sqrd-1 (F02H6.5) encodes the Caenorhabditis elegans sulfide:quinone oxidoreductase, an FAD-dependent flavoprotein of the SQRD family orthologous to human SQOR. By orthology it catalyses the first step of mitochondrial hydrogen sulfide oxidation: H2S is oxidized, the sulfane sulfur is passed to an acceptor (glutathione in the human enzyme, giving S-sulfanylglutathione), and the electrons pass through FAD to the membrane quinone pool. Modelling suggests the worm enzyme can bind both ubiquinone and rhodoquinone. The persulfide is then oxidized further by the persulfide dioxygenase ETHE-1. sqrd-1 mutants cannot survive low concentrations of H2S, and the gene is strongly induced by HIF-1 in response to H2S or HCN. Induced SQRD-1 is most abundant in the hypodermis and muscle. Without SQRD-1, H2S exposure triggers eIF2alpha phosphorylation, translational arrest and ER and mitochondrial stress responses. The gene encodes several isoforms, some of which lack the N-terminal FAD-binding motif. No purified-enzyme assay or direct localization study of the worm protein has been reported.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrion from the UniProt subcellular-location rule (ARBA). The worm protein has no direct localization experiment. Reason: Under the root-organelle policy, the organelle claim was checked. The UniProt location is an ARBA rule and not evidence on its own. The claim rests on two points. SQRD-1 belongs to the mitochondrial SQR subfamily (PANTHER PTHR10632:SF2), whose human member SQOR is a mitochondrial enzyme. Its catalytic cycle reduces the quinone pool of the mitochondrial respiratory chain. Horsman and Miller describe SQRD-1 as mitochondrial, but they cite Budde and Roth, whose GFP fusion shows tissue expression without a mitochondrial marker. The C6KRP5 gene model also has no obvious N-terminal presequence. The organelle claim holds by orthology and function, so the row is kept. A sub-compartment (inner membrane) is not added, because only the homology line supports it. Supporting Evidence: file:worm/sqrd-1/sqrd-1-uniprot.txt PTHR10632:SF2; SULFIDE:QUINONE OXIDOREDUCTASE, MITOCHONDRIAL PMID:25225291 Organization of the human mitochondrial hydrogen sulfide oxidation pathway. PMID:26677221 SQRD-1 localizes to mitochondria file:worm/sqrd-1/sqrd-1-deep-research-manual.md Neither predicted product carries an obvious N-terminal mitochondrial presequence comparable to the ~40-residue extension of human SQOR |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: Oxidoreductase activity from the InterPro FAD/NAD(P)-binding domain (IPR023753). Reason: This is correct but uninformative. The specific activity of the animal SQR family is the glutathione-dependent sulfide:quinone oxidoreductase activity (GO:0106436), a descendant of oxidoreductase activity that the gene already carries (IEA, EC 1.8.5.8). Proposed replacements: glutathione-dependent sulfide quinone oxidoreductase activity Supporting Evidence: file:worm/sqrd-1/sqrd-1-uniprot.txt IPR015904; Sulphide_quinone_reductase PMID:21840852 SQRD-1 is an oxidoreductase, oxidizing H2S to polysulfide and reducing ubiquinone |
| GO:0070224 sulfide:quinone oxidoreductase activity | IEA GO_REF:0000117 | MODIFY | Summary: Sulfide:quinone oxidoreductase activity (H2S + quinone giving sulfane sulfur and quinol) from an ARBA rule. Reason: The enzyme class is right, but GO:0070224 is defined by the bacterial-type reaction, which releases free sulfane sulfur (S0). The animal group II SQRs, to which SQRD-1 belongs, transfer the sulfane sulfur to an acceptor. The human ortholog uses glutathione and forms glutathione persulfide (EC 1.8.5.8). That reaction is GO:0106436, a sibling term that the gene already carries. The worm acceptor has not been measured, so the change rests on orthology. It matches the treatment of fly Sqor and the fly sulfide-oxidation GO-CAM. Proposed replacements: glutathione-dependent sulfide quinone oxidoreductase activity Supporting Evidence: PMID:25225291 Human SQR uses glutathione as an acceptor forming glutathione persulfide (GSSH), which is preferentially converted to thiosulfate by human rhodanese. PMID:21840852 The C. elegans gene sqrd-1 encodes a member of the group II SQRD enzymes, which also includes human, mouse, and Drosophila homologs. |
| GO:0106436 glutathione-dependent sulfide quinone oxidoreductase activity | IEA GO_REF:0000003 | ACCEPT | Summary: Glutathione-dependent SQR activity from the EC 1.8.5.8 mapping. Reason: This is the core activity of the animal SQR subfamily. Human SQOR performs this reaction with glutathione as acceptor. Worm genetics places SQRD-1 at the entry of the ETHE-1 sulfide-oxidation pathway, and the quinone site is modelled to bind ubiquinone and rhodoquinone. No enzyme assay of the worm protein exists, so the acceptor specificity is inferred. Supporting Evidence: PMID:25225291 Human SQR uses glutathione as an acceptor forming glutathione persulfide (GSSH), which is preferentially converted to thiosulfate by human rhodanese. PMID:21840852 SQRD-1 catalyzes the first step in the H2S-oxidation pathway PMID:39178951 sqrd-1 uses both benzoquinones |
| GO:0019418 sulfide oxidation | ISS PMID:21840852 The response of Caenorhabditis elegans to hydrogen sulfide a... | NEW | Summary: Proposed process: SQRD-1 catalyses the first step of mitochondrial sulfide oxidation. sqrd-1 and ethe-1 mutants are both H2S-sensitive, and SQR performs that step in other animals. Reason: This passes the participation test: the gene product itself catalyses a step of the process, the oxidation of sulfide to a persulfide with transfer of the electrons to quinone. The term is not based on the mutant phenotype alone. The mechanism comes from orthology with human SQOR, and the worm genetics places sqrd-1 in the same pathway as the persulfide dioxygenase ethe-1. Comparators: fly Sqor carries GO:0019418 by ISS, and the fly sulfide-oxidation GO-CAM (gomodel 69d8496c00000431) types Sqor with GO:0106436, part of GO:0019418. The obsolete GO:0070221 ("sulfide oxidation, using sulfide:quinone oxidoreductase") points to GO:0019418. Response to hydrogen sulfide and the downstream proteostasis phenotypes are not proposed. Supporting Evidence: PMID:21840852 SQRD-1 catalyzes the first step in the H2S-oxidation pathway, ultimately resulting in production of sulfate and thiosulfate. PMID:21840852 is sensitive to RA/H2S, which suggests that sqrd-1 confers resistance to H2S PMID:21840852 The available deletion allele of sqrd-1 (tm3378) phenocopies and fails to complement these mutants PMID:25225291 Organization of the human mitochondrial hydrogen sulfide oxidation pathway. |
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Download this section (compressed HTML)Q: What is the physiological sulfane-sulfur acceptor of worm SQRD-1 (glutathione, sulfite or another thiol), and does the enzyme reduce rhodoquinone as well as ubiquinone in vivo?
Q: How is SQRD-1 targeted to mitochondria? The C6KRP5 and O62133 gene models lack an obvious N-terminal presequence. Is there an unannotated upstream exon?
Q: Which sqrd-1 isoforms are catalytically active? Isoforms lacking the N-terminal FAD motif (e.g. A0A061ADY3, C6KRP6) may be non-catalytic or regulatory.
Experiment: Express recombinant SQRD-1 (isoform b) and measure sulfide-dependent reduction of decylubiquinone and rhodoquinone analogues with glutathione, sulfite or cyanide as acceptor.
Hypothesis: SQRD-1 is a glutathione-dependent SQR that can use both benzoquinones.
Experiment: Co-localize an endogenously tagged SQRD-1 (CRISPR knock-in) with a mitochondrial matrix or inner-membrane marker in hypodermis after H2S induction, and fractionate mitochondria with ER markers as controls.
Hypothesis: SQRD-1 is a mitochondrial inner-membrane protein.
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