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Reaction Energetics and ¹³C Fractionation of Alanine Transamination in the Aqueous and Gas Phases

McNeill, Ashley S. and Dallas, Brooke H. and Eiler, John M. and Bylaska, Eric J. and Dixon, David A. (2020) Reaction Energetics and ¹³C Fractionation of Alanine Transamination in the Aqueous and Gas Phases. Journal of Physical Chemistry A, 124 (10). pp. 2077-2089. ISSN 1089-5639. doi:10.1021/acs.jpca.9b11783.

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The alanine transaminase (ALT) enzyme catalyzes the transfer of an amino group from alanine to α-ketoglutarate to produce pyruvate and glutamate. Isotope fractionation factors (IFFs) for the reaction ⁺H₃NCH(CH₃)COO⁻ + ⁻OOCCH₂CH₂C(O)COO⁻ ↔ CH₃C(O)COO⁻ + ⁻H₃NCH(CH₂CH₂COO⁻)COO⁻ (zwitterionic neutral alanine + doubly deprotonated α-ketoglutarate ↔ pyruvate + zwitterionic glutamate anion) were calculated from the partition functions of explicitly and implicitly solvated molecules at 298 K. Calculations were done for alanine (non-charge separated, zwitterion, deprotonated,), pyruvic acid (neutral, deprotonated), glutamic acid (non-charge separated, zwitterion, deprotonated, doubly deprotonated), and α-ketoglutaric acid (neutral, deprotonated, doubly deprotonated). The computational results, calculated from gas phase and aqueous optimized clusters with explicit H₂O molecules at the MP₂/aug-cc-pVDZ and MP₂/aug-cc-pVDZ/COSMO levels, respectively, predict that substitution of ¹³C at the C2 position of alanine and pyruvic acid and their various forms leads to the C2 position of pyruvic acid/pyruvate being enriched in ¹³C/¹²C ratio by 9 ‰. Simpler approaches that estimate the IFFs based solely on changes in the zero-point energies (ZPEs) are consistent with the higher-level model. ZPE-based IFFs calculated for simple analogues formaldehyde and methylamine (analogous to the C₂ positions of pyruvate and alanine, respectively) predict a ¹³C enrichment in formaldehyde of 7 to 8 ‰ at the MP₂/aug-cc-pVDZ and aug-cc-pVTZ levels. A simple predictive model using canonical functional group frequencies and reduced masses for ¹³C exchange between R₂C=O and R₂CH-NH₂ predicted enrichment in R₂C=O that is too large by a factor of two, but is qualitatively accurate compared with the more sophisticated models. Our models are all in agreement with the expectation that pyruvate and formaldehyde will be preferentially enriched in ¹³C due to the strength of their >C=O bond relative to that of the ≡C-NH₂ in alanine and methylamine. ¹³C/¹²C substitution is also modeled at the methyl and carboxylic acid sites of alanine and pyruvic acid, respectively.

Item Type:Article
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URLURL TypeDescription
McNeill, Ashley S.0000-0003-1957-3135
Dallas, Brooke H.0000-0002-1313-3270
Bylaska, Eric J.0000-0001-6405-599X
Dixon, David A.0000-0002-9492-0056
Additional Information:© 2020 American Chemical Society. Received: December 20, 2019; Revised: January 28, 2020; Published: January 30, 2020. This work was supported by the U.S. Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences (BES), Chemical Sciences, Geosciences, and Biosciences Division through its Geosciences program at Pacific Northwest National Laboratory (PNNL) by a subcontract to The University of Alabama. D.A.D. thanks the Robert Ramsay Fund of The University of Alabama for partial support. This research used computational resources of the National Energy Research Scientific Computing Center (NERSC), a User Facility supported by the Office of Science of the U.S. DOE under contract no. DE-AC02-05CH11231. We thank the support from the NERSC NESAP program for helping improve the performance of NWChem software on their machines. A portion of this research was performed using EMSL, a U.S. DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research, DE-AC06-76RLO 1830. The authors declare no competing financial interest.
Funding AgencyGrant Number
Department of Energy (DOE)DE-AC02-05CH11231
University of AlabamaUNSPECIFIED
Department of Energy (DOE)DE-AC06-76RLO1830
Issue or Number:10
Record Number:CaltechAUTHORS:20200130-131633898
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Official Citation:Reaction Energetics and 13C Fractionation of Alanine Transamination in the Aqueous and Gas Phases. Ashley S. McNeill, Brooke H. Dallas, John M. Eiler, Eric J. Bylaska, and David A. Dixon. The Journal of Physical Chemistry A 2020 124 (10), 2077-2089; DOI: 10.1021/acs.jpca.9b11783
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101006
Deposited By: Tony Diaz
Deposited On:30 Jan 2020 21:29
Last Modified:16 Nov 2021 17:58

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