UniProt: Q9BUX1 (CHAC1_HUMAN). Gene: CHAC1 (HGNC:28680). 222 aa. EC 4.3.2.7. Chr 15.
CHAC1 = Glutathione-specific gamma-glutamylcyclotransferase 1 ("Gamma-GCG 1"); ChaC subfamily of the
gamma-glutamylcyclotransferase (GGCT-like) family. Also historically named "Botch" (Blocks Notch) and
"cation transport regulator-like protein 1" (from the bacterial cha operon homology, which is not a
conserved function in mammals).
Catalytic activity (UniProt CATALYTIC ACTIVITY):
[file:human/CHAC1/CHAC1-uniprot.txt "Reaction=glutathione = L-cysteinylglycine + 5-oxo-L-proline"]
(Rhea:RHEA:47724; EC=4.3.2.7). It performs the committed, intracellular (cytosolic) step of a dedicated
glutathione (GSH) degradation route, distinct from the extracellular GGT1 route.
Substrate specificity — GSH only, not other gamma-glutamyl peptides:
[file:human/CHAC1/CHAC1-uniprot.txt "Acts specifically on glutathione, but not on"] "other gamma-glutamyl peptides".
The kinetics paper reports human ChaC1 Km = 2.2 mM and kcat = 225.2 min-1 for glutathione, ~10-20x more
catalytically efficient than the constitutive paralog ChaC2, and both are specific for reduced GSH
with no activity on gamma-glutamyl amino acids or oxidized glutathione
PMID:27913623
PMID:27913623.
Note: PMID:27913623 is abstract-only in cache (full_text_available: false), but the abstract itself
reports the human ChaC1 kinetic constants and specificity, matching the UniProt CATALYTIC ACTIVITY and
BIOPHYSICOCHEMICAL PROPERTIES blocks (Km 2.2 mM, kcat 225.2). GOA also has an IDA (FlyBase-assigned) to
the same term from this paper.
Cytosol (experimentally, human): CHAC1-V5eGFP fractionated to the cytosolic compartment and gave diffuse
cytoplasmic staining
PMID:19109178.
UniProt: [file:human/CHAC1/CHAC1-uniprot.txt "SUBCELLULAR LOCATION: Cytoplasm, cytosol"].
A second, trans-Golgi-network location is annotated only by similarity to the mouse ortholog Botch
(Q8R3J5) and comes from the Notch-regulation work; it is ISS/IEA on human, not experimentally shown for
human CHAC1. [file:human/CHAC1/CHAC1-uniprot.txt "Golgi apparatus, trans-Golgi network"] carries
ECO:0000250 (by similarity to Q8R3J5).
CHAC1 is a transcriptional target of the ATF4-ATF3-CHOP arm of the UPR/integrated stress response and is
strongly induced by ER-stress chemicals:
PMID:19109178
PMID:19109178.
UniProt INDUCTION: [file:human/CHAC1/CHAC1-uniprot.txt "Induced by chemical activators of the unfolded protein"] "response (UPR) such as tunicamycin, DTT and thapsigargin."
CHAC1 is pro-apoptotic: overexpression promotes and knockdown blocks apoptosis markers
PMID:19109178.
This underpins the GOA IMP to GO:0070059 (intrinsic apoptotic signaling pathway in response to ER stress).
Mechanistically the enzymatic GSH-depleting activity plausibly links CHAC1 to apoptosis and to
ferroptosis (GSH depletion sensitizes to ferroptosis), though the ferroptosis link is not directly in the
cited local files.
Reported (chiefly in mouse/rat, PMID:22445366) as a negative regulator of Notch during embryonic
neurogenesis. Botch binds the Notch1 extracellular region and blocks the S1 furin cleavage that matures
Notch, keeping Notch in its immature inactive full-length form, thereby de-repressing neuronal
differentiation:
PMID:22445366 "inhibiting the S1 furin-like cleavage of Notch"
PMID:22445366
PMID:22445366
PMID:22445366 "neuronal differentiation".
Localizes partly to the trans-Golgi (where furin S1 cleavage of Notch occurs):
PMID:22445366.
IMPORTANT: PMID:22445366 is largely a mouse Botch (NPG7) study; the human GOA IMP annotations
(GO:0010955, GO:0045746) are transferred from it. The human trans-Golgi / Notch binding / neurogenesis
terms are ISS/IEA by similarity to mouse Q8R3J5. These are real but non-core (moonlighting/secondary)
relative to CHAC1's core enzymatic GSH-catabolic function; keep as non-core rather than remove, since the
IMP experimental annotations should not be removed per policy.
GOA IPI GO:0005515 "protein binding" from PMID:16189514 (Rual et al., high-throughput Y2H human
interactome) — interaction partner RHOXF2 (Q9BQY4) per UniProt INTERACTION block
[file:human/CHAC1/CHAC1-uniprot.txt "Q9BUX1; Q9BQY4: RHOXF2; NbExp=2"]. This is a bare, uninformative
"protein binding" term from a large-scale screen; mark as over-annotated (do not remove IPI per policy).
CHAC2 (Q8WUX2) is the constitutive, slow-turnover cytosolic GSH-degrading paralog (~50% identity);
PMID:27913623 characterizes ChaC2 but reports ChaC1 kinetics in parallel. Keep the review focused on
CHAC1 (the tightly ATF4/UPR-regulated, high-activity member).