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Published on 06/02/2024
The chemical alteration of proteins by post-translational modifications (PTMs) plays an important role in diverse cellular and pathological processes. Lysine malonylation is a recently characterized PTM involved in various metabolic processes and stress responses. Besides, malonylation modifications are closely related to the pathogenesis of various diseases, such as inflammation, type 2 diabetes, and angiogenesis-associated diseases.
One drawback of the before-mentioned modification is its potential susceptibility to decarboxylation, making it difficult to analyze the original malonyllysine and causing artifactual detection of acetyllysine at former malonylation sites. Hence, studies of post-translational modifications greatly benefit from the development of stable analogues of these modifications, allowing for their incorporation in proteins and functional analysis.
To address this, we report on a stable isostere of malonyllysine. Replacement of the malonyl group by a tetrazole results in resistance towards thermal decarboxylation, while keeping similar physical properties such as a planar structure and nearly identical pKa values (carboxylate pKa 4.5; tetrazole pKa 4.9).
Malonyllysine suffers from decarboxylation resulting in the formation of acetyllysine. Malonyltetrazolelysine is a thermally and chemically stable isostere, which is available as Fmoc protected derivative, hence, can be incorporated into peptide sequences by standard synthetic protocols.
At Iris Biotech, we offer a Fmoc-protected derivative suitable for incorporation into a peptide by solid-phase peptide synthesis (SPPS). This compound is ideally for the analysis of post-translational lysine derivatizations. Besides, other protecting groups can be installed enabling the synthesis of all kinds of peptide substrates, chemical attachment to proteins, conjugation to antibodies, single-chain and nanobodies via incorporation of non-canonical amino acids and Click reaction, and to non-biological carriers, such as polymers, silicates, metal surfaces or metal oxides.
Besides its superior thermal and chemical stability, malonyltetrazolelysine is also recognized by anti-malonyllysine antibodies and SIRT5 decarboxylases with kinetics comparable to the original malonyllysine. Furthermore, UV absorption of the tetrazole derivative enables spectroscopic monitoring by a set of different analytical methods, which allows more accurate analysis than the endogeneous malonyl derivative.
The tetrazole isostere of malonyllysine is recognized by anti-malonyllysine and histone deacetylases. SIRT5 removes malonyl and malonyltetrazole, respectively, with comparable kinetics.
Summarized properties of malonyltetrazolelysine:
→ You are interested in another protection pattern? Get in contact and inquire for a custom synthesis!
→ Interested in anti-malonyl antibodies decorated with payloads via stable or self-immolative linkers?
Synthesis and Evaluation of a Stable Isostere of Malonyllysine**; Y. Jing, S. E. Bergholtz, A. Omole, R. A. Kulkarni, T. T. Zengeya, E. Yoo, J. L. Meier; Chembiochem : a European journal of chemical biology 2022; 23: e202100491. https://doi.org/https://doi.org/10.1002/cbic.202100491
Lysine Malonylation and Its Links to Metabolism and Diseases; L. Zou, Y. Yang, Z. Wang, X. Fu, X. He, J. Song, T. Li, H. Ma, T. Yu; Aging Dis. 2023; 14(1): 84-98. https://doi.org/10.14336/AD.2022.0711
Chapter 1 – Posttranslational Modifications of Proteins and Their Role in Biological Processes and Associated Diseases; I.-u.-R. Tak, F. Ali, J. S. Dar, A. R. Magray, B. A. Ganai, M. Z. Chishti; Protein Modificomics 2019; 1-35. https://doi.org/10.1016/B978-0-12-811913-6.00001-1