polyglutamation

Polyglutamation is the addition of multiple glutamate residues to a substrate to form a polyglutamate chain. The process occurs in two main contexts in biology: protein polyglutamylation, a post-translational modification of proteins such as tubulins, and folate polyglutamylation, where glutamate residues are appended to folate molecules to form polyglutamates.

In protein polyglutamylation, glutamate residues are appended to existing glutamate side chains by tubulin tyrosine ligase-like (TTLL) enzymes or related transferases, producing side chains linked through gamma-carboxyl to the next residue. The length and type of the chain are regulated by specific enzymes, and chains can be trimmed by cytosolic carboxypeptidases. Polyglutamylation affects microtubule properties, including stability and interactions with microtubule-associated proteins and motor proteins, thereby influencing intracellular transport and cell division. Detection methods include antibodies such as GT335 and mass spectrometry, with chain length varying by tissue and condition.

In folate metabolism, folylpolyglutamate synthase (FPGS) adds multiple glutamate residues to folate cofactors, forming polyglutamates that are retained longer within cells and serve as preferred substrates for folate-dependent enzymes such as dihydrofolate reductase and thymidylate synthase. Gamma-glutamyl hydrolase (GGH) can remove terminal glutamates, regulating polyglutamate length. This modification modulates intracellular folate pools and can influence sensitivity to antifolate chemotherapy agents.

Polyglutamation is conserved across eukaryotes and participates in both cellular structure and metabolism. Abnormal polyglutamylation is linked to neurological and ciliopathy phenotypes in experimental models, while folate polyglutamylation status can affect drug response. Research continues to map the enzymes involved, understand regulation of chain length, and clarify clinical implications for neurobiology and cancer therapy.