Crystal Structures of Vertebrate Dihydropyrimidinase and Complexes from Tetraodon nigroviridis with Lysine Carbamylation

Hsieh, Yin-Cheng; Chen, Mei Chun; Hsu, Ching Chen; Chan, Sunney I.; Yang, Yuh‐Shyong; Chen, Chun‐Jung

doi:10.1074/jbc.m113.496778

Cited by 27 publications

(31 citation statements)

References 55 publications

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“…Carbamylation is also an irreversible non-enzymatic modification process, and its formation process is that the decomposition products of urea react with the N-terminus of the protein or the side chain of lysine residues, which is related to protein aging [65]. Lysine carbamylation can promote the coordination of metal ions to specific enzyme activities [66,67]. It has been reported that the plasma carbamylation levels of patients with elevated urea levels (such as nephropathy) are significantly increased [68].…”

Section: Discussionmentioning

confidence: 99%

Oxidations and amino acid substitutions in urinary proteins are the distinguishing characteristics of aging

Liu

Pan

Hua

et al. 2020

Preprint

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Aging is an inevitable course of life. Additionally, the risk of chronic diseases or cancer increases with age. The comprehensive identification of signs related to aging can be beneficial for the prevention and early diagnosis of geriatric diseases. The comparison of global modifications in the urine proteome is a means of multidimensional information mining. This approach is based on urine, in which changes from whole-body metabolism can accumulate. This study used the urine of healthy people at different ages (22 children, 10 young people, 6 senior people) as the research object and using high-resolution tandem mass spectrometry, label-free quantitation combined with non-limiting modification identification algorithms and random group test, compared the differences in protein chemical modifications among three groups. The results show that multi-sites oxidative modifications and amino acid substitutions are noticeable features that distinguish these three age groups of people. The proportion of multi-site oxidations in urine proteins of senior (29.76%) is significantly higher than the young group (13.71% and 12.97%), which affect the biological processes of various proteins. This study could provide a reference for studies of aging mechanisms and biomarkers of age-related disease.

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Section: Discussionmentioning

confidence: 99%

Oxidations and amino acid substitutions in urinary proteins are the distinguishing characteristics of aging

Liu

Pan

Hua

et al. 2020

Preprint

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“…The chemical mechanism of the binuclear metal center-containing amidohydrolase likely involves three steps: (1) the hydrolytic water molecule must be activated for nucleophilic attack, (2) the amide bond of the substrate must be made more electrophilic by the polarization of the carbonyl–oxygen bond, and (3) the leaving group nitrogen must be protonated as the carbon-nitrogen bond is cleaved [ 38 , 48 ]. This catalytic mechanism is applicable to each member in the cyclic amidohydrolase family [ 41 , 48 , 49 ]. However, a question remains as to why a common mechanism-based inhibitor for these imide-hydrolyzing enzymes, such as imidase, hydantoinase, dihydropyrimidinase, allantoinase, and dihydroorotase, is difficult to find.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of a Putative Dihydropyrimidinase from Pseudomonas aeruginosa PAO1 by Flavonoids and Substrates of Cyclic Amidohydrolases

Huang

2015

PLoS ONE

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Dihydropyrimidinase is a member of the cyclic amidohydrolase family, which also includes allantoinase, dihydroorotase, hydantoinase, and imidase. These metalloenzymes possess very similar active sites and may use a similar mechanism for catalysis. However, whether the substrates and inhibitors of other cyclic amidohydrolases can inhibit dihydropyrimidinase remains unclear. This study investigated the inhibition of dihydropyrimidinase by flavonoids and substrates of other cyclic amidohydrolases. Allantoin, dihydroorotate, 5-hydantoin acetic acid, acetohydroxamate, orotic acid, and 3-amino-1,2,4-triazole could slightly inhibit dihydropyrimidinase, and the IC50 values of these compounds were within the millimolar range. The inhibition of dihydropyrimidinase by flavonoids, such as myricetin, quercetin, kaempferol, galangin, dihydromyricetin, and myricitrin, was also investigated. Some of these compounds are known as inhibitors of allantoinase and dihydroorotase. Although the inhibitory effects of these flavonoids on dihydropyrimidinase were substrate-dependent, dihydromyricetin significantly inhibited dihydropyrimidinase with IC50 values of 48 and 40 μM for the substrates dihydrouracil and 5-propyl-hydantoin, respectively. The results from the Lineweaver−Burk plot indicated that dihydromyricetin was a competitive inhibitor. Results from fluorescence quenching analysis indicated that dihydromyricetin could form a stable complex with dihydropyrimidinase with the K d value of 22.6 μM. A structural study using PatchDock showed that dihydromyricetin was docked in the active site pocket of dihydropyrimidinase, which was consistent with the findings from kinetic and fluorescence studies. This study was the first to demonstrate that naturally occurring product dihydromyricetin inhibited dihydropyrimidinase, even more than the substrate analogs (>3 orders of magnitude). These flavonols, particularly myricetin, may serve as drug leads and dirty drugs (for multiple targets) for designing compounds that target several cyclic amidohydrolases.

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“…许多含有脱氢丙氨酸的肽具有一定的毒性 [23] , 因此, 发生这种修饰的蛋白质或肽也都具有一 [24] . 赖氨酸氨基甲酰化可以促进金属离子对特定酶活性的配位作用 [25,26] . 据报道, 尿素水平升高的患者(例如肾病患者) 的血浆中氨甲酰化的量显著增加 [27] .…”

Section: Figureunclassified

Why are there proteins in the urine of healthy people?

Liu¹,

Zhao²,

Pan³

et al. 2020

Sci. Sin.-Vitae

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Crystal Structures of Vertebrate Dihydropyrimidinase and Complexes from Tetraodon nigroviridis with Lysine Carbamylation

Cited by 27 publications

References 55 publications

Oxidations and amino acid substitutions in urinary proteins are the distinguishing characteristics of aging

Oxidations and amino acid substitutions in urinary proteins are the distinguishing characteristics of aging

Inhibition of a Putative Dihydropyrimidinase from Pseudomonas aeruginosa PAO1 by Flavonoids and Substrates of Cyclic Amidohydrolases

Why are there proteins in the urine of healthy people?

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