| Structural highlights
Disease
GLNA_HUMAN Defects in GLUL are the cause of congenital systemic glutamine deficiency (CSGD) [MIM:610015. CSGD is a rare developmental disorder with severe brain malformation resulting in multi-organ failure and neonatal death. Glutamine is largely absent from affected patients serum, urine and cerebrospinal fluid.[1]
Function
GLNA_HUMAN This enzyme has 2 functions: it catalyzes the production of glutamine and 4-aminobutanoate (gamma-aminobutyric acid, GABA), the latter in a pyridoxal phosphate-independent manner (By similarity). Essential for proliferation of fetal skin fibroblasts.[2]
Publication Abstract from PubMed
The E3 ligase substrate adapter cereblon (CRBN), the primary target of clinical agents thalidomide and lenalidomide, recognizes endogenous substrates bearing the C-terminal cyclic imide modification. Although C-terminal cyclic imides can form spontaneously, an enzyme that regulates their formation and thereby promotes a biological pathway connecting substrates to CRBN is unknown. Here we report that protein carboxymethyltransferase (PCMT1) promotes formation of C-terminal cyclic imides on C-terminal asparagine residues of CRBN substrates. PCMT1 and CRBN coregulate the levels of metabolic enzymes including glutamine synthetase and inorganic pyrophosphatase 1 in vitro, in cells and in vivo, and this regulation is associated with the proepileptic phenotype of CRBN knockout mouse models. The discovery of an enzyme that regulates CRBN substrates through the C-terminal cyclic imide reveals a previously unknown biological pathway that is perturbed by thalidomide derivatives and provides a biochemical basis for the connection between multiple biological processes and CRBN.
PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates.,Zhao Z, Xu W, Feng EY, Cao S, Hermoso-Lopez A, Pena-Vega P, Lloyd HC, Porter AKD, Guzman M, Zheng N, Woo CM Nat Chem Biol. 2025 Dec 29. doi: 10.1038/s41589-025-02106-9. PMID:41461925[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Haberle J, Gorg B, Rutsch F, Schmidt E, Toutain A, Benoist JF, Gelot A, Suc AL, Hohne W, Schliess F, Haussinger D, Koch HG. Congenital glutamine deficiency with glutamine synthetase mutations. N Engl J Med. 2005 Nov 3;353(18):1926-33. PMID:16267323 doi:353/18/1926
- ↑ Vermeulen T, Gorg B, Vogl T, Wolf M, Varga G, Toutain A, Paul R, Schliess F, Haussinger D, Haberle J. Glutamine synthetase is essential for proliferation of fetal skin fibroblasts. Arch Biochem Biophys. 2008 Oct 1;478(1):96-102. doi: 10.1016/j.abb.2008.07.009., Epub 2008 Jul 17. PMID:18662667 doi:10.1016/j.abb.2008.07.009
- ↑ Zhao Z, Xu W, Feng EY, Cao S, Hermoso-López A, Peña-Vega P, Lloyd HC, Porter AKD, Guzmán M, Zheng N, Woo CM. PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates. Nat Chem Biol. 2025 Dec 29. PMID:41461925 doi:10.1038/s41589-025-02106-9
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