G6PC3 (Q9BUM1) review notes

Identity

Glucose-6-phosphatase 3 / glucose-6-phosphatase-beta (G6Pase-β) / ubiquitous
glucose-6-phosphatase catalytic subunit-related protein (UGRP). EC 3.1.3.9.
346 aa, integral ER membrane protein, 9 transmembrane helices with the active
site (Arg79, His114, His167) on the lumenal side of the ER membrane
[UniProt Q9BUM1; PMID:14718531].
Paralog of the liver/kidney/intestine-restricted G6PC1 (G6Pase-α). ~8x less
active than G6Pase-α under the same conditions
PMID:25492228.

Hydrolyzes glucose-6-phosphate (G6P) to glucose + inorganic phosphate in the ER
[UniProt CATALYTIC ACTIVITY: RHEA:16689, EC 3.1.3.9].
Forms a covalent phosphohistidine enzyme intermediate at His167 during catalysis;
active-site mutants R79A, H114A, H167A abolish the intermediate/activity
PMID:14718531.
Disease mutations abolish or reduce phosphohydrolase activity in a sensitive
rAd/COS-1 assay: 14/16 missense mutants had complete loss; S139I and R189Q
retained ~49%/45% (and are argued non-pathogenic) PMID:25492228.
UniProt CAUTION notes PubMed:12370122 (the original UGRP cloning paper) reported
no hydrolytic activity, but later studies (PubMed:12965222, 13129915) established
bona fide G6P hydrolase activity; the catalytic function is now well established.

ER membrane, multi-pass; active site in the ER lumen [UniProt SUBCELLULAR
LOCATION; PMID:14718531; PMID:25492228 "an enzyme embedded in the endoplasmic
reticulum membrane"]. HPA IDA supports ER localization.
Membrane (GO:0016020) HDA from an NK-cell membrane-proteome MS survey
(PMID:19946888) — generic membrane, less informative than ER membrane.

Directly hydrolyzes G6P → glucose 6-phosphate metabolic process (GO:0051156)
and intracellular glucose production.
Works with the ER G6P transporter SLC37A4 (G6PT); the ubiquitous G6Pase-β/G6PT
complex "maintains energy homeostasis and functionality in neutrophils and
macrophages" PMID:25492228.
Gluconeogenesis (GO:0006094): G6PC3 is ubiquitously expressed and, unlike the
hepatic G6PC1, is not a classic gluconeogenic/glucose-homeostasis enzyme; its
clinical phenotype is neutropenia, not fasting hypoglycemia. Gluconeogenesis is
an IBA/IEA/Reactome pathway-level assignment shared with the family; kept as
non-core rather than a core function.

Severe congenital neutropenia type 4 (SCN4, MIM 612541), autosomal recessive;
maturation arrest of granulopoiesis, ER stress and enhanced neutrophil apoptosis
[UniProt DISEASE; PMID:25492228]. Also Dursun syndrome (DURSS).
Non-hematological features: prominent superficial venous pattern, congenital
cardiac anomaly, urogenital malformations PMID:25492228.

Core MF: GO:0004346 glucose-6-phosphatase activity (multiple lines: EXP/IMP/IBA).
Core CC: GO:0005789 endoplasmic reticulum membrane.
Core-adjacent process: GO:0051156 glucose 6-phosphate metabolic process.
Gluconeogenesis annotations kept as non-core.
GO:0016020 membrane (HDA) marked over-annotated (generic, superseded by ER membrane).
GO:0005783 endoplasmic reticulum (IBA/IEA/IDA) accepted as correct but non-core
parent of ER membrane where applicable.