke several diseases. This study shows that accumulation of xanthurenic acid in the lens epithelial cells leads to an overexpression of endoplasmic reticulum (ER) resident stress chaperones proteins, glucose-regulated protein (Grp94), and calreticulin. Both chaperones proteins are overexpressed in the presence of unfolded proteins. A formation of the unfolded protein in the presence of xanthurenic acid may take place due to covalent binding of xanthurenic acid to protein. Grp94 is responsible for scavenging of the unfolded proteins. The results suggest that Grp94 scavenged xanthurenic acid-modified proteins, and for this reason become preferentially yellow-stained in the presence of yellow xanthurenic acid. Such a modified Grp94 is weakly recognized by anti-Grp94 antibody. An end point of the xanthurenic acid accumulation in the cell is the cell death. In conclusion xanthurenic acid can lead to cell pathology.

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Cited by (19)

Synthesis and structures of nickel(II) complexes with xanthurenate ions
2016, Inorganica Chimica Acta
Citation Excerpt :
It is a tryptophan metabolite whose presence was observed in the urine of humans, monkeys and rats in the case of vitamin B6 deficiency [2,3]. Although little is known of the role of xanthurenic acid in the cell, several studies reported the acid to be toxic [4]. Among other, it forms a complex with insulin and damages pancreatic β cells [5,6].
The reaction of nickel(II) chloride with xanthurenic acid afforded two crystalline products, [Ni(HXan)₂(H₂O)₄]·6H₂O (1) and [Ni₃(Xan)₂(H₂O)₁₀][Ni(Xan)₂]·4{(CH₃)₂CO}·2H₂O (2), with HXan⁻ and Xan²⁻ standing for the deprotonated forms of the acid. Both compounds were unambiguously characterized by means of X-ray structure analysis. Their solid state structures give evidence of a presence of different xanthurenate ions and their tautomeric forms in the solution. Compound 1 is a mononuclear nickel(II) complex with metal ion in a nearly octahedral environment of six ligands: four aqua ligands and two trans positioned HXan⁻ ions, each coordinated in a monodentate manner via a carboxylate oxygen. Compound 2 consists of trinuclear complex cations [Ni₃(Xan)₂(H₂O)₁₀]²⁺ and mononuclear complex anions [Ni(Xan)₂]²⁻. The Xan²⁻ ions of the complex ions in 2 are not the same, they differ in the position of the ionized hydroxyl moiety. With both compounds possessing several hydrogen bond donors and acceptors, intricate patterns of intramolecular connectivity may be observed in their solid state structures.
Photoactivity of kynurenine-derived UV filters
2008, Journal of Photochemistry and Photobiology B: Biology
Quantum yields of photodecomposition and triplet state formation under aerobic and anaerobic conditions are determined for kynurenine (KN), 3-hydroxykynurenine (3OHKN), xanthurenic acid (XAN), and kynurenine adducts of glutathione (GSH-KN), cysteine (Cys-KN), histidine (His-KN), and lysine (Lys-KN) in aqueous solutions. The highest yields of anaerobic photodecomposition were obtained for GSH-KN and His-KN adducts, which correlates with the highest triplet yields for these compounds. In aerobic conditions, the photodecomposition yields for all compounds under study increase; the highest decomposition rates were observed for His-KN and 3OHKN. The fast decomposition of the latter is attributed to the dark autoxidation of the starting compound.
Cataract: Window for systemic disorders
2007, Medical Hypotheses
Cataract is the leading cause of visual handicap throughout the world, and almost all elderly individuals develop lens opacities. Epidemiological studies have shown that nuclear cataracts in young adults are associated with higher mortality. Many cataractogenic stressors induce endoplasmic reticulum (ER) stress, which in turn induces the unfolded protein response (UPR). The UPR can damage or kill a wide range of cell types and may be involved in many human diseases. We hypothesize that a cataract can be considered a window that can indicate the presence of systemic disorders. This is important because cataract is easily detected during a routine ocular examination. The slightest opacity in any region of the lenses, especially in younger patients, may be a sign of systemic disorders. Earlier detection of systemic disorders can save the lives of patients. If our hypothesis is correct, then elimination of known ER/cataractogenic stressors from individuals with cataracts should be the one of the first steps for treatments of the systemic disorders. We discuss the potential risk factors and beneficial effects of removal of such risk factors in patients with early cataracts. All patients with cataract should be referred for comprehensive medical examination.
Photochemical and thermal reactivity of kynurenine
2006, Experimental Eye Research
Citation Excerpt :
Alternatively, xanthurenic acid can be produced via enzymatic transamination of kynurenines (Malina and Martin, 1995, 1996). It has been shown that xanthurenic acid promotes the photooxidation of lens proteins (Malina, 1999; Roberts et al., 2001). However, until recently no concrete evidence for the presence of xanthurenic acid in normal human lenses has been found (Hains et al., 2003).
The thermal and photochemical reactivity of kynurenine (KN), a tryptophan metabolite found in human lenses, has been studied in aqueous solution. The decarboxylation reaction of KN, resulting in the formation of 4-hydroxyquinoline, is reported for the first time. Rate constants for KN deamination and decarboxylation were determined in the temperature range 50–90 °C. The quantum yields for KN photodecomposition under argon were measured to be Φ_Ar = (2.0 ± 0.2) × 10⁻⁵ and under oxygen Φ_O2 = (1.1 ± 0.1) × 10⁻⁴.
Comment on 'The photosensitiser xanthurenic acid is not present in normal human lenses' by P.G. Hains et al. [Exp. Eye Res. 77 (2003) 547-553] (multiple letters)
2004, Experimental Eye Research
Abnormal signalling of 14-3-3 proteins in cells with accumulated xanthurenic acid
2003, Biochemical and Biophysical Research Communications
Citation Excerpt :
Xanthurenic acid accumulation with aging is observed in senile cataract development [2]. Previously, we have reported that xanthurenic acid unfolds proteins [3] and induces apoptosis-like cell-death associated with caspase-9 and caspase-3 activation [4]. Here we report that the signalling proteins 14-3-3, which regulate more than 100 proteins [5], are targeted by xanthurenic acid into lysosomes.
Xanthurenic acid is an endogenous molecule leading to caspase-9 and -3 activation. Here we report that xanthurenic acid targets signalling proteins 14-3-3 into lysosomes leading to interruption protein/protein interaction. Xanthurenic acid changed the localisation of 14-3-3 in the cells. At a concentration of 10 and 20 μM the 14-3-3 was translocated into lysosomes. At these concentrations Bad and cofilin were dephosphorylated. Translocation of dephosphorylated Bad into mitochondria and cytochrome c release were observed. Cofilin dephosphorylation in the presence of xanthurenic acid was associated with lack of the apoptotic actin cytoskeleton disintegration. In conclusion xanthurenic acid accumulation in cells abolished the regulatory function of the proteins 14-3-3 in the cell physiology and caused misfolding of the proteins leading to cell pathology.

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^☆: Abbreviations used: Grp, glucose regulated protein; ER, endoplasmic reticulum; FCS, fetal calf serum; MEM, minimal essential medium; NAD, nicotinamide adenine dinucleotide; PMSF, phenylmethylsulfonyl fluoride; SDS, sodium dodecyl sulfate; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate saline buffer.

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Regular ArticleXanthurenic Acid Provokes Formation of Unfolded Proteins in Endoplasmic Reticulum of the Lens Epithelial Cells☆

Abstract

Am. J. Clin. Nutr.

Clin. Chim. Acta

Methods Enzymol.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Gazetta Chimica Italiana

Cancer Res.

Rheumatol. Rehabil.

Acta Vitaminol. Enzymol.

Graefes Arch. Clin. Exp. Ophthalmol.

Eur. J. Ophthalmol.

J. Lab. Clin. Med.

Regular Article
Xanthurenic Acid Provokes Formation of Unfolded Proteins in Endoplasmic Reticulum of the Lens Epithelial Cells☆