| 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:10542323, PubMed:11508704, PubMed:10415095, PubMed:29976570, PubMed:22525402, PubMed:24526388). 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
The activity of beta-ureidopropionase, which catalyses the last step in the degradation of uracil, thymine, and analogous antimetabolites, is cooperatively regulated by the substrate and product of the reaction. This involves shifts in the equilibrium of the oligomeric states of the enzyme, but how these are achieved and result in changes in enzyme catalytic competence has yet to be determined. Here, the regulation of human beta-ureidopropionase was further explored via site-directed mutagenesis, inhibition studies, and cryo-electron microscopy. The active-site residue E207, as well as H173 and H307 located at the dimer-dimer interface, are shown to play crucial roles in enzyme activation. Dimer association to larger assemblies requires closure of active-site loops, which positions the catalytically crucial E207 stably in the active site. H173 and H307 likely respond to ligand-induced changes in their environment with changes in their protonation states, which fine-tunes the active-site loop stability and the strength of dimer-dimer interfaces and explains the previously observed pH influence on the oligomer equilibrium. The correlation between substrate analogue structure and effect on enzyme assembly suggests that the ability to favourably interact with F205 may distinguish activators from inhibitors. The cryo-EM structure of human beta-ureidopropionase assembly obtained at low pH provides first insights into the architecture of its activated state. and validates our current model of the allosteric regulation mechanism. Closed entrance loop conformations and dimer-dimer interfaces are highly conserved between human and fruit fly enzymes.
The Allosteric Regulation of Beta-Ureidopropionase Depends on Fine-Tuned Stability of Active-Site Loops and Subunit Interfaces.,Cederfelt D, Badgujar D, Au Musse A, Lohkamp B, Danielson UH, Dobritzsch D Biomolecules. 2023 Dec 8;13(12):1763. doi: 10.3390/biom13121763. PMID:38136634[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
- ↑ Cederfelt D, Badgujar D, Au Musse A, Lohkamp B, Danielson UH, Dobritzsch D. The Allosteric Regulation of Β-Ureidopropionase Depends on Fine-Tuned Stability of Active-Site Loops and Subunit Interfaces. Biomolecules. 2023 Dec 8;13(12):1763. PMID:38136634 doi:10.3390/biom13121763
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