| Structural highlights
Disease
BUP1_HUMAN Beta-ureidopropionase deficiency. The disease is caused by variants affecting the gene represented in this entry.
Function
BUP1_HUMAN Catalyzes a late step in pyrimidine degradation (PubMed:22525402, PubMed:24526388). Converts N-carbamoyl-beta-alanine (3-ureidopropanoate) into beta-alanine, ammonia and carbon dioxide (PubMed:10415095, PubMed:10542323, PubMed:11508704, PubMed:22525402, PubMed:24526388, PubMed:29976570). Likewise, converts N-carbamoyl-beta-aminoisobutyrate (3-ureidoisobutyrate) into beta-aminoisobutyrate, ammonia and carbon dioxide (Probable).[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
beta-Ureidopropionase (betaUP) catalyzes the third step of the reductive pyrimidine catabolic pathway responsible for breakdown of uracil-, thymine- and pyrimidine-based antimetabolites such as 5-fluorouracil. Nitrilase-like betaUPs use a tetrad of conserved residues (Cys233, Lys196, Glu119 and Glu207) for catalysis and occur in a variety of oligomeric states. Positive co-operativity toward the substrate N-carbamoyl-beta-alanine and an oligomerization-dependent mechanism of substrate activation and product inhibition have been reported for the enzymes from some species but not others. Here, the activity of recombinant human betaUP is shown to be similarly regulated by substrate and product, but in a pH-dependent manner. Existing as a homodimer at pH 9, the enzyme increasingly associates to form octamers and larger oligomers with decreasing pH. Only at physiological pH is the enzyme responsive to effector binding, with N-carbamoyl-beta-alanine causing association to more active higher molecular mass species, and beta-alanine dissociation to inactive dimers. The parallel between the pH and ligand-induced effects suggests that protonation state changes play a crucial role in the allosteric regulation mechanism. Disruption of dimer-dimer interfaces by site-directed mutagenesis generated dimeric, inactive enzyme variants. The crystal structure of the T299C variant refined to 2.08 A resolution revealed high structural conservation between human and fruit fly betaUP, and supports the hypothesis that enzyme activation by oligomer assembly involves ordering of loop regions forming the entrance to the active site at the dimer-dimer interface, effectively positioning the catalytically important Glu207 in the active site.
Crystal structure and pH-dependent allosteric regulation of human beta-ureidopropionase, an enzyme involved in anticancer drug metabolism.,Maurer D, Lohkamp B, Krumpel M, Widersten M, Dobritzsch D Biochem J. 2018 Jul 31;475(14):2395-2416. doi: 10.1042/BCJ20180222. PMID:29976570[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Van Kuilenburg AB, Van Lenthe H, Van Gennip AH. A radiochemical assay for beta-ureidopropionase using radiolabeled N-carbamyl-beta-alanine obtained via hydrolysis of [2-(14)C]5, 6-dihydrouracil. Anal Biochem. 1999 Aug 1;272(2):250-3. PMID:10415095 doi:10.1006/abio.1999.4181
- ↑ Vreken P, van Kuilenburg AB, Hamajima N, Meinsma R, van Lenthe H, Göhlich-Ratmann G, Assmann BE, Wevers RA, van Gennip AH. cDNA cloning, genomic structure and chromosomal localization of the human BUP-1 gene encoding beta-ureidopropionase. Biochim Biophys Acta. 1999 Oct 28;1447(2-3):251-7. PMID:10542323 doi:10.1016/s0167-4781(99)00182-7
- ↑ Sakamoto T, Sakata SF, Matsuda K, Horikawa Y, Tamaki N. Expression and properties of human liver beta-ureidopropionase. J Nutr Sci Vitaminol (Tokyo). 2001 Apr;47(2):132-8. PMID:11508704 doi:10.3177/jnsv.47.132
- ↑ van Kuilenburg AB, Dobritzsch D, Meijer J, Krumpel M, Selim LA, Rashed MS, Assmann B, Meinsma R, Lohkamp B, Ito T, Abeling NG, Saito K, Eto K, Smitka M, Engvall M, Zhang C, Xu W, Zoetekouw L, Hennekam RC. ß-ureidopropionase deficiency: phenotype, genotype and protein structural consequences in 16 patients. Biochim Biophys Acta. 2012 Jul;1822(7):1096-108. PMID:22525402 doi:10.1016/j.bbadis.2012.04.001
- ↑ Nakajima Y, Meijer J, Dobritzsch D, Ito T, Meinsma R, Abeling NG, Roelofsen J, Zoetekouw L, Watanabe Y, Tashiro K, Lee T, Takeshima Y, Mitsubuchi H, Yoneyama A, Ohta K, Eto K, Saito K, Kuhara T, van Kuilenburg AB. Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation [corrected]. J Inherit Metab Dis. 2014 Sep;37(5):801-12. PMID:24526388 doi:10.1007/s10545-014-9682-y
- ↑ Maurer D, Lohkamp B, Krumpel M, Widersten M, Dobritzsch D. Crystal structure and pH-dependent allosteric regulation of human β-ureidopropionase, an enzyme involved in anticancer drug metabolism. Biochem J. 2018 Jul 31;475(14):2395-2416. PMID:29976570 doi:10.1042/BCJ20180222
- ↑ van Kuilenburg AB, Dobritzsch D, Meijer J, Krumpel M, Selim LA, Rashed MS, Assmann B, Meinsma R, Lohkamp B, Ito T, Abeling NG, Saito K, Eto K, Smitka M, Engvall M, Zhang C, Xu W, Zoetekouw L, Hennekam RC. ß-ureidopropionase deficiency: phenotype, genotype and protein structural consequences in 16 patients. Biochim Biophys Acta. 2012 Jul;1822(7):1096-108. PMID:22525402 doi:10.1016/j.bbadis.2012.04.001
- ↑ Nakajima Y, Meijer J, Dobritzsch D, Ito T, Meinsma R, Abeling NG, Roelofsen J, Zoetekouw L, Watanabe Y, Tashiro K, Lee T, Takeshima Y, Mitsubuchi H, Yoneyama A, Ohta K, Eto K, Saito K, Kuhara T, van Kuilenburg AB. Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation [corrected]. J Inherit Metab Dis. 2014 Sep;37(5):801-12. PMID:24526388 doi:10.1007/s10545-014-9682-y
- ↑ Maurer D, Lohkamp B, Krumpel M, Widersten M, Dobritzsch D. Crystal structure and pH-dependent allosteric regulation of human β-ureidopropionase, an enzyme involved in anticancer drug metabolism. Biochem J. 2018 Jul 31;475(14):2395-2416. PMID:29976570 doi:10.1042/BCJ20180222
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