The antennae from three subunits within the trimers wrap around each other and undergo conformational changes as the catalytic cleft opens and closes.

Alignment of GLUD1 from various sources, shows that the antenna probably evolved in the protista prior to the formation of purine regulatory sites.

The adenosine moiety binds down into a hydrophobic pocket, with the ribose phosphate groups pointing outside towards the GTP allosteric site.

[10] GTP binding is antagonized by Pi and ADP but is synergistic with NADH bound in the noncatalytic allosteric site.

The allosteric regulators of GLUD1 - ADP, GTP, Leu, NAD+ and NADH - exert their effects by changing the energy required to open and close the catalytic cleft during enzymic turnover, in other words by destabilizing or stabilizing, respectively, the abortive complexes.

GLUD regulation is of particular biological importance as exemplified by observations showing that regulatory mutations of GLUD1 are associated with clinical manifestations in children.

ATP has complex concentration dependent effects on GLUD1 activity: GTP inhibits enzyme turnover over a wide range of conditions by increasing the affinity of GLUD1 for the reaction product, making product release rate limiting under all conditions in the presence of GTP.

GTP acts by keeping the catalytic cleft in a closed conformation thus stabilizing the abortive complexes.

Leu activates GLUD1 independently of the ADP, possessing a special allosteric site in the subunits interface area 8AR7.

[9] The enhanced responses of HI/HA patients (see HI/HA syndrom) to Leu stimulation of INS release3, which result from their impaired sensitivity to GTP inhibition, emphasize the physiological importance of inhibitory control of GLUD1.

In the newborn period, presenting symptoms may be nonspecific, including seizures, hypotonia, poor feeding, and apnea.

Individuals with autosomal recessive familial hyperinsulinism, caused by mutations in either ABCC8 or KCNJ11 (FHI-KATP), tend to be large for gestational age and usually present with severe refractory hypoglycemia in the first 48 hours of life; affected infants usually respond only partially to diet or medical management (i.e., diazoxide therapy) and thus may require pancreatic resection.

FHI-GCK, caused by mutations in GCK, may be much milder than FHI-KATP; however, some persons have severe, diazoxide-unresponsive hypoglycemia.

FHI-HADH, caused by mutations in HADH, tends to be relatively mild, although severe cases have been reported.

Individuals with FHI-HNF4A, caused by mutations in HNF4A, are typically born large for gestational age and have mild features that respond to diazoxide treatment.

Hyperammonemia/hyperinsulinism (HA/HI) is associated with mild-to-moderate hyperammonemia and with relatively mild, late-onset hypoglycemia; most but not all affected individuals have mutations in GLUD1.

[15] In the newborn period, presenting symptoms may be nonspecific, including seizures, hypotonia, poor feeding, and apnea.

[19] Long-term medical management includes the use of diazoxide, somatostatin analogs, nifedipine, glucagon, recombinant IGF-I, glucocorticoids, human growth hormone, dietary intervention, or combinations of these therapies.

[21] This article incorporates text from the United States National Library of Medicine, which is in the public domain.