Dataset Information

Robust detection of oncometabolic aberrations by 1H-13C heteronuclear single quantum correlation in intact biological specimens.

ABSTRACT: Magnetic resonance (MR) spectroscopy has potential to non-invasively detect metabolites of diagnostic significance for precision oncology. Yet, many metabolites have similar chemical shifts, yielding highly convoluted 1H spectra of intact biological material and limiting diagnostic utility. Here, we show that hydrogen-carbon heteronuclear single quantum correlation (1H-13C HSQC) offers dramatic improvements in sensitivity compared to one-dimensional (1D) 13C NMR and significant signal deconvolution compared to 1D 1H spectra in intact biological settings. Using a standard NMR spectroscope with a cryoprobe but without specialized signal enhancing features such as magic angle spinning, metabolite extractions or 13C-isotopic enrichment, we obtain well-resolved 2D 1H-13C HSQC spectra in live cancer cells, in ex vivo freshly dissected xenografted tumors and resected primary tumors. This method can identify tumors with specific oncometabolite alterations such as IDH mutations by 2-hydroxyglutarate and PGD-deleted tumors by gluconate. Results suggest potential of 1H-13C HSQC as a non-invasive diagnostic in precision oncology.

SUBMITTER: Barekatain Y

PROVIDER: S-EPMC7316726 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Robust detection of oncometabolic aberrations by 1H-13C heteronuclear single quantum correlation in intact biological specimens.

Barekatain Yasaman Y Yan Victoria C VC Arthur Kenisha K Ackroyd Jeffrey J JJ Khadka Sunada S De Groot John J Huse Jason T JT Muller Florian L FL

Communications biology 20200625 1

Magnetic resonance (MR) spectroscopy has potential to non-invasively detect metabolites of diagnostic significance for precision oncology. Yet, many metabolites have similar chemical shifts, yielding highly convoluted 1H spectra of intact biological material and limiting diagnostic utility. Here, we show that hydrogen-carbon heteronuclear single quantum correlation (1H-13C HSQC) offers dramatic improvements in sensitivity compared to one-dimensional (1D) 13< ...[more]

PMID: 32587392

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Project description:Fast magic angle spinning (MAS) NMR spectroscopy is becoming increasingly important in structural and dynamics studies of biological systems and inorganic materials. Superior spectral resolution due to the efficient averaging of the dipolar couplings can be attained at MAS frequencies of 40 kHz and higher with appropriate decoupling techniques, while proton detection gives rise to significant sensitivity gains, therefore making fast MAS conditions advantageous across the board compared with the conventional slow- and moderate-MAS approaches. At the same time, many of the dipolar recoupling approaches that currently constitute the basis for structural and dynamics studies of solid materials and that are designed for MAS frequencies of 20 kHz and below, fail above 30 kHz. In this report, we present an approach for (1)H-(13)C/(1)H-(15)N heteronuclear dipolar recoupling under fast MAS conditions using R-type symmetry sequences, which is suitable even for fully protonated systems. A series of rotor-synchronized R-type symmetry pulse schemes are explored for the determination of structure and dynamics in biological and organic systems. The investigations of the performance of the various RN(n)(v)-symmetry sequences at the MAS frequency of 40 kHz experimentally and by numerical simulations on [U-(13)C,(15)N]-alanine and [U-(13)C,(15)N]-N-acetyl-valine, revealed excellent performance for sequences with high symmetry number ratio (N/2n > 2.5). Further applications of this approach are presented for two proteins, sparsely (13)C/uniformly (15)N-enriched CAP-Gly domain of dynactin and U-(13)C,(15)N-Tyr enriched C-terminal domain of HIV-1 CA protein. Two-dimensional (2D) and 3D R16(3)(2)-based DIPSHIFT experiments carried out at the MAS frequency of 40 kHz, yielded site-specific (1)H-(13)C/(1)H-(15)N heteronuclear dipolar coupling constants for CAP-Gly and CTD CA, reporting on the dynamic behavior of these proteins on time scales of nano- to microseconds. The R-symmetry-based dipolar recoupling under fast MAS is expected to find numerous applications in studies of protein assemblies and organic solids by MAS NMR spectroscopy.

Dataset Information

Robust detection of oncometabolic aberrations by 1H-13C heteronuclear single quantum correlation in intact biological specimens.

Publications

Robust detection of oncometabolic aberrations by <sup>1</sup>H-<sup>13</sup>C heteronuclear single quantum correlation in intact biological specimens.

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