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Gamma-carboxyglutamic acid is a derivative of glutamic acid with an additional carboxyl group attached at the gamma carbon of the side chain. Its side chain can be written $-\mathrm{C}{\mathrm{H}}_2-\mathrm{CH}(\mathrm{COOH}{)}_2$ in the fully protonated representation. The extra carboxyl group changes the ion-binding properties of the corresponding gamma-carboxyglutamate residue within a protein.

In 1974, J. Stenflo and colleagues identified this unusual amino acid in prothrombin. Anomalous electrophoresis behaviour led to analysis by nuclear magnetic resonance and mass spectrometry, connecting a chemical modification with the special properties of this clotting protein.^[ref]

An illuminating comparison is to count the side-chain acid groups: glutamic acid has one, while gamma-carboxyglutamic acid has two. Their ionized forms provide additional negatively charged oxygen donors for calcium ions. The arrangement of several modified residues in a folded Gla domain gives the protein its calcium-binding architecture; an isolated modified amino acid is only one component of that structure.^[ref]

A Gla domain is a protein domain containing several gamma-carboxyglutamate residues. These are glutamate residues changed by a Vitamin K-dependent post-translational modification: an additional carboxyl group gives the modified residue extra capacity to bind calcium ions. In proteins such as prothrombin, the resulting calcium ion interactions help organize the domain's protein folding and its association with a phospholipid membrane. The residue chemistry, the folded domain and its membrane interaction are related but distinct levels of explanation.

The unusual residue was identified experimentally in 1974. J. Stenflo and colleagues found that a prothrombin fragment's electrophoretic mobility could not be explained by its ordinary amino acid composition. Nuclear magnetic resonance and mass spectrometry identified gamma-carboxyglutamic acid. The extra chemical group helped explain the fragment's calcium ion-binding behaviour.^[ref]

Later, M. Soriano-Garcia and colleagues used X-ray crystallography to resolve a calcium-bound prothrombin fragment at $2.2\text{A˚}$ resolution. Much of the Gla domain was disordered in the calcium-free crystal, whereas the calcium-bound structure was well defined and contained seven bound calcium ions. Their coordination by carboxylate groups and water connected residue chemistry to a three-dimensional structure. Seven is the count for that reported structure, rather than a universal definition of every Gla domain.^[ref]

J. Stenflo coauthored the 1974 work identifying gamma-carboxyglutamic acid in prothrombin, connecting Vitamin K dependence with a specific chemical modification of a clotting protein. The study isolated a four-residue peptide from the calcium-binding amino-terminal region and found mobility that ordinary amino-acid composition did not explain.^[ref]

Nuclear magnetic resonance and mass spectrometry identified two modified glutamic-acid residues in that peptide. The result supplied a chemical identity for the anomaly, rather than treating an altered migration pattern alone as a complete explanation.^[ref]

An additional carboxyl group changes a side chain's chemical possibilities, including its interactions with ions. This makes post-synthesis chemistry biologically significant: two protein preparations with the same genetically specified sequence can differ in modifications and function. The finding helped connect a nutritional requirement, a measurable molecular difference and the behavior of a calcium-binding protein, while preserving the distinction between a chemical observation and a physiological inference.