AGEomics Biomarkers and Machine Learning—Realizing the Potential of Protein Glycation in Clinical Diagnostics
Abstract
:1. Introduction
2. Focused Proteomics and Metabolomics of Protein Damage—“AGEomics” and Its Utility
2.1. Protein Glycation
2.2. Protein Oxidation
2.3. Protein Nitration
2.4. Other Common Modifications
3. Machine Learning in Protein Damage Biomarker Related Diagnostic Applications
4. Examples of Application of Machine Learning in Protein Damage Biomarker Related Diagnostic Using the AGEomics Platform
5. Future Perspectives
Funding
Acknowledgments
Conflicts of Interest
References
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Modification Process | Modified Amino Acid | Reporting Characteristic | Example of Analysis and Levels 1 |
---|---|---|---|
Early-stage glycation (formation of fructosamine adducts) 2 | Nε-Fructosyl-lysine (FL) | Early-stage glycation adduct formed from glucose, reporting on exposure to increased glucose concentration [23]. Repaired intracellularly by fructosamine 3-phosphokinase [24]. FL free adduct is absorbed after digestion of food proteins [25]. | Hb, 0.84 ± 0.30 mmol/mol lys; and Plasma protein, 1.35 ± 0.16 nmol/mol lys [26]. Used as markers of glycemic control in Hb (with N-terminal valine adducts) and albumin (with N-terminal aspartate adducts [5]. Urinary excretion: 26.5 (17.3–39.4) nmol/mg creatinine [16] |
Advanced-stage glycation (formation of AGEs) | Methylglyoxal-derived hydroimidazolone (MG-H1) | A major quantitative arginine-derived AGE formed from methylglyoxal. Linked to increased fasting and postprandial glucose exposure, insulin resistance and cardiovascular disease [18,26,27,28]. MG-H1 free adduct is absorbed after digestion of food proteins [18]. | Hb, 2.62 ± 0.60 mmol/mol arg; and Plasma protein, 0.31 ± 0.20 nmol/mol arg [26]. Urinary excretion: 20.1 (16.3–30.6) nmol/mg creatinine; endogenous formation 13.4 ± 2.1 nmol/mg creatinine [18] |
Nε-Carboxymethyl-lysine (CML) | Major lysine-derived AGE. Formed by the oxidative degradation of FL and other sources. CML/FL ratio is an indicator of oxidative stress [29]. CML free adduct is absorbed after digestion of food proteins [30]. | Hb, 0.075 ± 0.023 mmol/mol lys; and Plasma protein, 0.038 ± 0.010 mmol/mol lys [26]. | |
Glucosepane | Major quantitative crosslink formed in protein glycation by the degradation of FL residues [31]. | Urinary excretion: 2.84 (2.41–3.36) nmol/mg creatinine [16]. Plasma free adduct increased in early-stage osteoarthritis [32]. | |
Low-level pentose sugar-derived glycation crosslink and intense fluorophore. Considered to reflect pentosephosphate pathway activity [33]. | Urinary excretion: 0.258 (0.207–0.287) nmol/mg creatinine [16]. Urinary excretion is risk predictor of diabetic kidney disease [15]. | ||
Pyrraline | Glucose-derived AGE formed at high temperatures of culinary processing; originating only from food [17,34]. | Urinary excretion: 9.11 (5.69–13.67) nmol/mg creatinine in second void urine after overnight fasting [16]. | |
Oxidation | Methionine sulfoxide (MetSO; methionine-S-sulfoxide and methionine-R-sulfoxide) | Formed by the oxidation of Met and Met residues of proteins by ROS and RNS as a mixture of S- and R- diastereomers. Protein and free adduct forms are reduced to Met by methionine sulfoxide reductases, with the exception of the R-MetSO free adduct [35]. | Hb, 2.97 ± 0.55 mmol/mol met; and Plasma protein, 0.98 ± 0.13 nmol/mol met [26]. |
α-Aminoadipic semialdehyde (AASA) | “Protein carbonyl” formed by the oxidative deamination of lysine [36] | Plasma protein: 0.15 ± 0.05 mmol/mol lys [10] | |
Glutamic semialdehyde (GSA) | Major “protein carbonyl” formed by the oxidative deguanidylation of arginine and oxidative ring-opening of proline [36] | Plasma protein: 0.64 ± 0.33 mmol/mol arg [10] | |
Dityrosine (DT) | Oxidative crosslink formed spontaneously in oxidative stress and enzymatically by DUOX [9,23]. | Plasma protein: 0.025 (0.019–0.031) mmol/mol tyr [10]. Increased in autism | |
N-Formylkynurenine (NFK) | Formed by the oxidation of tryptophan by hydrogen peroxide, peroxynitrite and hypochlorite [37]. Formed enzymatically by IDO involved in immunoregulation, inflammation and host defense against infectious disease [38]. | Plasma protein: 15.6 ± 1.7 mmol/mol trp [10]. | |
Nitration | 3-Nitrotyrosine (3-NT) | Protein nitration marker. Major proteolysis product of proteins endogenously nitrated by peroxynitrite and nitryl chloride [23,39]. May reflect oxidative stress and/or nitric oxide availability | Plasma protein: 0.0006 ± 0.0004 mmol/mol tyr; increased in diabetes [40]. |
Citrullination | Citrulline residue | Citrullinated protein (CP). Formed enzymatically from arginine residues by PADs [41] | Plasma CP: 0.053 (0.043–0.091) mmol/mol arg; increased in early-stage arthritis [11] |
Transglutamination | Nε(γ-Glutamyl)lysine (GEEK) | Major protein crosslink formed enzymatically by transglutaminases from glutamine and lysine residues [42] | Urinary excretion: 0.42 (0.20–0.93) nmol/mg creatinine [16] |
Disorder or Disease (Algorithm Development Method) | Analytes (Adduct) | Diagnostic Indication 1 | Reference |
---|---|---|---|
Early-stage arthritis (GLMNET) | Plasma CP, hyp and anti-CCP anti-body status | Diagnostic algorithm for classification of good skeletal health or early-stage arthritis type (OA, RA or non-RA): for Good skeletal health, OA, RA and non-RA, LR+ = 1.6, 5.6, 6.3 and 1.0 and LR− = 0.79, 0.31, 0.47 and 0.99, respectively. | [11] |
Early-stage arthritis (Random forests) | Plasma free adducts (FL, CML, CEL, G-H1, MG-H1, 3DG-H, CEL, CMA, GSP, pentosidine; and MetSO, DT, NFK, 3-NT; and hyp and anti-CCP antibody status | Diagnostic algorithm for early-stage arthritis (any type) vs. good skeletal health: LR+ = 8.3 and LR− = 0.11. Diagnostic algorithm for classification of early-stage arthritis type (OA, RA or non-RA): for OA, RA and non-RA, LR+ = 16.1, 7.7 and 5.0 and LR− = 0.06, 0.34 and 0.36, respectively. | [50] |
Autism spectrum disorder (Support vector machines) | Glycated plasma protein (CML, CMA, 3DG-H and DT) | Combined in a diagnostic algorithm, gave moderate evidence for presence and borderline moderate/conclusive evidence for absence of ASD; LR+ = 5.7, LR− = 0.095. | [10] |
Early-stage decline in metabolic, vascular and renal health (Support vector machines) | Urinary free adduct (FL; and val, age and BMI) | Diagnostic algorithm classifying good health vs. early-stage health decline. LR+, 8.0. 2.8 and 13.2, and LR− 0.24, 0.43 and 0.13 for metabolic, vascular and renal health respectively. | [16] |
Diabetic kidney disease risk prediction (X-Gradient boost) | A1C, logACR, FECMA, FEG-H1 and [CML]plasma | Accuracy 87 ± 4%, sensitivity 74 ± 9%, specificity 91 ± 4%, AUROC 0.90, LR+ 11.0, | [63] |
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Rabbani, N. AGEomics Biomarkers and Machine Learning—Realizing the Potential of Protein Glycation in Clinical Diagnostics. Int. J. Mol. Sci. 2022, 23, 4584. https://doi.org/10.3390/ijms23094584
Rabbani N. AGEomics Biomarkers and Machine Learning—Realizing the Potential of Protein Glycation in Clinical Diagnostics. International Journal of Molecular Sciences. 2022; 23(9):4584. https://doi.org/10.3390/ijms23094584
Chicago/Turabian StyleRabbani, Naila. 2022. "AGEomics Biomarkers and Machine Learning—Realizing the Potential of Protein Glycation in Clinical Diagnostics" International Journal of Molecular Sciences 23, no. 9: 4584. https://doi.org/10.3390/ijms23094584