ACE phenotyping in Gaucher disease

Danilov, Sergei M.; Tikhomirova, Victoria E.; Metzger, Roman; Naperova, Irina A.; Букина, Т. М.; Göker-Alpan, Özlem; Tayebi, Nahid; Gayfullin, Nurshat M.; Schwartz, David E.; Samokhodskaya, L М; Кост, О. А.; Sidransky, Ellen

doi:10.1016/j.ymgme.2018.02.007

Cited by 31 publications

(33 citation statements)

References 51 publications

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“…The increase in this parameter could reflect conformational changes in cancer ACE in these patients (see below), or, alternatively, the presence of tumor marker which expression is increased dramatically in tumor tissues (for example serum amyloid A protein [38]), which could bind to ACE and change its catalytic properties. We discovered recently (but not identified yet) similar ACE effector, which is present at high levels in normal spleen, but disappears in Gaucher spleen [25].…”

Section: Resultsmentioning

confidence: 99%

“…In order to characterize the conformation of ACE in prostate tissues we performed conformational fingerprinting of ACE using a panel of mAbs directed against different epitopes located on the N and C domains of catalytically active human ACE [21]. We demonstrated previously that the pattern of precipitation of ACE activity by this set of mAbs provides a sensitive tool for detecting changes in local topography of the surface of ACE globule due to denaturation, inhibition [21, 22], mutations [39 and references therein, 40], or cell/tissue origin [21, 23, 25, 41].…”

Section: Resultsmentioning

confidence: 99%

“…3) Our studies with monoclonal antibodies (mAbs) to numerous conformational epitopes on the surface of human ACE revealed that the pattern of mAb binding to ACE - “conformational fingerprint of ACE” – is tissue specific, mainly due to tissue specific ACE glycosylation [21–25]. Moreover, the conformational fingerprint of prostate ACE was shown to be quite different from that for lung ACE [23] that opens up a theoretical possibility for the use the appearance of prostate-specific ACE in the blood as an early marker of prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

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Tissue ACE phenotyping in prostate cancer

et al. 2019

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Epithelial cells of prostate express significant level of ACE and, as a result, seminal fluid has 50-fold more ACE than plasma. The substitution of highly specialized prostate epithelial cells by tumor cells results in dramatic decrease in ACE production in prostate tissues. We performed detailed characterization of ACE status in prostate tissues from patients with benign prostate hyperplasia (BPH) and prostate cancer (PC) using new approach- ACE phenotyping, that includes evaluation of: 1) ACE activity with two substrates (HHL and ZPHL); 2) the ratio of the rates of their hydrolysis (ZPHL/HHL ratio); 3) the ratio of immunoreactive ACE protein to ACE activity; 4) the pattern of mAbs binding to different epitopes on ACE – ACE conformational fingerprint - to reveal conformational changes in prostate ACE due to prostate pathology. ACE activity dramatically decreased and the ratio of immunoreactive ACE protein to ACE activity increased in PC tissues. The catalytic parameter, ZPHL/HHL ratio, increased in prostate tissues from all patients with PC, but was did not change for most |BPH patients. Nevertheless, prostate tissues of several patients diagnosed with BPH based on histology, also demonstrated decreased ACE activity and increased immunoreactive ACE protein/ACE activity and ZPHL/HHL ratios, that could be considered as more early indicators of prostate cancer development than routine histology. Thus, ACE phenotyping of prostate biopsies has a potential to be an effective approach for early diagnostics of prostate cancer or at least for differential diagnostics of BPH and PC.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tissue ACE phenotyping in prostate cancer

et al. 2019

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“…In order to save valuable mAbs, we used not more than 3 μg/ml of pure mAbs (or 1/20 dilution of hybridoma cell culture medium) which was found to be sufficient for coating (Fig 1C and 1D). Usually the amount of ACE immunoreactive protein was estimated using the strongest mAb to ACE, clone 9B9 [16, 20], while a pattern of ACE activity precipitation by a panel of mAbs to different epitopes on ACE—conformational fingerprint of ACE—was used for the estimation of local conformational differences in ACE surface topography due to disease [5, 7, 21] or due to tissue origin of ACE [5, 9, 10].…”

Section: Resultsmentioning

confidence: 99%

“…Previously we found that the pattern of ACE activity precipitation by a set of mAbs—conformational fingerprint of ACE—could be sensitive to the presence of detergents [5]. Because we actively used this approach for the study of the fine conformation of ACE from different human tissues—tissue ACE specificity [9–10, 21]–we studied the effect of Triton X-100, used for ACE solubilization, on ACE conformational fingerprint. Fig 3 demonstrates the effect of different concentrations of Triton X-100 on ACE purified from human lung homogenate.…”

Section: Resultsmentioning

confidence: 99%

Conformational fingerprint of blood and tissue ACEs: Personalized approach

et al. 2018

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BackgroundThe pattern of binding of monoclonal antibodies (mAbs) to 18 epitopes on human angiotensin I-converting enzyme (ACE)–“conformational fingerprint of ACE”–is a sensitive marker of subtle conformational changes of ACE due to mutations, different glycosylation in various cells, the presence of ACE inhibitors and specific effectors, etc.Methodology/Principal findingsWe described in detail the methodology of the conformational fingerprinting of human blood and tissue ACEs that allows detecting differences in surface topography of ACE from different tissues, as well detecting inter-individual differences. Besides, we compared the sensitivity of the detection of ACE inhibitors in the patient’s plasma using conformational fingerprinting of ACE (with only 2 mAbs to ACE, 1G12 and 9B9) and already accepted kinetic assay and demonstrated that the mAbs-based assay is an order of magnitude more sensitive. This approach is also very effective in detection of known (like bilirubin and lysozyme) and still unknown ACE effectors/inhibitors which nature and set could vary in different tissues or different patients.Conclusions/SignificancePhenotyping of ACE (and conformational fingerprinting of ACE as a part of this novel approach for characterization of ACE) in individuals really became informative and clinically relevant. Appreciation (and counting on) of inter-individual differences in ACE conformation and accompanying effectors make the application of this approach for future personalized medicine with ACE inhibitors more accurate. This (or similar) methodology can be applied to any enzyme/protein for which there is a number of mAbs to its different epitopes.

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Human angiotensin I‐converting enzyme study by surface‐enhanced Raman spectroscopy

Boginskaya

Nechaeva

Tikhomirova

et al. 2021

J Raman Spectroscopy

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Angiotensin I‐converting enzyme (ACE) is a glycoprotein, consisting of two homologous domains within a single polypeptide chain. ACE concentration in biological fluids is an important parameter of clinical observation; its increase or decrease may accompany various pathologies. Currently, the exact crystal structure of the two‐domain ACE form is still unknown because of microheterogeneity and intensity of the enzyme glycosylation. Raman spectroscopy provides the qualitative and quantitative analysis of many compounds, including proteins. For the first time, surface‐enhanced Raman scattering (SERS) spectra of native and thermo‐denatured human ACE have been demonstrated with full assignment. Denaturation leads to SERS intensity increase and bands shifting. Detailed band assignment and discussion are included to elucidate the potential site of ACE interaction with the silver surface. Based on SERS spectra, we characterized the region on the ACE molecule in contact with the substrate and demonstrated the model of the two‐domain ACE adsorbed on a silver matrix.

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ACE phenotyping in Gaucher disease

Cited by 31 publications

References 51 publications

Tissue ACE phenotyping in prostate cancer

Tissue ACE phenotyping in prostate cancer

Conformational fingerprint of blood and tissue ACEs: Personalized approach

Human angiotensin I‐converting enzyme study by surface‐enhanced Raman spectroscopy

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