Literature summary for 1.8.5.8 extracted from

Landry, A.P.; Ballou, D.P.; Banerjee, R.
Hydrogen sulfide oxidation by sulfide quinone oxidoreductase (2021), ChemBioChem, 22, 949-960 .

Search for more literature for 1.8.5.8

Protein Variants

Protein Variants	Comment	Organism
E213K	naturally occuring mutation the mutation affects a residue that is remote from the active site, but predicted to disrupt hydrogen bonding with neighboring arginine residues. The mutation leads to greatly diminished SQOR levels in tissues expressing the E213K mutation	Homo sapiens
additional information	a patient is homozygous for a single base pair deletion (c446delT) in the SQOR gene, predicted to lead to mRNA degradation or production of nonfunctional enzyme due to the resulting frameshift, SQOR is not detected in fibroblasts carrying the deletion mutation	Homo sapiens

KM Value [mM]

KM Value [mM]	KM Value Maximum [mM]	Substrate	Comment	Organism	Structure
additional information	-	additional information	substrate promiscuity and comparative kinetic analysis	Homo sapiens

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
mitochondrial inner membrane	mitochondrial inner membrane-anchored enzyme	Homo sapiens	5743	-

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
hydrogen sulfide + glutathione + coenzyme Q	Homo sapiens	-	S-sulfanylglutathione + reduced coenzyme Q	-	?
additional information	Homo sapiens	under physiological conditions, the primary sulfane sulfur acceptor for the SQOR reaction is GSH, generating glutathione persulfide (GSSH) as the product. Substrate promiscuity leads to dead-end complexes. Human SQOR exhibits remarkable substrate promiscuity, and in addition to sulfide, a number of nucleophiles can add to the resting trisulfide. The addition of alternative nucleophiles to resting SQOR leads to the corresponding 379Cys mixed disulfide and the 201Cys-SS- persulfide that forms an intense charge transfer (CT) complex with FAD. Unlike the sulfide-induced CT complex, which decays quickly to yield FADH2, the alternative CT complexes represent dead-end complexes and decay slowly at rates that approximate the respective dissociation rate constants (koff) for the nucleophiles. Although these dead-end complexes could entrap SQOR in an unproductive state, their formation is suppressed to some extent by the membrane environment of SQOR	?	-	-

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q9Y6N5	-	-

Reaction

Reaction	Comment	Organism	Reaction ID
hydrogen sulfide + glutathione + a quinone = S-sulfanylglutathione + a quinol	mechanisms of protein persulfidation, overview	Homo sapiens	a

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
hydrogen sulfide + glutathione + coenzyme Q	-	Homo sapiens	S-sulfanylglutathione + reduced coenzyme Q	-	?
hydrogen sulfide + glutathione + decylubiquinone	-	Homo sapiens	S-sulfanylglutathione + decylubiquinol	-	?
additional information	under physiological conditions, the primary sulfane sulfur acceptor for the SQOR reaction is GSH, generating glutathione persulfide (GSSH) as the product. Substrate promiscuity leads to dead-end complexes. Human SQOR exhibits remarkable substrate promiscuity, and in addition to sulfide, a number of nucleophiles can add to the resting trisulfide. The addition of alternative nucleophiles to resting SQOR leads to the corresponding 379Cys mixed disulfide and the 201Cys-SS- persulfide that forms an intense charge transfer (CT) complex with FAD. Unlike the sulfide-induced CT complex, which decays quickly to yield FADH2, the alternative CT complexes represent dead-end complexes and decay slowly at rates that approximate the respective dissociation rate constants (koff) for the nucleophiles. Although these dead-end complexes could entrap SQOR in an unproductive state, their formation is suppressed to some extent by the membrane environment of SQOR	Homo sapiens	?	-	-
additional information	SQOR accommodates alternative sulfane sulfur acceptors, e.g. small thiophilic acceptors. Structural basis for substrate promiscuity, overview	Homo sapiens	?	-	-

Synonyms

Synonyms	Comment	Organism
SQOR	-	Homo sapiens
sulfide quinone oxidoreductase	-	Homo sapiens

Cofactor

Cofactor	Comment	Organism	Structure
FAD	required	Homo sapiens

General Information

General Information	Comment	Organism
evolution	SQOR is a member of the diverse and extensive flavin disulfide reductase (FDR) superfamily. Group 4 FDRs, which includes SQOR, are the most diverse both structurally and functionally. SQORs contain two redox active cysteines that are widely separated in the primary sequence but are spatially proximal. A hallmark of this subgroup is that they can utilize diverse substrates. Many members, including SQOR and flavocytochrome c sulfide dehydrogenase (FCSD), do not use pyridine nucleotides, but instead, substitute CoQ (in SQOR), or cytochrome c (in FCSD) as an electron acceptor. In both of these cases, the enzymes oxidize sulfide. SQOR utilizes several of the chemical principles common to the FDR superfamily, as well as some unique sulfurbased chemistry during the catalytic cycle	Homo sapiens
malfunction	inherited deficiency of SQOR presents as a cause of Leigh disease with decreased complex IV activity. The symptoms include lactic acidosis, multi-organ failure, neurological disorders, and Leigh-like brain lesions. Two patients who are siblings are homozygous for the Glu213Lys mutation, affecting a residue that is remote from the active site, but predicted to disrupt hydrogen bonding with neighboring arginine residues. The third patient is homozygous for a single base pair deletion (c446delT) in the SQOR gene, predicted to lead to mRNA degradation or production of nonfunctional enzyme due to the resulting frameshift. The mutations lead to greatly diminished SQOR levels in tissues expressing the Glu213Lys mutation while SQOR is not detected in fibroblasts carrying the deletion mutation. Complex IV activity but not its assembly is adversely affected by SQOR deficiency. The gastrointestinal defects and accumulation of acylcarnitines reported for ETHE1 deficiency are not seen in SQOR deficiency although elevated H2S is reported for both conditions	Homo sapiens
metabolism	sulfide quinone oxidoreductase (SQOR) catalyzes the first and committing step in the mitochondrial sulfide oxidation pathway, overview. Hydrogen sulfide (H2S) is an environmental toxin and a heritage of ancient microbial metabolism, acting as a neuromodulator. While many physiological responses have been attributed to low H2S levels, higher levels inhibit complex IV in the electron transport chain. To prevent respiratory poisoning, a dedicated set of enzymes that make up the mitochondrial sulfide oxidation pathway exists to clear H2S. The committed step in this pathway is catalyzed by sulfide quinone oxidoreductase (SQOR), which couples sulfide oxidation to coenzyme Q10 reduction in the electron transport chain. The SQOR reaction prevents H2S accumulation and generates highly reactive persulfide species as products. These can be further oxidized or can modify cysteine residues in proteins by persulfidation. Alternatively, sulfite is oxidized to sulfate by sulfite oxidase, which resides in the intermembrane space. Electrons from the sulfide oxidation pathway enter the electron transfer chain at the level of Complex III (from SQOR) and cytochrome c/Complex IV (from sulfite oxidase). Interplay of sulfide and butyrate oxidation. The activities of SQOR and ACADS both drive electrons into the mitochondrial Q pool, which restricts the capacity for sulfide oxidation during acute H2S exposure. As a countermeasure, SQOR can catalyze the formation of CoA-SSH, a tightbinding inhibitor of ACADs. Inhibition of ACADS by CoA-SSH relieves competition for the Q pool to prioritize sulfide oxidation. Under certain pathological conditions, such as sulfite oxidase deficiency that is marked by elevated sulfite, oxidative stress conditions that lead to GSH depletion, or periodontitis marked by elevated methanethiol, adventitious nucleophilic additions into the active site trisulfide in SQOR can become physiologically relevant and lead to impaired H2S clearance. Sulfide oxidation by SQOR can exert a direct influence on bioenergetics via the mitochondrial CoQ pool, which represents a major redox nexus. Coupling of SQOR activity to the CoQ pool creates intersections between sulfide metabolism and: 1. complex I, which oxidizes NADH, 2. complex II, which oxidizes succinate and FADH2, 3. dihydroorotate dehydrogenase, which is involved in de novo pyrimidine biosynthesis, 4. glycerol-3-phosphate dehydrogenase, which links to both carbohydrate and lipid metabolism, and 5. the electron-transferring flavoprotein dehydrogenase, which is involved in fatty acid and branched chain amino acid metabolism. Acute exposure to high H2S levels in the colon, with a consequent decrease in the CoQ/CoQH2 ratio could limit other activities that rely on an oxidized CoQ pool. Thus, in addition to respiratory inhibition, H2S oxidation can also inhibit other oxidative metabolic pathways	Homo sapiens
additional information	structural basis for catalytic promiscuity in SQOR, overview. Electrostatic surface potential map of the SQOR monomer, revealing a large electropositive cavity containing the exposed 379Cys-SSH persulfide. GSH is docked in the cavity, binding structure analysis	Homo sapiens
physiological function	higher H2S levels inhibit complex IV in the electron transport chain. To prevent respiratory poisoning, a dedicated set of enzymes that make up the mitochondrial sulfide oxidation pathway exists to clear H2S. The committed step in this pathway is catalyzed by sulfide quinone oxidoreductase (SQOR), which couples sulfide oxidation to coenzyme Q10 reduction in the electron transport chain. The SQOR reaction prevents H2S accumulation and generates highly reactive persulfide species as products. These can be further oxidized or can modify cysteine residues in proteins by persulfidation. The human SQOR shows unconventional redox cofactor configuration and substrate promiscuity leading to sulfide clearance and potentially expand the signaling potential of H2S. SQOR is a mitochondrial inner membrane-anchored flavoenzyme that is poised to play a critical role in H2S-based signaling while also serving as a guardian of the electron transfer chain against H2S poisoning. Interplay of sulfide and butyrate oxidation. The activities of SQOR and ACADS both drive electrons into the mitochondrial Q pool, which restricts the capacity for sulfide oxidation during acute H2S exposure. As a countermeasure, SQOR can catalyze the formation of CoA-SSH, a tightbinding inhibitor of ACADs. Inhibition of ACADS by CoA-SSH relieves competition for the Q pool to prioritize sulfide oxidation. The promiscuity of SQOR can be traced to the large electropositive entrance to the active site that accommodates a range of substrates and has the potential to generate a variety of low-molecular-weight persulfides. The production of CoA-SSH, long known as a tight binding inhibitor of ACADS, has been traced to the relaxed substrate specificity of SQOR and can prioritize sulfide over butyrate oxidation during acute colonic exposure to H2S. It is yet not known whether other persulfides are produced via SQOR in a tissue-specific manner and in response to intra- or extracellular triggers. SQOR was proposed to play a role in proteostasis overview	Homo sapiens

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Release 2023.1 (January 2023)