β-Ureidopropionase deficiency due to novel and rare UPB1 mutations affecting pre-mRNA splicing and protein structural integrity and catalytic activity

The Allosteric Regulation of Β-Ureidopropionase Depends on Fine-Tuned Stability of Active-Site Loops and Subunit Interfaces

“…The active site remains accessible despite its partial occlusion by the entrance loops, allowing the activated state to be maintained throughout many catalytic cycles. An interesting feature of the mechanism is that the increase in catalytic activity may be solely achieved by an increase in the number of catalytically competent active sites brought about by enzyme oligomerization (Figure 8): EL stabilization cannot be achieved in dimeric species, and hence both active sites are catalytically incompetent, explaining the inactivity of all βUP mutants that lack the ability to oligomerize [14,15,24,44], including the H173, H307, and E207 mutants reported here. Assembly of two dimers to a tetramer makes two of the four active sites catalytically competent, whereas the other two are still "inactive".…”

“…Deficiencies in pyrimidine-degrading enzymes alter the homeostasis of pyrimidines and their metabolites and are associated with neurological abnormalities [14][15][16][17][18][19], although the relationship of βUP deficiency to human phenotypes remains uncertain [20]. Moreover, they are a risk factor for the development of life-threatening side effects in cancer patients receiving 5-fluorouracil (5FU)-based chemotherapy [21]; 5FU and its prodrugs are among the most frequently prescribed drugs for chemotherapy in a variety of cancers, but the rapid metabolic deactivation of ~80% of the administered 5FU dose, unpredictable bioavailability, and metabolite toxicity limit their efficacy [17,21].…”

The genetic basis of dispersal in a vertebrate metapopulation

“…It has been shown that ADORA2A encodes a member of the G protein‐coupled receptor superfamily that is involved in increasing intracellular cAMP levels and is a regulator of functions including sleep cycles, cardiac rhythm and circulation, immune function and pain regulation (NCBI), as well as glycogenesis (González‐Benítez et al., 2002), whereas UPB1 encodes a highly conserved protein that catalyses a late step in the nucleic acid pyrimidine degradation leading to biosynthesis of beta‐alanine in animals (Matthews et al., 1992). In humans, UPB1 deficiency is associated with neurological problems (Dobritzsch et al., 2022; Van Kuilenburg et al., 2004), and beta‐alanine supplementation has been shown to increase performance during intense exercise by acid buffering of the blood (Hobson et al., 2012; Milioni et al., 2019).…”

Machine-learning-based integrative –‘omics analyses reveal immunologic and metabolic dysregulation in environmental enteric dysfunction

“…Of those genes that correlated to over 100 features, beta-ureidopropionase (UPB1) catalyzes the final step of pyrimidine metabolism by converting N-carbamyl-beta-alanine to beta-alanine, a key mediator of immune homeostasis. 29 , 30 A previous study of the Pakistan EED cohort as part of SEEM found UPB1 was downregulated in patients with EED compared to controls. 20 Transcriptomic studies of celiac disease have also found UPB1 to be downregulated in celiac disease, an inflammatory enteropathy with shared histologic features with EED.…”