Aliases: KIAA0838, GLS1, GAC, GAM, KGA.
GLS (kidney-type glutaminase, also known as GLS1) is a mitochondrial, phosphate-activated glutaminase (EC 3.5.1.2) that catalyzes the hydrolytic deamidation of L-glutamine to L-glutamate plus ammonia, the first and committed step of glutaminolysis. The gene produces two catalytically active splice isoforms, KGA (isoform 1) and the shorter GAC/glutaminase C (isoform 3), and a catalytically inactive muscle isoform GAM (isoform 2). The enzyme is synthesized as a ~74-kDa cytosolic precursor that is imported into mitochondria and processed by the mitochondrial-processing peptidase into mature 68- and 65-kDa chains that reside in the mitochondrial matrix. It assembles into homotetramers (dimers of dimers), and phosphate-driven tetramerization is coupled to catalytic activation; C-terminal ankyrin repeats modulate higher-order assembly. The glutamate produced feeds the TCA cycle (via glutamate dehydrogenase and transaminases to alpha-ketoglutarate) for energy and anaplerosis. GLS is central to renal ammoniagenesis and acid-base homeostasis, to the brain glutamate/glutamine cycle that supplies neurotransmitter glutamate, and to the elevated glutamine metabolism of many proliferating cancers, where it is an actively pursued drug target (allosteric inhibitors such as BPTES and CB-839/telaglenastat). Loss-of-function GLS variants cause severe neonatal developmental and epileptic encephalopathy and a global developmental delay/ataxia syndrome, whereas a gain-of-function variant causes cataract with glutamate excess and profound developmental delay.
Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.
| Disorder | Relationship | Where the gene appears |
|---|---|---|
| Global Developmental Delay, Progressive Ataxia, and Elevated Glutamine | causative | |
| Infantile Cataract, Skin Abnormalities, Glutamate Excess, and Impaired Intellectual Development | causative de novo | |
| Neonatal Epileptic Encephalopathy Due to Glutaminase Deficiency | causative | |
| Chromosome 2q32-q33 Deletion Syndrome | no genetic record |
mechanism: Additional contiguous-gene contribution to the behavioural and ectodermal phenotype; Contiguous-gene 2q32-q33 haploinsufficiency
|
An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.
| ClinGen disease | MOI | Classification | dismech entry |
|---|---|---|---|
| infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685 | AD | Limited 2024-07-26 |
|
| glutaminase deficiency MONDO:0600001 | AR | Definitive 2021-07-09 |
no dismech entry |
Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.