Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jun 16;5(25):15063-15068.
doi: 10.1021/acsomega.0c00877. eCollection 2020 Jun 30.

Pyruvate Aldol Condensation Product: A Metabolite That Escaped Synthetic Preparation for Over a Century

Andro C Rios  1   2   3 , Partha P Bera  4   5 , Jennifer A Moreno  2   3 , George Cooper  1   3
Affiliations

Pyruvate Aldol Condensation Product: A Metabolite That Escaped Synthetic Preparation for Over a Century

Andro C Rios et al. ACS Omega. .

Abstract

The homoaldol condensation product of pyruvate, 2-methyl-4-oxopent-2-enedioic acid (OMPD), has been recently implicated as a catabolic intermediate in the bacterial degradation of lignin and previously identified from other biological sources in reports ranging over 60 years. Yet, while a preparation of the pyruvate homoaldol product precursor, 4-hydroxy-4-methyl-2-oxoglutaric acid (HMOG/Parapyruvate), was first reported in 1901, there has not been a complete published synthesis of OMPD. Analyses of reaction mixtures have helped identify zymonic acid, the lactone of HMOG, as the direct precursor to OMPD. The reaction appears to proceed through an acid- or base-mediated ring opening that does not involve formal lactone hydrolysis. In addition to a preparative protocol, we provide a proposed mechanism for the formation of methylsuccinic acid that arises from the nonoxidative decarboxylation of OMPD. Finally, we calculated the relative stability of the isomers of OMPD and found Z-OMPD to be the lowest in energy. These computations also support our observations that Z-OMPD is the most abundant isomer across a range of pH values.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Structures of All Compounds Used in This Study
Isomers of the homoaldol condensation product of pyruvate are 2-methyl-4-oxopent-2-enedioic acid (OMPD, 4 and 5), 4-methylene-2-oxo-glutaric acid (4-MEOG, 6), and 4-carboxy-2-hydroxypenta-2,4-dienoate (CHPD, 7 and 8).
Scheme 2
Scheme 2. Summary of the Reaction Pathways of Pyruvic Acid under Aqueous Conditions Previously Known,−,, and Newly Identified Here
While all keto acid structures are shown as neutral and unhydrated at the keto position to maintain simplicity, their actual states (hydration, tautomer, and ionic) vary with pH in aqueous solutions.
Figure 1
Figure 1
(A) Extracted ion chromatogram displaying a mixture of products resulting from zymonic acid in heated pH 4 buffered solutions at 60 °C (See the Supporting Information (SI)). The asterisk denotes a tentative assignment of (E or Z) CHPD on the shoulder. (B) Extracted ion chromatogram of synthetically prepared Z-OMPD with the emerging decarboxylation product, methylsuccinic acid. Extracted ion peaks in negative mode: red (m/z = 157), green (m/z = 131), black (m/z = 175), purple (m/z = 129), and blue (m/z = 87).
Scheme 3
Scheme 3. Synthetic Preparation of Z-OMPD, the Dominant Isomer of the Pyruvate Homoaldol Condensation Product
Figure 2
Figure 2
(A) Reaction monitoring of 0.1 M HCl solution of HMOG at 75 °C. (B) Proposed mechanism for the formation of methylsuccinic acid proceeding through a keto hydrated state.
Figure 3
Figure 3
Energy profile of the isomeric distribution of OMPD and decarboxylation reactions via cis and trans pathways.
See this image and copyright information in PMC

References

    1. Waters K. L. The α-keto acids. Chem. Rev. 1947, 41, 585–598. 10.1021/cr60130a005. - DOI - PubMed
    1. Cooper A. J. L.; Ginos J. Z.; Meister A. Synthesis and properties of the α-keto acids. Chem. Rev. 1983, 83, 321–358. 10.1021/cr00055a004. - DOI
    1. Penteado F.; Lopes E. F.; Alves D.; Perin G.; Jacob R. G.; Lenardao E. J. α -Keto acids: acylating agents in organic synthesis. Chem. Rev. 2019, 119, 7113–7278. 10.1021/acs.chemrev.8b00782. - DOI - PubMed
    1. Varman A. M.; He L.; Follenfant R.; Wu W. H.; Wemmer S.; Wrobel S. A.; Tang Y. J. J.; Singh S. Decoding how a soil bacterium extracts building blocks and metabolic energy from ligninolysis provides road map for lignin valorization. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, E5802–E5811. 10.1073/pnas.1606043113. - DOI - PMC - PubMed
    1. Kamimura N.; Takahashi K.; Mori K.; Araki T.; Fujita M.; Higuchi Y.; Masai E. Bacterial catabolism of lignin-derived aromatics: New findings in a recent decade: Update on bacterial lignin catabolism. Environ. Microbiol. Rep. 2017, 9, 679–705. 10.1111/1758-2229.12597. - DOI - PubMed