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Proc Natl Acad Sci U S A
Proc Natl Acad Sci U S A
PNAS
Proceedings of the National Academy of Sciences of the United States of America
0027-8424
1091-6490
National Academy of Sciences

202412390
10.1073/pnas.2412390121
letterLettermicrobioMicrobiologyenv-sci-physEnvironmental Sciences417
42
423
Letters
Biological Sciences
Microbiology
Physical Sciences
Environmental Sciences
Active involvement of compartmental, inter- and intramolecular deuterium disequilibrium in adaptive biology
Boros László G. contact@laszlogboros.com
a 1 2 https://orcid.org/0000-0003-1211-9933

Seneff Stephanie b https://orcid.org/0000-0001-8191-1049

Túri Marianna c https://orcid.org/0000-0001-9341-3004

Palcsu László c https://orcid.org/0000-0002-6542-7537

Zubarev Roman A. roman.zubarev@ki.se
d e f 2 https://orcid.org/0000-0001-9839-2089

aDepartment of Physics and Astronomy, Physics of Living Systems, Sub-Molecular Medical Sciences Deutenomics Core, Vrije University Amsterdam, Amsterdam 1081 HV, The Netherlands
bComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139
cIsotope Climatology and Environmental Research Centre, Hungarian Research Network Institute for Nuclear Research, Debrecen H-4001, Hungary
dDivision of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 171 77, Sweden
eDepartment of Pharmacological & Technological Chemistry, I. M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
fThe National Medical Research Center for Endocrinology, Moscow 117292, Russia
2To whom correspondence may be addressed. Email: contact@laszlogboros.com or roman.zubarev@ki.se.
1Present address: Comparative Linguistics Section, Scientific Translators of Arcane Scripts, Törökszentmiklós H-5200, Hungary.

30 8 2024
10 9 2024
30 8 2024
121 37 e2412390121Copyright © 2024 the Author(s). Published by PNAS.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

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pmcThe biosynthetic natural depletion of deuterium (2H) in palmitic acid of tumor cells, when compared to water of fresh growth medium, readily distinguishes respiration from fermentation, as elegantly reported by Maloney et al. (1). Accelerated cellular growth remarkably decreased deuterium to protium (2H/1H) ratios, particularly in glycerol-respiring cells, by about 200‰ (~125 ppm). The authors conclude that metabolite 2H/1H ratios may be used “as passive natural trackers of eukaryotic metabolism” that complement complex isotope-tracer methods. The importance of water and product isotope chemistry is evident, which allows a systematic and, more importantly, a mechanistic interpretation, shifting the emphasis from passive to active role of deuterium in the regulation of metabolism in adaptive biology.

While fatty acids show a deuterium depleted (“deupleted”) profile over extracellular water in rapidly dividing cells, another natural 2H tracer study showed abnormally high deuterium content in collagen, just to redefine hydrogen chemical mass in biology (2). Notably, δ2H values in (hydroxy)proline of collagen extracted from grey seals show about twice as much deuterium as its ceiling (~157 ppm) in seawater. This corresponds to at least four times higher δ2H than in any previously reported biogenic sample. As diet was ruled out as a plausible mechanism for such anomalous enrichment, evolution seems to depend on deuterium-related regulatory processes via submolecular proton tunneling event (reaction) architectures, with coinciding significant isotope fractionation properties.

There are apparent adaptive mechanisms: Some derive from traditional biochemistry, whereas others are yet to be clarified behind the overwhelming disequilibrium patterns in compartmental, inter- and intramolecular deuterium levels reported in recent studies. The deupleted fatty acid profile in comparison with water, as reported by Maloney et al. (1) in rapidly dividing eukaryotic cells, also tracks ribonucleoside diphosphate reductase activity, for example, during the formation of deuterium rich deoxyribonucleotides, along with significant deuterium-trapping metabolic water production from 2H-labeled glucose as the single tracer (3, 4). The natural depletion of deuterium in fatty acids occurs essentially the same way and involves identical enzymatic channels (routes). This is because compartmentalized water-related deuteron and proton tunneling reactions toward nonoxidative pentose-phosphate-dependent nucleotide synthesis (5, 6) readily limit mitochondrial fatty acid precursor (citrate) synthesis in rapidly dividing cells.

The mechanism of accumulation of deuterons in specific imino acids of bone collagen high above natural mean oceanic water abundance (2) is another example, yet more challenging to answer. This phenomenon, seen in predators with phenotypic adaptation to rapid dives in water, likely involves instant, reversible isomerase reactions with selective proton tunneling (7), nuclear quantum destabilization of metabolic water protons (8), and thus significant deuterium discriminating properties in hydrophobic cellular and mitochondrial nanoconfinements (9).

We suggest that deutenomics, the study of inherent autonomic hydrogen isotope discrimination processes in nature, should be introduced into translational research. It is important to determine the magnitude of intrinsic kinetic isotope effects, as they are critical in deuterium fractionation, yet often misinterpreted. The Human Deutenome should also not be ignored as an active player (as opposed to passive tracker) in forming the biological reaction coordinate (10).

Author contributions

L.G.B., L.P., and R.A.Z. designed research; S.S., M.T., L.P., and R.A.Z. performed research; M.T. and L.P. contributed new reagents/analytic tools; L.G.B., S.S., M.T., L.P., and R.A.Z. analyzed data; and L.G.B., S.S., and R.A.Z. wrote the paper.

Competing interests

The authors declare no competing interest.
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