Reactive carbonyls - as in ketones and aldehydes - readily react with amino and hydroxyl groups of biomolecules at physiological conditions. These carbonyls are present, e.g., in reducing sugars like glucose and their metabolites. In the case of glucose and the free amino groups of lysine and arginine, advanced glycation end products (AGEs) are formed. AGEs are associated with diseases like atherosclerosis, cancer, and diabetes. Glycated hemoglobin (HbA1c) is an important and well-established parameter for monitoring the long-term glycemic control in diabetes mellitus. In addition, AGEs may be utilized as indicator for the extent of thermal food processing.

Carboxymethylated amino acids are formed in vivo by a non-enzymatic reaction with glyoxal or methylglyoxal, which are found in increased concentrations when their detoxification pathways are impaired. More than 1000 sites of potential protein carboxymethylation have been identified in the proteome of primary human cells.


Reaction of a lysine residue with glyoxal (R = H) and methylglyoxal (R = CH₃) via an aldimine to N(6)‑carboxymethyl lysine as example for the non-enzymatic modification of amino acids by sugar metabolites.

Excess glycation and carboxymethylation of proteins affect their degradation and are leading, e.g., to the dysregulation of the cell cycle and to disturbed microtubule dynamics. Besides, carboxymethylated amino acids are reported for various other applications, including the incorporation in biological active substances. O‑carboxymethylation may mimic phosphorylation and thus can interfere with signal transduction processes. In pharmaceutical research, glycated building blocks are playing a substantial role in macrocyclic inhibitors, e.g., for blocking the interactions of PD-L1 with its receptor PD-1, which is an important concept in the therapy of certain tumors.

At Iris, we offer a selection of protected carboxymethylated amino acid derivatives, which can be conveniently incorporated by solid-phase peptide synthesis (SPPS). OtBu and Boc serve as protection groups for the carboxymethyl functionalization and can be removed by TFA during overall cleavage of the peptide from the solid support.

Carboxymethylated amino acid building blocks with side chain protection as OtBu ester to prevent undesired branching during SPPS. The protecting group is easily removed by TFA.

→ You are interested in a specific carboxymethylated building block not yet available in our portfolio? Get in contact for a custom synthesis! 

→ For more information about Maillard Reaction Products (MRPs) and food control, see our flyer! 

References:

Mapping protein carboxymethylation sites provides insights into their role in proteostasis and cell proliferation; S. Di Sanzo, K. Spengler, A. Leheis, J. Kirkpatrick, T. Rändler, T. Baldensperger, T. Dau, C. Henning, L. Parca, C. Marx, Z. Wang, M. Glomb, A. Ori, R. Heller; Nat Commun. 2021; 12: 6743. https://doi.org/10.1038/s41467-021-26982-6

Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation; G. Vistoli, D. De Maddis, A. Cipak, N. Zarkovic, M. Carini, G. Aldini; Free Radical Res. 2013; 47(S1): 3-27. https://doi.org/10.3109/10715762.2013.815348

Advanced Glycation End Products - Sparking the Development of Diabetic Vascular Injury; A. Goldin, J. Beckman, A. Schmidt, M. Creager; Circulation 2006; 114(6): 597-605. https://doi.org/10.1161/CIRCULATIONAHA.106.621854

Maillard products as biomarkers in cancer; B. Bachmeier, A. Nerlich, H. Rohrbach, E. Schleicher, U. Friess; Ann. N.Y. Acad. Sci. 2008; 1126(1): 283-7. https://doi.org/10.1196/annals.1433.057

Structural and biological characterization of pAC65, a macrocyclic peptide that blocks PD-L1 with equivalent potency to the FDA-approved antibodies; I. Rodriguez, J. Kocik-Krol, L. Skalniak, B. Musielak, A. Wisniewska, A. Ciesiołkiewicz, Ł. Berlicki, J. Plewka, P. Grudnik, M. Stec, M. Siedlar, T. Holak, K. Magiera-Mularz; Mol Canc. 2023; 22: Article 150. https://doi.org/10.1186/s12943-023-01853-4

Advanced glycation end-products (AGEs) in foods and their detecting techniques and methods: A review; Q. Wei, T. Liu, D.-W. Sun; Trends Food Sci Technol. 2018; 82: 32-45. https://doi.org/10.1016/j.tifs.2018.09.020

A glycolytic metabolite bypasses “two-hit” tumor suppression by BRCA2; L. Kong, K. Gupta, A. Wu, D. Perera, R. Ivanyi-Nagy, S. Ahmed, T. Tan, S. Tan, A. Fuddin, E. Sundaramoorthy, G. Goh, R. Wong, A. Costa, C. Oddy, H. Wong, C. Patro, Y. Kho, X. Huang, J. Choo, M. Shehata, S. Lee, B. Goh, C. Frezza, J. Pitt, A. Venkitaraman; Cell 2024; 187(9): 1-19. https://doi.org/10.1016/j.cell.2024.03.006