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- W2019922737 abstract "Defective xanthine dehydrogenase (XDH) activity in humans results in xanthinuria and xanthine calculus accumulation in kidneys. Bovine xanthinuria was demonstrated in a local herd and characterized as xanthinuria type II, similar to the Drosophila ma-l mutations, which lose activities of molybdoenzymes, XDH, and aldehyde oxidase, although sulfite oxidase activity is preserved. Linkage analysis located the disease locus at the centromeric region of bovine chromosome 24, where a ma-l homologous, putative molybdopterin cofactor sulfurase gene (MCSU) has been physically mapped. We found that a deletion mutation at tyrosine 257 inMCSU is tightly associated with bovine xanthinuria type II. Defective xanthine dehydrogenase (XDH) activity in humans results in xanthinuria and xanthine calculus accumulation in kidneys. Bovine xanthinuria was demonstrated in a local herd and characterized as xanthinuria type II, similar to the Drosophila ma-l mutations, which lose activities of molybdoenzymes, XDH, and aldehyde oxidase, although sulfite oxidase activity is preserved. Linkage analysis located the disease locus at the centromeric region of bovine chromosome 24, where a ma-l homologous, putative molybdopterin cofactor sulfurase gene (MCSU) has been physically mapped. We found that a deletion mutation at tyrosine 257 inMCSU is tightly associated with bovine xanthinuria type II. xanthine dehydrogenase molybdopterin cofactor sulfurase gene molybdenum cofactor aldehyde oxidase sulfite oxidase reverse transcriptase polymerase chain reaction open reading frame base pair(s) bovine chromosome fluorescence in situ hybridization expressed sequence tags yeast artificial chromosome rapid amplification of cDNA ends Xanthine dehydrogenase (XDH)1 activity is essential for the degradation of purine bases in mammals catalyzing the oxidation reactions of both hypoxanthine to xanthine and xanthine to uric acid. Defective XDH activity elevates xanthine concentration in plasma and urine, whereas hypoxanthine can be salvaged to inosine by hypoxanthine-guanine phosphoribosyltransferase. XDH requires molybdopterin cofactor (also referred as molybdenum cofactor, MoCo) for its enzymic activity. The cofactor is also essential for the enzymic activities of aldehyde oxidase (AO) and sulfite oxidase (SO) in mammals (1.Simmonds J.A. Reiter S. Nishino T. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 1781-1797Google Scholar, 2.Johnson J.L. Wadman S.K. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 2271-2283Google Scholar, 3.Rajagopalan K.V. Johnson J. J. Biol. Chem. 1992; 267: 10199-10202Abstract Full Text PDF PubMed Google Scholar). Both XDH and AO require the sulfide form of molybdopterin cofactor for their enzymic activities, whereas SO does not in the Drosophila ma-l mutant (4.Finnerty V. McCarron M. Johnson G.B. Mol. Gen. Genet. 1979; 172: 37-43Crossref PubMed Scopus (17) Google Scholar, 5.Bogaart A.M. Bernini L.F. Biochem. Genet. 1981; 19: 929-946Crossref PubMed Scopus (12) Google Scholar, 6.Kamdar K.P. Primus J.P. Shelton M.E. Archangeli L.L. Wittle A.E. Finnerty V. Biochem. Soc. Trans. 1997; 25: 778-783Crossref PubMed Scopus (13) Google Scholar, 7.Wahl R.C. Warner C.K. Finnerty V. Rajagopalan K.V. J. Biol. Chem. 1982; 257: 3958-3962Abstract Full Text PDF PubMed Google Scholar). Molybdopterin cofactor extracted from ma-l mutant flies lacked the sulfide moiety (desulfo form) (7.Wahl R.C. Warner C.K. Finnerty V. Rajagopalan K.V. J. Biol. Chem. 1982; 257: 3958-3962Abstract Full Text PDF PubMed Google Scholar). Resulfuration of desulfo MoCo in vitro reactivated xanthine dehydrogenase of thema-l mutant (7.Wahl R.C. Warner C.K. Finnerty V. Rajagopalan K.V. J. Biol. Chem. 1982; 257: 3958-3962Abstract Full Text PDF PubMed Google Scholar). Therefore, it was hypothesized that theDrosophila ma-l gene encodes a putative enzyme that catalyzes sulfuration of desulfo MoCo, the last step of MoCo synthesis. XDH deficiency in humans results in xanthinuria and the accumulation of xanthine calculi in renal tubules that leads to renal dysfunction (1.Simmonds J.A. Reiter S. Nishino T. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 1781-1797Google Scholar,2.Johnson J.L. Wadman S.K. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 2271-2283Google Scholar). Loss-of-function mutations in the XDH gene and genes responsible for MoCo biosynthesis can result in xanthinuria. In fact, hereditary xanthinuria in humans is classified into three categories (1.Simmonds J.A. Reiter S. Nishino T. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 1781-1797Google Scholar, 2.Johnson J.L. Wadman S.K. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 2271-2283Google Scholar). Xanthinuria type I is caused by a loss-of-function mutation in the XDH gene (8.Ichida K. Amaya Y. Kamatani N. Nishino T. Hosoya T. Sakai O. J. Clin. Invest. 1997; 99: 2391-2397Crossref PubMed Scopus (108) Google Scholar). Xanthinuria type II lacks both XDH and AO activities (1.Simmonds J.A. Reiter S. Nishino T. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 1781-1797Google Scholar, 9.Reiter S. Simmonds H.A. Zollner N. Braun S.L. Knedel M. Clin. Chim. Acta. 1990; 187: 221-234Crossref PubMed Scopus (66) Google Scholar); although the causative gene of xanthinuria type II is unknown, it has been suggested to be equivalent to theDrosophila ma-l mutation (4.Finnerty V. McCarron M. Johnson G.B. Mol. Gen. Genet. 1979; 172: 37-43Crossref PubMed Scopus (17) Google Scholar, 5.Bogaart A.M. Bernini L.F. Biochem. Genet. 1981; 19: 929-946Crossref PubMed Scopus (12) Google Scholar, 6.Kamdar K.P. Primus J.P. Shelton M.E. Archangeli L.L. Wittle A.E. Finnerty V. Biochem. Soc. Trans. 1997; 25: 778-783Crossref PubMed Scopus (13) Google Scholar). The third category is found in MoCo deficiency produced by a loss-of-function mutation of the MoCo synthetase gene catalyzing the first steps in MoCo synthesis (10.Reiss J. Cohen N. Dorche C. Mandel H. Mendel R.R. Stallmeyer B. Zabot M.T. Dierks T. Nat. Genet. 1998; 20: 51-53Crossref PubMed Scopus (100) Google Scholar). In humans, this condition is lethal in the perinatal period due to the absence of SO activity, which catalyzes sulfite oxidation (2.Johnson J.L. Wadman S.K. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 2271-2283Google Scholar). Recently, xanthinuria was demonstrated in a local cattle herd (11.Mizoguchi H. Livestock Technol. (Japan). 1997; 509: 2-6Google Scholar). Here, we show that this form of bovine xanthinuria is an autosomal recessive trait by which affected cattle lose XDH and AO activities, although SO activity is preserved, suggesting that this disorder is xanthinuria type II (1.Simmonds J.A. Reiter S. Nishino T. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 1781-1797Google Scholar, 9.Reiter S. Simmonds H.A. Zollner N. Braun S.L. Knedel M. Clin. Chim. Acta. 1990; 187: 221-234Crossref PubMed Scopus (66) Google Scholar). We report that a deletion mutation at theDrosophila ma-l orthologue is strongly associated with bovine xanthinuria type II. Total genomic DNA was prepared from peripheral blood leukocytes using standard protocols with an Easy-DNATM Kit (Invitrogen). The PCR conditions for microsatellite markers were optimized (12.Kappes S.M. Keele J.W. Stone R.T. McGraw R.A. Sonstegard T.S. Smith T.P. Lopez-Corrales N.L. Beattie C.W. Genome Res. 1997; 7: 235-249Crossref PubMed Scopus (461) Google Scholar), and additional reaction conditions were set as recommended by the manufacturer. Microsatellite polymorphisms were analyzed using PCR amplification and gel electrophoresis by an ABI 377 DNA sequencer as described (13.Hirano T. Nakane S. Mizoshita K. Yamakuchi H. Inoue-Murayama M. Watanabe T. Barendse W. Sugimoto Y. Anim. Genet. 1996; 27: 365-368Crossref PubMed Scopus (24) Google Scholar). Genotype data were captured by means of GENESCAN and Genotyper software (Perkin-Elmer Applied Biosystems), and linkage analysis was performed with the GENEHUNTER package (14.Kruglyak L. Daly M.J. Reeve-Daly M.P. Lander E.S. Am. J. Hum. Genet. 1996; 58: 1347-1363PubMed Google Scholar). Crude liver extracts for XDH and AO activities were prepared as described (15.Felsted R.L. Chu A.E. Chaykin S. J. Biol. Chem. 1973; 248: 2580-2587Abstract Full Text PDF PubMed Google Scholar). Briefly, the liver homogenates were treated at 55 °C for 11 min followed by 50% ammonium sulfate precipitation. The dialyzed crude extracts were then assayed for XDH and AO activities. XDH activity was estimated by the oxidation of hypoxanthine to uric acid as described (16.Kojima T. Nishina T. Kitamura M. Hosoya T. Nishioka K. Clin. Chim. Acta. 1984; 137: 189-198Crossref PubMed Scopus (37) Google Scholar). AO activity was measured by the oxidation ofN 1-methylnicotinamide to 2- and 4-pyridones in the presence of the XDH inhibitor allopurinol as described (15.Felsted R.L. Chu A.E. Chaykin S. J. Biol. Chem. 1973; 248: 2580-2587Abstract Full Text PDF PubMed Google Scholar). The preparation of crude liver extracts for SO activity and the assay were performed as described (3.Rajagopalan K.V. Johnson J. J. Biol. Chem. 1992; 267: 10199-10202Abstract Full Text PDF PubMed Google Scholar). A mouse EST, AA450702, corresponding to Pro-499 → Val-622 of Drosophila Ma-l, was chosen to design PCR primers (545F, 5′-GACCGGAGCTGGATGGTTGTG-3′; 596R, 5′-CCTCAAGAGGCACCTGGATAGG-3′) to amplify a ma-l homologous fragment by RT-PCR using bovine liver mRNA. A 150-bp PCR product corresponding to Asp-545 → Asp-596 of Drosophila Ma-l was confirmed by direct sequencing. We subsequently designed PCR primers (552F, 5′-ATCACAACGGCATTTGCCTGA-3′; 588R, 5′-CTCCATCCCTTGGGCTTTGATGAC-3′) from the bovine partial cDNA sequence to amplify a 110-bp fragment corresponding to Asp-552 → Ile-588 of Drosophila Ma-l using bovine genomic DNA. Direct sequencing revealed the PCR product was identical to the corresponding part of the bovine cDNA sequence. A bovine YAC clone 13H10 was screened by a PCR-based method as described (17.Takeda H. Yamakuchi H. Ihara N. Hara K. Watanabe T. Sugimoto Y. Oshiro T. Kishine H. Kano Y. Kohno K. Anim. Genet. 1998; 29: 216-219Crossref PubMed Google Scholar), using primers 552F and 588R, and hybridized with bovine metaphase chromosome spreads essentially as described (18.Wada M. Abe K. Okumura K. Taguchi H. Kohno K. Imamoto F. Schlessinger D. Kuwano M. Nucleic Acids Res. 1994; 22: 1651-1654Crossref PubMed Scopus (14) Google Scholar) using reagents supplied in the Oncor® chromosome in situ kit. YAC 13H10 was also used to construct a cosmid library. Briefly, YAC DNA (20 μg) was partially digested with Sau3AI. The resulting 20–30-kilobase fragments were collected by agarose gel electrophoresis followed by ligation into the pWE15 cosmid vector. Microsatellite loci from a cosmid clone were isolated using a poly(dA·dC)·poly(dG·dT) (Amersham Pharmacia Biotech) probe as described (13.Hirano T. Nakane S. Mizoshita K. Yamakuchi H. Inoue-Murayama M. Watanabe T. Barendse W. Sugimoto Y. Anim. Genet. 1996; 27: 365-368Crossref PubMed Scopus (24) Google Scholar). The following primer pairs were synthesized for DIK-124: forward, 5′-GCTAAATAAACCCTGTAGTGTTG-3′; reverse, 5′-GAGGGCAGTGTCTCAGGAGGGA-3′. Total RNA was extracted from bovine liver with Trizol (Life Technologies, Inc.) and reverse-transcribed with SuperScript II (Life Technologies, Inc.). 5′- and 3′-RACE reactions were performed with primers designed from the bovine cDNA sequence using the 5′-RACE kit (Life Technologies, Inc.) and SMART RACE cDNA amplification kit (CLONTECH), respectively. To detect the Tyr-257 deletion, PCR primers (714F, 5′-TGGCCTGGGCGCTCTGCTGGTGAATAAC-3′; 800R, 5′-AGGTACGCAGCGGCCGTGCCTCCTC-3′) were prepared to amplify the normal (87 bp) and mutant (84 bp) alleles using Pfu Turbo DNA polymerase (Stratagene), to avoid 3′-terminal adenylation and to make electropherograms clear, followed by separation with a 12% polyacrylamide gel electrophoresis. The GenBankTM accession number for bovine MCSU cDNA is AB036422. Bovine xanthinuria in a local herd of Japanese Black cattle was characterized by elevated xanthine secretion in the urine associated with lethal growth retardation at approximately 6 months of age (11.Mizoguchi H. Livestock Technol. (Japan). 1997; 509: 2-6Google Scholar). Affected cattle had expanded renal tubules containing xanthine calculi ranging from 1–3 mm in diameter (11.Mizoguchi H. Livestock Technol. (Japan). 1997; 509: 2-6Google Scholar). We confirmed that more than 300 xanthinuria-affected cattle have been recorded over the last 20 years and that all parents were descendants of a putative founder sire. Affected male, female, and unknown offspring numbered 177, 148, and 9, respectively. Pedigree analysis in this herd indicates that bovine xanthinuria is inherited as an autosomal recessive trait. Three types of xanthinuria can be classified based on the activities of the MoCo-requiring enzymes XDH, AO, and SO (1.Simmonds J.A. Reiter S. Nishino T. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 1781-1797Google Scholar, 2.Johnson J.L. Wadman S.K. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 2271-2283Google Scholar). We found that XDH and AO activities in liver extracts were decreased in affected cattle, whereas SO activity was preserved (Fig.1 A). Therefore, we classified this type of bovine xanthinuria as xanthinuria type II (1.Simmonds J.A. Reiter S. Nishino T. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 1781-1797Google Scholar, 9.Reiter S. Simmonds H.A. Zollner N. Braun S.L. Knedel M. Clin. Chim. Acta. 1990; 187: 221-234Crossref PubMed Scopus (66) Google Scholar). Twenty-one xanthinuria type II-affected offspring (11 males and 10 females) and their parents, 21 dams and two sires, were collected (Fig.1 B) and subjected to linkage analysis. A battery of 200 markers (12.Kappes S.M. Keele J.W. Stone R.T. McGraw R.A. Sonstegard T.S. Smith T.P. Lopez-Corrales N.L. Beattie C.W. Genome Res. 1997; 7: 235-249Crossref PubMed Scopus (461) Google Scholar) covering all bovine autosomes at approximately 15-centimorgan intervals, and showing heterozygosity for at least one of the two sires, was used in an initial genome scan in the family segregated for the disorder. The putative xanthinuria type II locus was mapped at the centromeric region of bovine chromosome (BTA) 24 (Z = 36.6, p < 1.9 × 10−6) (Fig. 1 C) (14.Kruglyak L. Daly M.J. Reeve-Daly M.P. Lander E.S. Am. J. Hum. Genet. 1996; 58: 1347-1363PubMed Google Scholar). Because the Drosophila ma-l orthologue, putative MoCo sulfurase gene has been suggested as causative for xanthinuria type II (4.Finnerty V. McCarron M. Johnson G.B. Mol. Gen. Genet. 1979; 172: 37-43Crossref PubMed Scopus (17) Google Scholar, 5.Bogaart A.M. Bernini L.F. Biochem. Genet. 1981; 19: 929-946Crossref PubMed Scopus (12) Google Scholar, 6.Kamdar K.P. Primus J.P. Shelton M.E. Archangeli L.L. Wittle A.E. Finnerty V. Biochem. Soc. Trans. 1997; 25: 778-783Crossref PubMed Scopus (13) Google Scholar), we investigated whether bovine Drosophila ma-lorthologue is located at the same region of xanthinuria type II locus on BTA24. The deduced amino acid sequence encoded byDrosophila ma-l (GenBankTM accession numberAF162681; kindly provided by Victoria Finnerty, Emory University, Atlanta, GA) was subjected to a TBLASTN-search on the dbEST DNA sequence data base of the GenBankTM to collect ESTs derived from mammalian orthologues. One hundred ESTs showing more than 40% identity to the ma-l amino acid sequence were obtained. A mouse EST (AA450702) was chosen to design PCR primers (552F and 588R) to amplify a ma-l homologous fragment using bovine genomic DNA. The direct sequencing of a 110-bp PCR product confirmed the Asp-552 → Ile-588 of Drosophila Ma-l. The bovineDrosophila ma-l orthologue was physically mapped by FISH using a bovine YAC clone 13H10 identified by PCR-based screening with the 552F and 588R primers. The YAC clone harboring the ma-lorthologue was located at BTA24q13.1–13.3 by FISH (Fig.1 D), where the xanthinuria type II locus genetically mapped (Fig. 1 C). MicrosatelliteDIK124 isolated from a cosmid clone harboring thema-l orthologue 110-bp DNA fragment was subjected to linkage analysis using the United States Department of Agriculture reference panel (12.Kappes S.M. Keele J.W. Stone R.T. McGraw R.A. Sonstegard T.S. Smith T.P. Lopez-Corrales N.L. Beattie C.W. Genome Res. 1997; 7: 235-249Crossref PubMed Scopus (461) Google Scholar) and mapped closely to loci CSSM031 (θ = 0.00) and ILSTS065 (θ = 0.02) on BTA24 at the peak between 25 and 38 centimorgan in Fig. 1 C. These results strongly suggest that a bovine xanthinuria type II causative gene is the ma-l orthologue. To isolate a putative homologous Drosophila ma-l MoCo sulfurase gene, we extended the core fragment of the ma-lorthologue 110 bp using internal primers and bovine liver-derived cDNA in 5′- and 3′-RACE, respectively. We detected an open reading frame (ORF) with an in-frame upstream stop codon. The ORF has 2547 nucleotides and encodes a protein of 849 amino acids. Because the sequence revealed approximately 40% amino acid similarity toDrosophila ma-l (GenBankTM accession numberAF162681) and Aspergillus hxB (GenBankTMaccession number AF128114; Ref. 19.Amrani L. Cecchetto G. Scazzocchio C. Glatigny A. Mol. Microbiol. 1999; 31: 1065-1073Crossref PubMed Scopus (19) Google Scholar) (Fig.2 A), we designated this gene as MoCo sulfurase (MCSU). Analysis of the genomic organization indicated that MCSU consists of at least 15 exons spanning 25 kilobases, with each exon flanked by canonical splice donor and acceptor sequences (Table I). We estimated MCSU expression by semiquantitative RT-PCR and demonstrated ubiquitous expression among diverse normal tissues (Fig.2 B). Normal lung tissue showed the highest expression. Affected cattle also expressed MCSU in the liver at levels equivalent to normal, suggesting that the level of MCSUexpression was not impaired. MCSU expression was not detected in normal tissues by Northern blot, probably because of a low level of expression.Table IIntron-exon boundary sequences of MCSUExoncDNA positionSplice acceptorSplice donor15′ UTR 435′ UTR - ATGCAAAGCACGGTCCCCAGgtgggaaaag244–133tttctttcagGAACTGTCTAAACGTTTATGgtaaagaaaa3134–201aaccttccagGTAACCCTCATGCGCTTCAGgtgagcaaat4202–847cttcttccagGATCCTGGCGTGGCTGAGAGgtaacctggt5848–925actgttgcagGTTTGAAGATCGCCTCACAGgtcagtggac6926–1126ctgctctgagGTGGGATGGATTACTCCCAGgtgggtttcc71127–1244aaacccatagGTGGATAAAAGCATCTTCAGgttggtactg81245–1707tttctcctagGCTGGTCATGAGCATTTGAGgtaagggttt91708–1871ttttttttagGTGATCAGGTAAAGCCCAAGgtcagaaaac101872–1951tgttcattagGGATGGAGCCGTGCGGACAGgtgagactgt111952–2077tttttgtcagGGTAAACACACATGGCAAAGgtattgcatt122078–2184ccttttttagATCAGTCTGCTAAGCACAAGgtaagaagac132185–2324tcttaaaaagCTGTGAGAATGCGTTTCCAGgtaagtttcc142325–2430caccgcccagGTTTTGGGACAGAGAGAAAGgtaagcatga152431–3′ UTRttgttcacagGTGAAGTTTGGGCTACCGAGTAA 3′ UTRThe intronic sequence is indicated in lowercase letters and the exonic sequence in uppercase. Open table in a new tab The intronic sequence is indicated in lowercase letters and the exonic sequence in uppercase. To detect a mutation associated with xanthinuria type II inMCSU, we compared ORF sequences from normal individuals with those from affected cattle. A two-base substitution at 478 and 479 resulting in the conversion of Pro-160 → Gly-160 was detected among normal cattle. This substitution is not related to the xanthinuria type II. A three-base deletion at 769–771 encoding Tyr-257 was identified in affected cattle (Fig. 3 A). PCR primers (714F and 800R) were designed to amplify the 87-bp fragment containing Tyr-257 using genomic DNA as template. Twenty-one affected offspring as shown in Fig. 1 B were demonstrated to harbor the homozygous Tyr-257 deleted 84-bp allele, whereas heterozygous 87- and 84-bp alleles were detected in their parents, which were expected carriers (Fig. 3 B). In contrast, more than 100 normal cattle from various cattle breeds, such as Japanese Black (unrelated to the xanthinuria type II founder sire), Limousine, Hereford, Holstein, and Angus, contained only the 87-bp normal alleles. This mutation detection method by simple PCR is applicable for practical diagnosis to detect heterozygous carrier cattle. To further address the issue of whether Tyr-257 is essential for MCSU function, MCSU sequences around Tyr-257 were compared between cattle, human, mouse, pig, fly, and fungus. Fig. 3 C shows that Tyr-257 was widely conserved and was situated in a highly conserved region in mammals. Even in the fly and fungus, two phenylalanine aromatic amino acid residues are preceded by basic amino acids and followed by a four-amino acid stretch, GGGT, conserved in mammals. These data strongly suggest that deletion of Tyr-257 results in the loss of MCSU function, leading to the occurrence of type II xanthinuria. Although we do not as yet have direct evidence demonstrating the enzymic nature of MCSU, loss-of-function mutations of ma-land hxB have been reported to be MoCo sulfuration-deficient in Drosophila and Aspergillus, respectively (7.Wahl R.C. Warner C.K. Finnerty V. Rajagopalan K.V. J. Biol. Chem. 1982; 257: 3958-3962Abstract Full Text PDF PubMed Google Scholar,19.Amrani L. Cecchetto G. Scazzocchio C. Glatigny A. Mol. Microbiol. 1999; 31: 1065-1073Crossref PubMed Scopus (19) Google Scholar). MoCo sulfuration activities of these gene products have not yet been confirmed biochemically. Wahl et al. (7.Wahl R.C. Warner C.K. Finnerty V. Rajagopalan K.V. J. Biol. Chem. 1982; 257: 3958-3962Abstract Full Text PDF PubMed Google Scholar) reported that application of the resulfuration procedure to crude extracts ofDrosophila ma-l mutants reactivates XDH and AO and proposed that the mutants are defective in the sulfuration of desulfo MoCo. Interestingly, Ma-l protein has a weak homology to NifS protein, which is involved in nitrogen fixation of bacteria and has a transulfurase activity (6.Kamdar K.P. Primus J.P. Shelton M.E. Archangeli L.L. Wittle A.E. Finnerty V. Biochem. Soc. Trans. 1997; 25: 778-783Crossref PubMed Scopus (13) Google Scholar). MCSU protein does not have significant homology to known proteins except for tRNA splicing protein SPL1 of Candida maltosa, sharing a 25.5% amino acid identity in the region from position 17 to 261 of MCSU. Twenty-one amino acid residues from 223 to 243 of MCSU (ADFVPISFYKIFGFPTGLGAL) have a similarity to the pyridoxal phosphate binding motif ((LIVFYCHT)-(DGH)-(LIVMFYAC)-(LIVMFYA)-x 2-(GSTAC)-(GSTA)-(HQR)-K-x 4, 6-G-x-(GSAT)-x-(LIVMFYSAC); Prosite motif ID, PS00595) such as that of C. maltosa SPL1 (IDLLSISSHKIYGPKGIGAC). Corresponding regions of Ma-l and HxB are highly conserved (PDYVCLSFYKIFGYPTGVGAL and PDFTVLSFYKIFGFPDLGAL, respectively). Because most enzymes that have transulfurase activity, such as cystathionine γ-lyase, require pyridoxal phosphate as a cofactor, we suggest that MCSU protein may bind pyridoxal phosphate and catalyze the transulfuration reaction of MoCo. Further investigation will be needed to confirm MCSU transulfurylase activity. We thank Victoria Finnerty for providing the amino acid sequence of ma-l and for critical reading of the manuscript, Claudio Scazzocchio for providing the amino acid sequence of hxB prior to publication, and Laurence B. Schook and Craig W. Beattie for critical readings. We also thank Kazuo Hara, Haruko Takeda, and Shinji Hirotsune for valuable discussions." @default.
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- W2019922737 title "Deletion Mutation in Drosophila ma-l Homologous, Putative Molybdopterin Cofactor Sulfurase Gene Is Associated with Bovine Xanthinuria Type II" @default.
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