XDH gene mutation is the underlying cause of classical xanthinuria: A second report

Levartovsky, David; Lagziel, Ayala; Sperling, Oded; Liberman, Uri; Yaron, Michael; Hosoya, Tatsuo; Ichida, Kimiyoshi; Peretz, Hava

doi:10.1046/j.1523-1755.2000.00082.x

Cited by 50 publications

(42 citation statements)

References 21 publications

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“…The iron K near-edge spectra (not illustrated) are typical of a [Fe 2 S 2 ] 2ϩ cluster and are essentially superimposable with the spectra of bovine XO and with 2Fe ferredoxins. 3 Molybdenum K-edge and Tungsten L III -edge X-ray Absorption Spectroscopy-In order to compare the active sites of the molybdenum-and tungsten-substituted enzymes, we measured the molybdenum K and tungsten L III -edge EXAFS spectra of samples of these forms of the enzyme. Fig.…”

Section: Investigation Of the Fe/s Clusters Of R Capsulatus Xdh Usinmentioning

confidence: 99%

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Recombinant Rhodobacter capsulatus Xanthine Dehydrogenase, a Useful Model System for the Characterization of Protein Variants Leading to Xanthinuria I in Humans

Leimkühler

Hodson

George

et al. 2003

Journal of Biological Chemistry

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Rhodobacter capsulatus xanthine dehydrogenase (XDH) forms an (␣␤) 2 heterotetramer and is highly homologous to homodimeric eukaryotic XDHs. The crystal structures of bovine XDH and R. capsulatus XDH showed that the two proteins have highly similar folds. We have developed an efficient system for the recombinant expression of R. capsulatus XDH in Escherichia coli. The recombinant protein shows spectral features and a range of substrate specificities similar to bovine milk xanthine oxidase. However, R. capsulatus XDH is at least 5 times more active than bovine XDH and, unlike mammalian XDH, does not undergo the conversion to the oxidase form. EPR spectra were obtained for the FeS centers of the enzyme showing an axial signal for FeSI, which is different from that reported for xanthine oxidase. X-ray absorption spectroscopy at the iron and molybdenum K-edge and the tungsten L III -edge have been used to probe the different metal coordinations of variant forms of the enzyme. Based on a mutation identified in a patient suffering from xanthinuria I, the corresponding arginine 135 was substituted to a cysteine in R. capsulatus XDH, and the protein variant was purified and characterized. Two different forms of XDH-R135C were purified, an active (␣␤) 2 heterotetrameric form and an inactive (␣␤) heterodimeric form. The active form contains a full complement of redox centers, whereas in the inactive form the FeSI center is likely to be missing.Xanthine dehydrogenase/oxidase (XDH 1 /XO) is a complex metallo-flavoprotein catalyzing the oxidative hydroxylation of purines, pyrimidines, pterines, and aldehyde substrates using NAD ϩ or molecular oxygen as electron acceptor. Mammalian XDH (EC 1.1.1.204) is a homodimer (290 kDa), with each subunit containing a single molybdenum cofactor (Moco) as well as two iron-sulfur clusters and an FAD molecule. Inherited XDH deficiency, referred to as xanthinuria I, is an autosomal recessive disease that is characterized by hyperuricemia, hyperuricosuria, and xanthinuria and is based on base pair exchanges in the structural gene for XDH (1). The affected individuals may develop urinary tract calculi, acute renal failure, or myositis, because of tissue deposition of xanthine, although some subjects with homozygous xanthinuria remain asymptomatic (1). Several mutations in the human XDH gene in patients with classical xanthinuria have been reported (2-4).In their native form, mammalian xanthine oxidizing enzymes exist as dehydrogenases that transfer electrons to NAD but can undergo a dehydrogenase to oxidase conversion by proteolytic cleavage or by oxidation, with the concomitant loss of the ability to use NAD ϩ as electron acceptor, and nearly 10-fold increase in the oxidase activity. The crystal structures of bovine milk XDH in both the dehydrogenase and oxidase forms have been solved at 2.1 and 2.5 Å resolution, respectively (5). It was shown that during the conversion of XDH to XO, a specific structural rearrangement blocks access of NAD ϩ to its binding site near the FAD moiety and changes ...

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Section: Investigation Of the Fe/s Clusters Of R Capsulatus Xdh Usinmentioning

confidence: 99%

“…The affected individuals may develop urinary tract calculi, acute renal failure, or myositis, because of tissue deposition of xanthine, although some subjects with homozygous xanthinuria remain asymptomatic (1). Several mutations in the human XDH gene in patients with classical xanthinuria have been reported (2)(3)(4).…”

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confidence: 99%

Recombinant Rhodobacter capsulatus Xanthine Dehydrogenase, a Useful Model System for the Characterization of Protein Variants Leading to Xanthinuria I in Humans

Leimkühler

Hodson

George

et al. 2003

Journal of Biological Chemistry

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“…Xanthinuria types I and II are secondary to an autosomal recessive defect in purine metabolism, resulting in increased total body levels xanthine and subsequent xanthing stones [86,87]. In xanthinuria type I, there is a deficiency of the enzyme xanthine dehydrogenase (XDH) which normally converts both hypoxanthine to xanthine, and xanthine to uric acid.…”

Section: Xanthinuriamentioning

confidence: 99%

Animal models of urinary stone disease

Tzou

Taguchi

Chi

et al. 2016

International Journal of Surgery

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h i g h l i g h t sMultiple methods induce animal hyperoxaluria and calcium oxalate crystal formation. Knockout mice models have been shown to produce hypercalciuria and cystinuria. Drosophila melanogaster represents a powerful genetic model for stone disease. a r t i c l e i n f o a b s t r a c tThe etiology of stone disease remains unknown despite the major technological advances in the treatment of urinary calculi. Clinically, urologists have relied on 24-h urine collections for the last 30e40 years to help direct medical therapy in hopes of reducing stone recurrence; yet little progress has been made in preventing stone disease. As such, there is an urgent need to develop reliable animal models to study the pathogenesis of stone formation and to assess novel interventions. A variety of vertebrate and invertebrate models have been used to help understand stone pathogenesis. Genetic knockout and exogenous induction models are described. Surrogates for an endpoint of stone formation have been urinary crystals on histologic examination and/or urinalyses. Other models are able to actually develop true stones. It is through these animal models that real breakthroughs in the management of urinary stone disease will become a reality.

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“…Ksantin taşları, infantil dönem de dahil her yaşta görülebilir [1]. Bu hastalık oldukça nadir görülmekle birlikte insidansı 1:6,000 ile 1:69,000 arasında değişmektedir [2].…”

Section: Introductionunclassified

“…Herediter ksantinürinin bu iki tipi dışında tanımlanan diğer bir klinik antite, ksantin dehidrogenaz, aldehid oksidaz ve sülfid oksidaz enzim eksikliğidir. Molibden kofaktörün konjenital eksikliği nedeni ile oluşan bu tip hastalarda, yenidoğan döneminde başlayan nöbet, ciddi nörolojik bulgular ve dismorfik özellikler görü-lebilir [2,3].…”

Section: Introductionunclassified

Hypoxanthine urolithiasis in an 11-month-old child: A case report of

Elmacı¹,

Akın²

2014

J Clin Exp Invest

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Hereditary xanthinuria is a novel autosomal recessive disorder of purine metabolism resulting from the deficiency of xanthine dehydrogenase. An 11-month-old boy admitted with the complaints of irritability for 6 months, darkening of the urine and spontaneous passage of stone. Both serum and urine levels of uric acid were below normal. Urinary ultrasonography was normal. Stone analysis revealed that it was a hypoxanthine stone. The case is reported because hereditary xanthinuria is a rare cause of childhood urolithiasis. J Clin Exp Invest 2014; 5 (1): 128-130 Key words: Hypoxanthinuria; urolithiasis; infancy ÖZETHerediter ksantinüri, doğuştan ksantin dehidrogenaz enzim eksikliğinin neden olduğu, nadir görülen, otozomal resesif geçişli, pürin metabolizma bozukluğudur. Yaklaşık 6 aydır huzursuzluk, idrar renginde koyulaşma ve taş düşürme şikayeti ile getirilen 11 aylık erkek hastanın serum ve idrar ürik asit düzeyleri normalden düşüktü. Üriner ultrasonografisi normal olan hastanın taş analiz sonucu, hipoksantin taşı olarak rapor edildi. Herediter ksantinüri, çocukluk çağı böbrek taşı hastalığının nadir bir sebebi olduğu için bu vaka sunulmuştur.

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XDH gene mutation is the underlying cause of classical xanthinuria: A second report

Cited by 50 publications

References 21 publications

Recombinant Rhodobacter capsulatus Xanthine Dehydrogenase, a Useful Model System for the Characterization of Protein Variants Leading to Xanthinuria I in Humans

Recombinant Rhodobacter capsulatus Xanthine Dehydrogenase, a Useful Model System for the Characterization of Protein Variants Leading to Xanthinuria I in Humans

Animal models of urinary stone disease

Hypoxanthine urolithiasis in an 11-month-old child: A case report of

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