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Structure and enzymology of glutaminase S482C and H461L variants associated with excess brain glutamate and neurological disease.

Overview

Authors: Cléa S Crane1, Thora K McIssac1, Shawn K Milano1,2, Richard A Cerione1,2, Scott M Ulrich3
ORCID iDs: Cléa S Crane, Richard A Cerione, Scott M Ulrich
  1. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA
  2. Department of Molecular Medicine, Cornell University, Ithaca, New York, USA
  3. Department of Chemistry, Ithaca College, Ithaca, New York, USA
Institutions: Cornell University (United States); Ithaca College (United States)
Journal: The Journal of biological chemistry, volume 302, issue 6, article 113091
Dates: received 8 January 2026; published online 27 April 2026; in print June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.jbc.2026.113091 · PMID 42055345 · PMCID PMC13218152 · OpenAlex W7156050552
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), cellular / molecular (subfield)
Methods: Spectral & time-frequency
Keywords: glutaminase, disease-associated variant, excitotoxicity, glutamate, neurotransmission, enzyme mechanism, protein structure
MeSH: Brain*, Glutamic Acid*, Glutaminase*, Nervous System Diseases*, Animals, Humans, Models, Molecular, Mutation (* major topic)
Topic: Amino Acid Enzymes and Metabolism (Biochemistry, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: National Institute of General Medical Sciences (R35 GM152206); National Institutes of Health (S10OD030470-01, 1-P30-GM124166); NIH HHS (S10 OD030470); NIGMS NIH HHS (P30 GM124166, R35 GM152206)
Citations: not cited yet (Europe PMC); 53 references in the paper

Abstract

Glutaminase variants associated with neurological diseaseGlutaminase (GLS) catalyzes the hydrolysis of glutamine to produce glutamate, the brain’s principal excitatory neurotransmitter. Two de novo gain-of-function mutations in GLS, S482C and H461L, were recently identified in patients with developmental delay, epilepsy, and infantile cataract. These patients exhibited high glutamate and low glutamine concentrations in the brain, suggesting that the GLS variants have abnormal enzymology. Here, we examined the enzymatic properties of the mutant enzymes and found that they no longer require the anionic activator phosphate to stimulate enzymatic activity or induce filament formation. The mutant enzymes also exhibit a total (S482C) or partial (H461L) loss of glutamate product inhibition, lifting this restriction on glutamate accumulation. Structural analysis of the S482C variant shows the mutation shifts the key catalytic residue Y466 into its catalytically active configuration and disrupts a key hydrogen bond between Y466 and the glutamate product, explaining how the S482C variant has enzymatic activity in the absence of phosphate and is insensitive to glutamate product inhibition. These results shed new light on the mechanism of phosphate activation and glutamate product inhibition of GLS and show that loss of these enzymatic properties disrupts glutamate homeostasis in the brain and causes neurological disease.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data availability

Coordinates for S482C GAC have been deposited in the RCSB Protein Data Bank (www.rcsb.org) with accession code 9PIA. All other data are contained within the manuscript and the Supporting Information.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 7 keywords, 8 MeSH terms, 4 funders, 52 references.

Cite

This paper

Crane, C. S., McIssac, T. K., Milano, S. K., Cerione, R. A., & Ulrich, S. M. (2026). Structure and enzymology of glutaminase S482C and H461L variants associated with excess brain glutamate and neurological disease. The Journal of biological chemistry, 302(6), 113091. https://doi.org/10.1016/j.jbc.2026.113091

BibTeX

@article{crane2026structure,
author = {Crane, Cléa S and McIssac, Thora K and Milano, Shawn K and Cerione, Richard A and Ulrich, Scott M},
title = {{Structure and enzymology of glutaminase S482C and H461L variants associated with excess brain glutamate and neurological disease}},
journal = {The Journal of biological chemistry},
year = {2026},
month = apr,
volume = {302},
number = {6},
pages = {113091},
publisher = {American Society for Biochemistry and Molecular Biology},
issn = {0021-9258},
doi = {10.1016/j.jbc.2026.113091},
url = {https://doi.org/10.1016/j.jbc.2026.113091},
pmid = {42055345},
pmcid = {PMC13218152}
}

RIS

TY - JOUR
AU - Crane, Cléa S
AU - McIssac, Thora K
AU - Milano, Shawn K
AU - Cerione, Richard A
AU - Ulrich, Scott M
TI - Structure and enzymology of glutaminase S482C and H461L variants associated with excess brain glutamate and neurological disease
T2 - The Journal of biological chemistry
J2 - J Biol Chem
PY - 2026
DA - 2026/04/27
VL - 302
IS - 6
SP - 113091
SN - 0021-9258
PB - American Society for Biochemistry and Molecular Biology
DO - 10.1016/j.jbc.2026.113091
UR - https://doi.org/10.1016/j.jbc.2026.113091
LA - en
ER -

CSL-JSON

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