Protein carbamylation links inflammation, smoking, uremia and atherogenesis

Wang, Zeneng; Nicholls, Stephen J.; Rodríguez, E. René; Kummu, Outi; Hörkkö, Sohvi; Barnard, John; Reynolds, Wanda F.; Topol, Eric J.; DiDonato, Joseph A.; Hazen, Stanley L.

doi:10.1038/nm1637

Cited by 620 publications

(770 citation statements)

References 47 publications

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“…138 In humans, isocyanic acid is a product of the spontaneous decomposition of urea, but at sites of inflammation and atherosclerotic plaques it may also derive from the oxidation of thiocyanate by MPO. 138,139 Double immunofluorescence assays revealed colocalization of MPO with carbamylated proteins within atherosclerotic plaques. 139 Intriguingly, HDL isolated from human atherosclerotic lesions carried high amounts of carbamyllysines.…”

Section: Protein Carbamylationmentioning

confidence: 99%

“…138,139 Double immunofluorescence assays revealed colocalization of MPO with carbamylated proteins within atherosclerotic plaques. 139 Intriguingly, HDL isolated from human atherosclerotic lesions carried high amounts of carbamyllysines. 140,141 These results are consistent with the assumption that HDL trapped in the vascular wall becomes a target for carbamylation.…”

Section: Protein Carbamylationmentioning

confidence: 99%

“…Exposure of aortic endothelial cells to carbamylated HDL induced apoptosis of these cells and carbamylated HDL was clearly less potent at preventing endothelial apoptosis elicited by growth factor withdrawal. 139 Also, HDL particles modified through carbamylation not only had poorer cholesterol efflux activities, but instead facilitated further accumulation of cholesterol in human monocytes. 140 Another important observation is that cyanate-treated HDL had lower LCAT activity.…”

Section: Protein Carbamylationmentioning

confidence: 99%

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Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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Section: Protein Carbamylationmentioning

confidence: 99%

Section: Protein Carbamylationmentioning

confidence: 99%

Section: Protein Carbamylationmentioning

confidence: 99%

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Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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“…In general, human studies in patients with CKD have suggested that MPO plays an important role. For example, MPO-derived protein carbamylation is associated with CVD in the CKD population (46)(47)(48)(49). Plasma MPO levels increase with each stage of CKD and are linked to CVD mortality in patients with end-stage renal disease (ESRD) who are undergoing peritoneal dialysis (50)(51)(52)(53).…”

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confidence: 99%

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Zeng

Mathew

Byun

et al. 2018

Journal of Biological Chemistry

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Increased myeloperoxidase (MPO) levels and activity are associated with increased cardiovascular risk among individuals with chronic kidney disease (CKD). However, a lack of good animal models for examining the presence and catalytic activity of MPO in vascular lesions has impeded mechanistic studies into CKD-associated cardiovascular diseases. Here, we show for the first time that exaggerated atherosclerosis in a pathophysiologically relevant CKD mouse model is associated with increased macrophage-derived MPO activity. Male 7-week-old LDL receptordeficient mice underwent sham (control mice) or 5/6 nephrectomy and were fed either a low-fat or high-fat, high-cholesterol diet for 24 weeks, and the extents of atherosclerosis and vascular reactivity were assessed. MPO expression and oxidation products, and the protein-bound oxidized tyrosine moieties 3-chlorotyrosine, 3-nitrotyrosine, and o,o′-dityrosine were examined with immunoassays and confirmed with mass spectrometry (MS). As anticipated, the CKD mice had significantly higher plasma creatinine, urea nitrogen, and intact parathyroid hormone along with lower hematocrit and body weight. On both the diet regimens, CKD mice did not have hypertension but had lower cholesterol and triglyceride levels than the control mice. Despite the lower cholesterol levels, CKD mice had increased aortic plaque areas, fibrosis, and luminal narrowing. They also exhibited increased MPO expression and activity (i.e., increased oxidized tyrosines) that co-localized with infiltrating lesional macrophages and diminished vascular reactivity. In summary, unlike non-CKD mouse models of atherosclerosis, CKD mice exhibit increased MPO expression and catalytic activity in atherosclerotic lesions, which colocalize with lesional macrophages. These results implicate macrophage-derived MPO in CKDaccelerated atherosclerosis.Chronic kidney disease (CKD) affects 15% of Americans, and cardiovascular disease (CVD) continues to be the leading cause of mortality in Myeloperoxidase oxidizes artery proteins in kidney disease2 these patients (>10-fold mortality compared to the general population) (1-6). An increased risk for CVD is evident even in milder and non-albuminuric forms of CKD and cannot be fully explained by traditional risk factors (7-10). Furthermore, control of established risk factors such as hyperlipidemia results in substantially lower risk reduction in CKD patients compared to the general population (11). Recent evidence supports the key role of nontraditional risk factors (e.g., oxidative stress) in the pathogenesis of CVD in CKD (12-17), suggesting that CKD-specific mechanisms are responsible for CVD in kidney patients.Atherosclerosis, the major cause of CVD, is a chronic inflammatory disease characterized by the infiltration of lipids and inflammatory cells, such as monocyte-derived macrophages and Tlymphocytes, into the artery wall (18). While elevated levels of low-density lipoprotein (LDL) are known to increase the risk of atherosclerosis greatly (19), in vitro studies sugges...

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“…19 Protein modification by carbamylation of ε-NH 2 group of lysine has been particularly reported. 17,20,21 R-Amino groups of alanine, cysteine, and glycine have also been reported as possible carbamylation sites. [22][23][24] To the best of our knowledge, the present communication represents the first experimental report on carbamylation of N-terminal proline in protein.…”

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confidence: 99%

Carbamylation of N-Terminal Proline

Olajuyigbe

Demitri²,

Ajele

et al. 2010

ACS Med. Chem. Lett.

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Protein carbamylation is of great concern both in vivo and in vitro. Here, we report the first structural characterization of a protein carbamylated at the N-terminal proline. The unexpected carbamylation of the R-amino group of the least reactive codified amino acid has been detected in high-resolution electron density maps of a new crystal form of the HIV-1 protease/saquinavir complex. The carbamyl group is found coplanar to the proline ring with a trans conformation. The reaction of N-terminal with cyanate ion derived from the chaotropic agent urea was confirmed by mass spectra analysis on protease single crystals. Implications of carbamylation process in vitro and in vivo are discussed.KEYWORDS Carbamylation, N-terminal proline, HIV-1 protease/saquinavir complex, single crystals T he HIV protease (PR) is an aspartic protease that shares sequence homology around the active site with other retroviral proteases, as the conserved Asp-ThrGly catalytic triad. 1 PR is required for proteolytic cleavage of viral Gag and Gag-Pol polyproteins into individual structural and functional proteins during viral maturation. 2 In the absence of this proteolysis, immature noninfectious virions are produced, thus making PR a prime target for structureassisted drug design in antiviral therapy. 3,4 The structure-assisted drug design and discovery process utilizes techniques such as protein crystallography, nuclear magnetic resonance (NMR), and computational biochemistry to guide synthesis of potential drugs. PR has been widely characterized biochemically and structurally, which has led to the discovery of HIV protease inhibitors (PIs). Their utilization in highly active antiretroviral therapy (HAART) has been a major turning point in the management of HIV/acquired immune-deficiency syndrome (AIDS). 5 Recently, we have demonstrated that high-resolution X-ray crystallography can be used as a powerful method to identify the most potent PR inhibitor present in an epimeric mixture. 6 The pseudosymmetric peptidomimetic inhibitor based on a novel Phe-Pro isostere core matched the 2-fold symmetry of the homodimeric structure of the PR. Fourier maps obtained by high-resolution diffraction data (1.3 Å) clearly showed the catalytic site fully occupied by a single ordered stereoisomer. On the contrary, several X-ray crystal structures of PR complexed with more asymmetric FDAapproved inhibitors, like darunavir, nelfinavir, and saquinavir (SQV), have the catalytic site occupied by the inhibitor oriented in two almost equivalent positions related by a pseudo-2-fold symmetry. [7][8][9][10][11][12] To investigate this order/disorder phenomenon and its possible relationship with crystal packing, we have undertaken a systematic search for new crystal forms of wild-type PR in complex with SQV. Single crystals of the PR/SQV complex were obtained by a vapor diffusion technique and analyzed by X-ray diffraction. These crystals belong to a new monoclinic crystal form, which contains two dimers of the complex in the asymmetric unit. Other crystal...

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Protein carbamylation links inflammation, smoking, uremia and atherogenesis

Cited by 620 publications

References 47 publications

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Carbamylation of N-Terminal Proline

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