Avenues for post-translational protein modification prevention and therapy

Tang, Mengyao; Kalim, Sahir

doi:10.1016/j.mam.2022.101083

Cited by 6 publications

(4 citation statements)

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“…52 Further study of carbamylation in CKD is compelling because of growing evidence that carbamylation is readily modifiable. 53 Decreasing blood urea levels and boosting amino acid levels (which react with and “scavenge” cyanate, thus shielding proteins from modification) have been shown as promising methods to reduce carbamylation. 21,53,54 Recent translational work demonstrated pathologic carbamylation of a receptor required for platelet aggregation (potentially explaining some of the common bleeding diatheses seen in ESKD) could be ameliorated with amino acid supplementation in vitro .…”

Section: Discussionmentioning

confidence: 99%

“…53 Decreasing blood urea levels and boosting amino acid levels (which react with and “scavenge” cyanate, thus shielding proteins from modification) have been shown as promising methods to reduce carbamylation. 21,53,54 Recent translational work demonstrated pathologic carbamylation of a receptor required for platelet aggregation (potentially explaining some of the common bleeding diatheses seen in ESKD) could be ameliorated with amino acid supplementation in vitro . 55 In humans, amino acid administration during hemodialysis was able to lower C-Alb in a small proof-of-concept study without clinical end points.…”

Section: Discussionmentioning

confidence: 99%

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Protein Carbamylation and the Risk of ESKD in Patients with CKD

Kalim

Zhao

Tang

et al. 2023

JASN

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Significance Statement Protein carbamylation, a nonenzymatic post-translational protein modification partially driven by elevated blood urea levels, associates with mortality and adverse outcomes in patients with ESKD on dialysis. However, little is known about carbamylation's relationship to clinical outcomes in the much larger population of patients with earlier stages of CKD. In this prospective observational cohort study of 3111 individuals with CKD stages 2–4, higher levels of carbamylated albumin (a marker of protein carbamylation burden) were associated with a greater risk of developing ESKD and other significant adverse clinical outcomes. These findings indicate that protein carbamylation is an independent risk factor for CKD progression. They suggest that further study of therapeutic interventions to prevent or reduce carbamylation is warranted. Background Protein carbamylation, a post-translational protein modification partially driven by elevated blood urea levels, associates with adverse outcomes in ESKD. However, little is known about protein carbamylation's relationship to clinical outcomes in the much larger population of patients with earlier stages of CKD. Methods To test associations between protein carbamylation and the primary outcome of progression to ESKD, we measured baseline serum carbamylated albumin (C-Alb) in 3111 patients with CKD stages 2–4 enrolled in the prospective observational Chronic Renal Insufficiency Cohort study. Results The mean age of study participants was 59 years (SD 10.8); 1358 (43.7%) were female, and 1334 (42.9%) were White. The mean eGFR at the time of C-Alb assessment was 41.8 (16.4) ml/minute per 1.73 m2, and the median C-Alb value was 7.8 mmol/mol (interquartile range, 5.8–10.7). During an average of 7.9 (4.1) years of follow-up, 981 (31.5%) individuals developed ESKD. In multivariable adjusted Cox models, higher C-Alb (continuous or quartiles) independently associated with an increased risk of ESKD. For example, compared with quartile 1 (C-Alb ≤5.80 mmol/mol), those in quartile 4 (C-Alb >10.71 mmol/mol) had a greater risk for ESKD (adjusted hazard ratio, 2.29; 95% confidence interval, 1.75 to 2.99), and the ESKD incidence rate per 1000 patient-years increased from 15.7 to 88.5 from quartile 1 to quartile 4. The results remained significant across numerous subgroup analyses, when treating death as a competing event, and using different assessments of eGFR. Conclusions Having a higher level of protein carbamylation as measured by circulating C-Alb is an independent risk factor for ESKD in individuals with CKD stages 2–4. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_04_24_JSN_URE_EP22_042423.mp3

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Protein Carbamylation and the Risk of ESKD in Patients with CKD

Kalim

Zhao

Tang

et al. 2023

JASN

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“…Although the integral interaction network can reflect the overall connection, the subdivided clusters can present more details of mRNAs bound to BTBD7_hsa_circ_0000563. For example, the functional enrichment analysis of clusters showed that, in addition to translation and necroptosis, other processes that mRNA bound to BTBD7_hsa_circ_0000563 might take part in, such as post-translational protein modification [ 45 , 46 ], glucose homeostasis [ 47 , 48 ], neutrophil and lymphocyte [ 49 , 50 ], and FoxO signaling pathway [ 51 ], can make an impact on CAD or atherosclerosis as well.…”

Section: Discussionmentioning

confidence: 99%

Exploration and bioinformatic prediction for profile of mRNA bound to circular RNA BTBD7_hsa_circ_0000563 in coronary artery disease

Guo,

Zhou,

Zhang

et al. 2024

BMC Cardiovasc Disord

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Background As a novel circRNA, BTBD7_hsa_circ_0000563 has not been fully investigated in coronary artery disease (CAD). Our aim is to reveal the possible functional role and regulatory pathway of BTBD7_hsa_circ_0000563 in CAD via exploring genes combined with BTBD7_hsa_circ_0000563. Methods A total of 45 peripheral blood mononuclear cell (PBMC) samples of CAD patients were enrolled. The ChIRP-RNAseq assay was performed to directly explore genes bound to BTBD7_hsa_circ_0000563. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted to reveal possible functions of these genes. The interaction network was constructed by the STRING database and the Cytoscape software. The Cytoscape software were used again to identify clusters and hub genes of genes bound to BTBD7_hsa_circ_0000563. The target miRNAs of hub genes were predicted via online databases. Results In this study, a total of 221 mRNAs directly bound to BTBD7_hsa_circ_0000563 were identified in PBMCs of CAD patients via ChIRP-RNAseq. The functional enrichment analysis revealed that these mRNAs may participate in translation and necroptosis. Moreover, the interaction network showed that there may be a close relationship between these mRNAs. Eight clusters can be further subdivided from the interaction network. RPS3 and RPSA were identified as hub genes and hsa-miR-493-5p was predicted to be the target miRNA of RPS3. Conclusions BTBD7_hsa_circ_0000563 and mRNAs directly bound to it may influence the initiation and progression of CAD, among which RPS3 and RPSA may be hub genes. These findings may provide innovative ideas for further research on CAD.

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“…Some of these aspects have been addressed recently in this regard (Hermann et al, 2022). Several reviews have addressed the relevance of PTMs in aging and disease (Santos & Lindner, 2017) and the potential modalities for prevention and therapy (Tang & Kalim, 2022). Some have even studied PTMs directly brought about by DRS (Wenske et al, 2020).…”

Section: Murburn Modifications: (Patho)physiology Clinical Investigat...mentioning

confidence: 99%

Murburn posttranslational modifications of proteins: Cellular redox processes and murzyme‐mediated metabolo‐proteomics

Manoj¹

2023

Journal Cellular Physiology

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Murburn concept constitutes the thesis that diffusible reactive species or DRS are obligatorily involved in routine metabolic and physiological activities. Murzymes are defined as biomolecules/proteins that generate/modulate/sustain/utilize DRS. Murburn posttranslational modifications (PTMs) result because murburn/murzyme functionalism is integral to cellular existence. Cells must incorporate the inherently stochastic nature of operations mediated by DRS. Due to the earlier/inertial stigmatic perception that DRS are mere agents of chaos, several such outcomes were either understood as deterministic modulations sponsored by house‐keeping enzymes or deemed as unregulated nonenzymatic events resulting out of “oxidative stress”. In the current review, I dispel the myths around DRS‐functions, and undertake systematic parsing and analyses of murburn modifications of proteins. Although it is impossible to demarcate all PTMs into the classical or murburn modalities, telltale signs of the latter are evident from the relative inaccessibility of the locus, non‐specificities and mechanistic details. It is pointed out that while many murburn PTMs may be harmless, some others could have deleterious or beneficial physiological implications. Some details of reversible/irreversible modifications of amino acid residues and cofactors that may be subjected to phosphorylation, halogenation, glycosylation, alkylation/acetylation, hydroxylation/oxidation, etc. are listed, along with citations of select proteins where such modifications have been reported. The contexts of these modifications and their significance in (patho)physiology/aging and therapy are also presented. With more balanced explorations and statistically verified data, a definitive understanding of normal versus pathological contexts of murburn modifications would be obtainable in the future.

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Avenues for post-translational protein modification prevention and therapy

Cited by 6 publications

References 148 publications

Protein Carbamylation and the Risk of ESKD in Patients with CKD

Protein Carbamylation and the Risk of ESKD in Patients with CKD

Exploration and bioinformatic prediction for profile of mRNA bound to circular RNA BTBD7_hsa_circ_0000563 in coronary artery disease

Murburn posttranslational modifications of proteins: Cellular redox processes and murzyme‐mediated metabolo‐proteomics

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